Nitroimidazole external preparations for dermatosis

专利摘要:
General formula (I) (I) (Wherein R 1 , R 3 and R 4 are the same or different and represent a hydrogen atom, a nitro group, a lower alkyl group, a substituted lower alkyl group, a lower alkenyl group, a substituted lower alkenyl group, R 2 is a hydrogen atom, Lower alkyl group, substituted lower alkyl group, lower alkenyl group, substituted lower alkenyl group, provided that any one of R 1 , R 3 and R 4 is a nitro group) An external preparation for skin diseases containing nitroimidazole derivatives represented by the following.
公开号:KR20020020780A
申请号:KR1020027000421
申请日:2000-07-14
公开日:2002-03-15
发明作者:니시무타니시즈미；니시무타가즈히로
申请人:가부시키가이샤 쇼에이；
IPC主号:

专利说明:

External preparation for skin diseases containing nitroimidazole {NITROIMIDAZOLE EXTERNAL PREPARATIONS FOR DERMATOSIS}
[2] (Atopic dermatitis)
[3] Atopic dermatitis is called a type I allergic reaction involving IgE, and various external preparations for treating atopic dermatitis, including compounds having an action of inhibiting the PCA response involving IgE, have been developed. However, in practical applications, it is not so effective. Currently, as an external preparation for treating atopic skin diseases, steroids, which are corticosteroids, still occupy the mainstream.
[4] Currently, steroids used in atopic dermatitis and related skin diseases and other skin diseases have excellent therapeutic effects, but when used over a long period of time, systemic effects such as inhibition of hypothalamus, pituitary gland and adrenal cortical system occur. Side effects occur. In addition, even for external preparations, there are many side effects of skin symptoms such as deterioration of skin infections and acne, which are peculiar to corticosteroids, and problems such as scars, liver spots and ovulation plaques during the administration period are also pointed out. have.
[5] Because of these problems, immunosuppressants, antihistamines or antiallergic agents and the like have been developed as therapeutic agents for atopic dermatitis. However, the immunosuppressive agent is a problem such as deterioration of bacterial skin infections, and there is a problem that the antihistamine has side effects such as weakness.
[6] With regard to atopic dermatitis, in which no such cause is identified, patients with symptoms and their families suffer from various symptoms such as pruritus, pain, and insomnia every day. The current situation is that there is no established treatment method for treatment institutions such as universities, hospitals, etc., and for the treatment of more effective atopic dermatitis, which has no side effects, in place of steroidal anti-inflammatory external preparations or Development of preventive external preparations was urgently desired.
[7] (psoriasis)
[8] Among skin diseases, psoriasis is one of the most difficult to treat, the mechanism of its manifestation is not clear, the symptoms repeat recurrence, and no fundamental treatment is established.
[9] Treatments for psoriasis include salicylic ointment, urea ointment, moisturizing ointment, vitamin A ointment, heat therapy, gentle X therapy, tranilast, cyclosporin, methotrexate, etc. Although there are treatments by ointments such as ointments, there is almost no healing effect, and since steroid external preparations are relatively effective, they are mainly used. Today, the effect of steroid external preparations in psoriasis is not as therapeutic as other therapeutic effects for other skin diseases, but since there is no treatment that can be used elsewhere, treatment has been carried out with long-term use of steroid external agents. However, as is well known, side effects caused by steroid external preparations have been problematic.
[10] In the treatment of psoriasis, there are problems such as the therapeutic effect and side effects of steroid external preparations, and instead of these, vitamin D3 external preparations are attracting attention these days. For example, currently available commercially available active vitamin D3 external preparations include tacalcitol, have no side effects such as steroid external preparations, and are known to have a relatively good therapeutic effect compared to steroid external preparations.
[11] However, in the treatment with the steroid external preparation or the vitamin D3 external preparation, the treatment period is carried out for several weeks to several months as well as for several to several decades for long patients. In addition, most of the patients suffer from relapses, and again enter long-term treatment.
[12] Therefore, if there are external preparations that can effectively treat or prevent psoriasis, these problems can be solved, and such external preparations have long been desired.
[13] (Odor, body odor and drunkenness)
[14] Liquid odor is a body odor such as foot odor, which is thought to be a result of decomposition of components of apocrine sweat secreted from the apocrine glands in the pores of the skin by various types of bacteria. As a medical treatment for liquid odor, for example, external preparations such as aluminum chloride liquid and formalin alcohol liquid are prescribed and used. However, they are not lost even if the odor is suppressed to some extent due to the restricting action. The smell recurs. It is also known that after use of these medicines, side effects such as inflammation, pruritus and redness of the skin are high.
[15] However, there are currently no medical drugs for the treatment of body odor, such as odor, foot odor, in the dermatology area. In the present situation, satisfactory therapeutic results are not obtained with known limiting agents such as aluminum chloride liquid and formalin alcohol liquid.
[16] Because of this, there is a method to remove the apocrine gland by removing the skin of the armpit as a surgical therapy, but it requires a lot of effort, and after surgery, a wide range of surgical traces, skin or muscle atrophy, keloid type, etc. It is economically burdensome and can be relatively recurrent. In addition, the sequelae often complain of disability to the nerve due to the mistake of surgery. The hassle, traces of surgery, side effects, and mental pains caused by these surgical therapies are pains that are unknown to you.
[17] Therefore, there has been a demand for an external treatment or preventive medicine that is economical against liquid odor, body odor and drunkenness and does not cause pain to a patient.
[18] (Pigmentation, spots, scars)
[19] Although scars as a sequelae from weakness, burns, herpes, keloids, and insoles, pigmentation and blemishes caused by UV irradiation or cosmetics have significant effects on life, there has been no effective external medicine so far, and their development has been required. .
[20] (Contact dermatitis, etc.)
[21] Treatment or prevention of contact dermatitis, plant dermatitis or hyperemia, treatment or prevention of skin pruritus or weakness, treatment or prevention of alumni, treatment or prevention of ringworm, treatment or prevention of ringworm, treatment or prevention of purulent skin disease, bedsores Treatment or prevention of trauma, treatment or prevention of trauma and intestinal pustules, squamous thyroiditis, glossy thymus, follicular erythematosus, gibberous rosacea, erythematosis (polymorphic exudative erythema, nodular erythema, centrifugal annular erythema on the leg), chronic disc Lupus erythematosus, weakness / addictiveness, alopecia areata, laceration (including scars and keloids), swelling group, chelating herpes dermatitis (including milk swelling), seborrheic dermatitis, skin stomatitis, Candidiasis (interstitial erosion, examination, skin candidiasis, infant parasitic erythema, prostheticitis, vulvar candidiasis) or acute stroke does not have side effects and is effective External preparations that can be treated or prevented are desired.
[22] Further, among the nitroimidazole derivatives of the present invention, the following are known regarding metronidazole and tinidazole.
[23] The compound metronidazole [2- (2-methyl-5-nitroimidazol-1-yl) ethanol] is a nitroimidazole derivative synthesized by Jacob Jacob, France, in 1957 and has a strong antitrichomonas action. Having was found by Cosar and Julou. In 1959 Durel reported for the first time the loss of the protozoan trichomonas using this agent in human trichomoniasis. In addition, it is known to have a strong antibacterial activity against heterogeneous amoeba. In addition, it has been reported to have a bactericidal action for oral administration and topical administration to other anaerobic bacteria, and its mechanism of action is that the nitro group of the metronidazole is reduced by the microorganism, which is a function such as double-strand cleavage of the DNA of the microorganism. It is thought that this is because it causes a disorder and controls the proliferation of cleavage.
[24] Tinidazole has a stronger action than the orally used chemotherapy metronidazole, and is also a low toxicity compound synthesized by Paiza, USA in 1966, and mainly has antitrichomonas action. Therefore, it has been used clinically as a compound having not only an excellent effect against Trichomonas vaginalis infected with the vulva, cervix, urinary tract, rectum, etc., but also with anaerobic bacteria. Came. It is believed that the mechanism of action is that the nitro group of tinidazole is reduced by the microorganisms, and this reducing agent controls the proliferation of microorganisms by causing functional disorders such as double-helix cleavage of the microorganism's DNA.
[25] Moreover, regarding metronidazole, the following is known as an effect which the administration affects immunity. Int. Arch. Allergy appl. In Immun., 54 , 422 (1977), mice administered orally with metronidazole inhibited the formation of granulomas by intravenous injection of eggs of Manson strains, but did not inhibit the formation of nonspecific granulomas. It turns out, Int. J. Radiation Oncology Biol. Phys, 9 , 701 (1983) is known that intraperitoneal administration of metronidazole inhibits ear swelling caused by dinitrofluorobenzene in mice sensitized with dinitrofluorobenzene. In addition, Indian J. Exp. Intraperitoneal administration of metronidazole in Biol., 25, 177 (1987) significantly inhibited the elevation of anti-TBA antibody titers against TBA vaccine in rabbit bodies, and Indian J. Exp. In Biol., 29, 867 (1991), it has been found that intraperitoneal administration of metronidazole exhibits a delayed immune response to the dosing of both erythrocytes and a leukocyte-suppressing action. In addition, the effect that metronidazole imparts to inflammation is that the topical agent of metronidazole is effective for inflammatory skin diseases such as alcohol (international publication WO88 / 06888, international publication WO89 / 06537, international publication WO94 / 08350, international publication WO96). / 01117, International Publication WO98 / 27960) are known. In addition, Mykosen, 27 , 475 (1984) states that metronidazole exhibits a therapeutic effect at concentrations that do not exhibit antimicrobial activity in P. ovale and the like due to anti-inflammatory activity. In J. Dermatol., 114, 231 (1986), metronidazole has an inhibitory activity against the production of reactive oxygen species, and the effect of metronidazole on alcohol is partially due to anti-inflammatory activity, and International Surgery, 60 , 75 ( 1975) shows that oral administration of metronidazole is effective for foot skin ulcers.
[26] On the other hand, with regard to tinidazole, Indian J. Exp. In Biol., 29, 867 (1991), it is evident that intraperitoneal administration of tinidazole has a tendency to suppress the delayed immune response to the dosing of positive erythrocytes, and exhibits leukocyte-suppressive action. . Moreover, regarding inflammation, the use of the external preparation of tinidazole (the international publication WO93 / 20817, the international publication WO98 / 27960) is known.
[27] In addition, the use of metronidazole for psoriasis treatment is disclosed in U.S. Patent Publication No. 4,491,588 that oral drugs of metronidazole are effective for the treatment of psoriasis, and psoriasis is an internationally available publication WO96 as one of the inflammatory diseases that can be treated with an external agent of metronidazole. / 01117.
[28] However, among the above documents, it is observed in the literature on immunity that Int. J. Radiation Oncology Biol. Except for Phys, 9 , 701 (1983), all are immune responses outside the skin surface, and the observed immunosuppressive effects are also significantly lower compared to immunosuppressants used in the clinic, and the external preparations of metronidazole or tinidazole are It is not expected to be effective as a therapeutic agent for atopic dermatitis. Moreover, Int. Which only observes the immune response on the skin surface. J. Radiation Oncology Biol. The effectiveness of the contact dermatitis model used in Phys, 9, 701 (1983) and the treatment of atopic dermatitis have no correlation. It is also not known that general inflammatory disease therapies are used for the treatment of atopic dermatitis. In addition, the use of nitroimidazole derivatives for the treatment of atopic dermatitis is unknown until now.
[29] Also disclosed in US Pat. No. 4,491,588 is oral psoriasis treatment of metronidazole. Similarly, ketoconazole disclosed as effective for the treatment of psoriasis is an oral preparation (US Pat. No. 4,491,588) and an external preparation (US Patent publication US4,569,935, but only oral preparations for metronidazole. The present application finds that the topical preparation of metronidazole is superior in efficacy and toxicity to oral preparations. In addition, the therapeutic use of psoriasis presented in International Publication No. WO96 / 01117 is one of the general inflammatory diseases, and the disclosure only indicates that the external preparation of metronidazole can suppress the formation of several species caused by local irritation by arachidonic acid. Applicant himself or her own "non-steroidal anti-inflammatory agents such as cyclooxygenase or lipoxygenase reaction inhibitors (indometacin, naproxen, phenylbutazone, etc.), agents capable of inhibiting conduit plasma reflux (vascular vasoconstrictors, etc.) Is a good anti-inflammatory agent in this model, a conventional nonsteroidal anti-inflammatory drug (NSAID) is also an experimental system showing excellent action, and only by confirming the action is "eczema, psoriasis, alcohol, vulgar acne, ulcers. It is deduced that we can use for the treatment of "seborrheic dermatitis", but the cause of the expression of psoriasis is unknown And, most NSAID will not exhibit a therapeutic effect on psoriasis, since it does not actually confirm the therapeutic effect of the psoriasis, the application is considered to not be in the example cited herein below.
[1] The present invention provides an external preparation for preventing, treating or improving a skin disease containing a nitroimidazole derivative as an active ingredient, the use in the preparation of an external preparation for preventing, treating or improving a skin disease of a nitroimidazole derivative, and a nitroimidazole derivative. The present invention relates to the prevention and treatment of skin diseases using external preparations for the prevention, treatment or improvement of skin diseases containing as an active ingredient.
[30] The present inventors have conducted extensive studies on the treatment or prevention of atopic dermatitis, and found that external preparations containing nitroimidazole derivatives as active ingredients are very effective as treatment or prevention of atopic dermatitis, and have high safety and no side effects. It has been found to complete the present invention. In addition, the inventors have found that the present invention is particularly effective for the treatment and prevention of facial atopy and childhood atopy.
[31] In addition, the present inventors have found that the external preparations containing nitroimidazole derivatives are effective for the improvement of skin blemishes, pigmentation or scars, and are effective for the treatment or prevention of psoriasis, and for the treatment or prevention of odor, body odor or drunkenness. And in addition to, treatment or prevention of contact dermatitis, plant dermatitis or hyperplasia, treatment or prevention of skin pruritus or weakness, treatment or prevention of alumni, treatment or prevention of ringworm, treatment or prevention of ringworm, purulent skin disease Treatment or prophylaxis, treatment or prevention of bedsores, treatment or prevention of trauma and intestinal pustules, squamous thyroiditis, gloss lichen erythematosus, pore red nasal cavity, gerber rosaceous nasal rash, erythematosis (polymorphic exudative erythema, nodular erythema, centrifugal to the leg) Circular erythema), chronic disc erythematous lupus erythematosus, weakness / addiction, alopecia areata, laceration (including scars and keloids), pemphigus, during Fact dermatitis (including current pemphigus), seborrheic dermatitis, skin sores, candidiasis in the treatment or prevention of (long span erosion increases, Jean ganchal and skin candidiasis, infant parasites St. erythema, Joe gastritis, vulva candidiasis) or Tian Feng found valid.
[32] The present inventors found that antipruritic effect appeared quickly when the external preparation containing nitroimidazole derivatives contained crotamiton.
[33] Another subject of the present invention is to prepare an external preparation for skin diseases to treat or prevent atopic dermatitis, to improve skin blemishes, pigmentation or scars, to treat or prevent psoriasis, and to treat or prevent odors, body odors or odors. The use of nitroimidazole derivatives for the treatment and treatment, prevention and amelioration of these diseases using external preparations for skin diseases containing nitroimidazole derivatives.
[34] In addition, the inventors of the present invention provide at least one compound of nitroimidazole derivatives, antifungal agents, antibacterial agents, sulfa agents, immunosuppressants, anti-inflammatory agents, antibiotics, antiviral agents, metabolic antagonists, antihistamines, tissue repair accelerators, vitamins, antiallergic drugs Or topical anesthetics, hair preparations or steroids, or external preparations administered separately over time to reduce the concentration of these agents other than these nitroimidazoles, to eliminate their side effects, and to have immediate effects. It was found that the same effects were found even when the concentrations of drugs other than these nitroimidazole derivatives did not exhibit drug efficacy by themselves.
[35] External preparations for the treatment, prevention or improvement of skin diseases of the present invention as an active ingredient
[36] General formula (I) which is a nitroimidazole derivative
[37] (I)
[38] (Wherein R ¹ , R ³ and R ⁴ are the same or different independently from each other and are the same or different substituents selected from hydrogen atom, nitro group, lower alkyl group, <substituent group α> and <substituent group β>) Lower alkyl group, lower alkenyl group substituted with 1 or 2 or more, or lower alkenyl group substituted with 1 or 2 or more by the same or different substituent selected from <substituent group α> and <substituent group β>, R ² represents a hydrogen atom , Lower alkyl group, lower alkyl group, lower alkenyl group substituted with 1 or 2 or more or the same or different substituents selected from <substituent group α> and <substituent group β>, or <substituent group α> and <substituent group β> Lower alkenyl group substituted with one or two or more same or different substituents, provided that any one of R ¹ , R ³ and R ⁴ is a nitro group, a pharmacologically acceptable salt thereof, and its s Ter or other derivatives.
[39] <Substituent group α>
[40] A lower alkyloxy group, a lower alkyloxy group substituted with one or two or more substituents selected from the same or different substituents selected from <substituent group β>, a lower alkylcarbonyloxy group, and a same or different substituent selected from <substituent group β> Or from a lower alkylcarbonyloxy group substituted with two or more, a lower alkylsulfonyl group, a lower alkylsulfonyl group substituted with one or two or more substituents or the same or another substituent selected from <substituent group β>, a cycloalkyl group, and a <substituent group β> Cycloalkyl group, heteroaryl group, at least 1 or 2 substituted with the same or different substituents selected, heteroaryl group, aryl group, and <substituted group β at least 1 or 2 substituted with the same or different substituents selected from <substituent group β> An aryl group substituted by one or two or more with the same or different substituents selected from>.
[41] <Substituent group β>
[42] Hydroxy group, mercapto group, halogen atom, amino group, lower alkylamino group, lower alkyloxy group, lower alkenyl group, cyano group, carboxyl group, carbamoyloxy group, carboxyamide group, thiocarboxyamide group and morpholino group .
[43] Among the external preparations,
[44] (1) an external preparation wherein R ⁴ is a nitro group,
[45] (2) the lower alkyl group according to (1), wherein R ¹ and R ² are the same or different and are substituted with one or two or more substituents selected from the lower alkyl group, <substituent group α> and <substituent group β>; A lower alkenyl group or a lower alkenyl group substituted with one or two or more of the same or different substituents selected from <substituent group α> and <substituent group β>, wherein R ³ is a hydrogen atom,
[46] (3) The external preparation according to (2), wherein <substituent group α> is a lower alkyloxy group, and <substituent group β> is a hydroxy group, an amino group, a halogen atom, a cycloalkyl group, a heteroaryl group, and an aryl group;
[47] (4) The external preparation according to (3), wherein <substituent group β> is a hydroxy group, an amino group, a halogen atom or a heteroaryl group,
[48] (5) The external preparation according to (3), wherein R ¹ is a lower alkyl group,
[49] (6) The external preparation according to (3), wherein R ² is a lower alkyl group substituted with a hydroxy group,
[50] (7) In (2), <substituent group α> is a lower alkylsulfonyl group substituted with the same or another substituent selected from a lower alkylsulfonyl group or <substituent group β>, and <substituent group β> is a hydroxy group or a halogen External preparations which are atoms, amino groups, lower alkylamino groups, lower alkyloxy groups, lower alkenyl groups, cyano groups, carboxy groups, cycloalkyl groups and aryl groups,
[51] (8) The external preparation according to (7), wherein R ¹ is a lower alkyl group or a lower alkyl group substituted with the same or different substituent selected from <substituent group β>,
[52] (9) The external preparation as described in (7) whose R < ² > is a lower alkyl group substituted by the lower alkylsulfonyl group or the lower alkylsulfonyl group substituted by the same or another substituent selected from <substituent group (beta)>.
[53] In addition, the above-mentioned (1) to (2), (3) to (5) or (7) to (8) according to the number is larger, shows a more preferred compound, according to formula (I), R ¹ to The external preparation obtained by arbitrarily selecting R <^4> from (1)-(9) and combining these arbitrarily is also preferable, More preferably, it is (5)-(6) and (8)-(9), and even more preferable Preferably it is an external preparation selected from the following group.
[54] <Compound Group>
[55] 2- (2-methyl-5-nitroimidazol-1-yl) ethanol (common name: metronidazole)
[56] 1- (2-ethylsulfonylethyl) -2-methyl-5-nitroimidazole (common name: tinidazole).
[57] In the above, examples of the "lower alkyl group" of "lower alkyl group" of R ¹ to R ⁴ and "lower alkyl group substituted with 1 or 2 or more by the same or different substituents selected from <substituent group α> and <substituent group β> are examples. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n -Hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2 Linear or branched alkyl groups having 1 to 6 carbon atoms such as -dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl and 2-ethylbutyl, and preferably 1 to 3 carbon atoms a branched chain alkyl group, more preferably a methyl group in the R ^1, and more preferably an ethyl group according to R ^2.
[58] In the above formula, one or two or more of the same or different substituents selected from "lower alkenyl groups" and "<substituent group α> and <substituent group β> in R ¹ to R ⁴ , substituent group α and substituent group β Examples of the "lower alkenyl group" of the substituted lower alkenyl group "include ethenyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl, 2- Methyl-1-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-2-butenyl, 1-methyl-1- Butenyl, 3-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3- Butenyl, 1-pentenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3 -Pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexe Straight or branched chain alkenyl groups having 2 to 6 carbon atoms such as cenyl; And preferably a straight or branched chain alkenyl group having 3 to 5 carbon atoms.
[59] In the formula (I), the "halogen atom" in the substituent group β includes, for example, a fluorine atom, a chlorine atom, a bromine atom or a urea atom, and preferably a fluorine atom or a chlorine atom.
[60] In the above formula (I), "lower alkyloxy group" and "lower alkyloxy group substituted one or two or more with the same or different substituent selected from <substituent group β>" in substituent group α and substituent group β " Lower alkyloxy group "refers to a group in which the" lower alkyl group "is bonded to an oxygen atom, and as such a group, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy , s-butoxy, tert-butoxy, n-pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy, n-hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2- Methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylpart C1-C6 linear or branched alkyloxy groups, such as oxy, are preferable, It is a C1-C3 linear or branched alkyloxy group, More preferably, a methoxy group is .
[61] In the above formula (I), "lower alkylcarbonyloxy group" and "lower alkylcarbonyloxy group substituted one or two or more with the same or different substituents selected from <substituent group β>" in the substituent group α " Lower alkylcarbonyloxy group "refers to a group in which the" lower alkyl group "is bonded to a carbonyloxy group, and as such groups, for example, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy And straight or branched chain alkylcarbonyloxy groups having 2 to 7 carbon atoms, such as pivaloyloxy, valeryloxy, isovaleryloxy and hexanoyloxy, and preferably straight or branched chain having 2 to 4 carbon atoms It is an alkylcarbonyloxy group, More preferably, it is a formyloxy group or an acetyloxy group.
[62] In the formula (I), the "lower alkylsulfonyl group" of "lower alkylsulfonyl group" and "lower alkylsulfonyl group substituted with one or two or more substituents selected from the same or another substituent selected from <substituent group β>" Refers to a group in which the "lower alkyl group" is bonded to a sulfonyl group, and such groups include, for example, methanesulfonyl, ethanesulfonyl, n-propanesulfonyl, isopropanesulfonyl, n-butanesulfonyl, iso Butanesulfonyl, s-butanesulfonyl, tert-butanesulfonyl, n-pentanesulfonyl, isopentansulfonyl, 2-methylbutanesulfonyl, neopentanesulfonyl, n-hexanesulfonyl, 4-methylpentansul Ponyl, 3-methylpentanesulfonyl, 2-methylpentanesulfonyl, 3,3-dimethylbutanesulfonyl, 2,2-dimethylbutanesulfonyl, 1,1-dimethylbutanesulfonyl, 1,2-dimethylbutanesul C1-C6 linear or branched alkylsulfonyl groups, such as a fonyl, a 1, 3- dimethyl butanesulfonyl, and a 2, 3- dimethyl butane sulfonyl, are preferable. It is a C1-C3 linear or branched alkylsulfonyl group, More preferably, it is an ethanesulfonyl group.
[63] In the formula (I), the "lower alkylamino group" in the substituent group β refers to a group in which the "lower alkyl group" is substituted with an amino group, and as such a group, methylamino, ethylamino, n-propylamino, isopropyl Amino, n-butylamino, isobutylamino, s-butylamino, tert-butylamino, n-pentylamino, isopentylamino, 2-methylbutylamino, neopentylamino, 1-ethylpropylamino, n-hexylamino Isohexylamino, 4-methylpentylamino, 3-methylpentylamino, 2-methylpentylamino, 1-methylpentylamino, 3,3-dimethylbutylamino, 2,2-dimethylbutylamino, 1,1-dimethyl Linear or branched alkylamino groups having 1 to 6 carbon atoms such as butylamino, 1 2-dimethylbutylamino, 1,3-dimethylbutylamino, 2,3-dimethylbutylamino, 2-ethylbutylamino, Preferably a straight chain or branched alkylamido having 1 to 6 carbon atoms Group, and more preferably a methylamino group or ethylamino group.
[64] In the above formula (I), "cycloalkyl group" of "cycloalkyl group" and "cycloalkyl group substituted with 1 or 2 or more by the same or different substituents selected from <substituent group β> in substituent And 3- to 10-membered saturated cyclic hydrocarbon groups which may be condensed such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, adamantyl, and preferably 5 to 7 membered saturated cyclic hydrocarbons. It is.
[65] Examples of "heteroaryl group" of "heteroaryl group" and "heteroaryl group substituted with one or two or more substituents by the same or different substituent selected from <substituent group β> in said substituent group α in said Formula (I) For example furyl, thienyl, pyrrolyl, azepineyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl 5-7 membered aromatic heterocyclic groups, such as thiadiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, are mentioned, Preferably it is a pyridyl group.
[66] In the above formula (I), the "aryl group" of the "aryl group" in the substituent group α and the "aryl group substituted with one or two or more with the same or different substituents selected from <substituent group β>", for example, Aromatic hydrocarbon group of 5 to 14 carbon atoms, such as phenyl, indenyl, naphthyl, phenanthrenyl, and anthracenyl, may be mentioned, preferably an aromatic hydrocarbon group of 6 to 10 carbon atoms, and more preferably a phenyl group.
[67] The term " pharmacologically acceptable salt thereof " refers to the salt of the compound (I) of the present invention because it can be a salt, and such salts preferably include alkali metal salts such as sodium salts, potassium salts, lithium salts, Metal salts such as alkaline earth metal salts such as calcium salts and magnesium salts, aluminum salts, iron salts, zinc salts, copper salts, nickel salts and cobalt salts; Inorganic salts such as ammonium salt, t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, tri Ethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-phenethylamine salt, piperazine salt, tetramethyl Amine salts such as ammonium salts and organic salts such as tris (hydroxymethyl) aminomethane salts; Inorganic acid salts such as hydrofluoric acid hydrochloride, nitrate, perchlorate, sulfate, phosphate, such as hydrofluoric acid salt, hydrochloride salt, hydrobromide salt, and iodide salt salt; Lower alkanesulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, arylsulfonate such as p-toluenesulfonate, acetate, malate, humate, succinate, citrate, tin Organic acid salts such as acid salts, oxalates and maleates; And amino acid salts such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamate salts, and asparagine salts. However, when it becomes a metal salt or an amine salt, it is limited when compound (I) has an acidic group.
[68] In addition, the compound (I) of the present invention may be left in the air to absorb moisture, thereby adsorb water or form a hydrate, and such salts are also included in the present invention.
[69] In addition, although the compound (I) of this invention may absorb another kind of solvent and may become a solvate, such a salt is also contained in this invention.
[70] "It's ester" refers to the ester because the compound (I) of the present invention can be an ester, and such ester refers to "related" and "carboxy ester" and each ester residue is " General protecting groups "or" protecting groups that can be cleaved by biological methods such as hydrolysis in vivo ".
[71] The term "general protecting group" refers to a protecting group that can be cleaved by chemical methods such as hydrogenolysis, hydrolysis, electrolysis, photolysis, and the "general protecting group" for "related", for example, formyl, acetyl, Propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, 3-methylnonanoyl, 8-methylnonanoyl, 3- Ethyloctanoyl, 3,7-dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, 1-methylpentadecanoyl, 14-methylpentadecanoyl, Alkylcarbonyl groups such as 13,13-dimethyltetradecanoyl, heptadecanoyl, 15-methylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl, nonadecanoyl, aicosanoyl and henacosanoyl, succinoyl, Carboxylated alkylcarbonyl groups such as glutaroyl, adipoyl, chloroa Halogeno lower alkyl groups such as methyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl carbonyl, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, cyclooctylcarbonyl "Aliphatic acyl groups" such as saturated cyclic hydrocarbon-carbonyl groups, lower alkoxy lower alkyl groups such as methoxyacetyl, and unsaturated alkylcarbonyl groups such as (E) -2-methyl-2-butenoyl; benzoyl, α-naphthoyl , arylcarbonyl groups such as β-naphthoyl, pyridoyl, thienoyl, furoyl, halogeno arylcarbonyl groups such as 2-bromobenzoyl, 4-chlorobenzoyl, 2,4,6-trimethylbenzoyl, 4-toluoyl and Lower alkylated arylcarbonyl groups, such as lower alkoxylated arylcarbonyl groups, such as 4-anisoyl, 2-carboxyl benzoyl, 3-carboxylbenzoyl, 4-car Carboxylated arylcarbonyl groups such as carboxyl benzoyl, 4-nitrobenzoyl, nitrated arylcarbonyl groups such as 2-nitrobenzoyl, lower alkoxycarbonylated arylcarbonyl groups such as 2- (methoxycarbonyl) benzoyl, 4-phenylbenzoyl and "Aromatic acyl groups" such as arylated arylcarbonyl groups; phenylacetyl, α-naphthylpropionyl, β-naphthylbutyryl, diphenylisobutyryl, triphenylacetyl, α-naphthyldiphenylisobutyryl, 9 Lower alkyl groups substituted with 1 to 3 aryl groups such as anthrylpentanoyl, 4-methylphenylacetyl, 2,4,6-trimethylphenylformyl, 3,4,5-trimethylphenylbutyryl, 4 -Methoxyphenylisobutyryl, 4-methoxyphenyldiphenylpivaloyl, 2-nitrophenylacetyl, 4-nitrophenylpropionyl, 4-chlorophenylbutyryl, 4-bromophenylacetyl, 4-cyano Lower alkyl groups such as phenylpentanoyl, lower alkoxy, nitro, Such as a halogen atom, a cyano group into an aryl ring substituted with 1 to 3 aryl groups substituted with a lower alkyl group "aralkyl group"; Tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydrothiopyran- "Tetrahydropyranyl or tetrahydrothiopyranyl groups" such as 4-yl; "Tetrahydrofuranyl or tetrahydrothiofuranyl groups" such as tetrahydrofuran-2-yl and tetrahydrothiofuran-2-yl; Tri lower alkyl groups such as trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl, triisopropylsilyl, diphenylmethylsilyl, di "Silyl groups" such as tri lower alkyl group silyl groups substituted with 1 to 2 aryl groups such as phenylbutylsilyl, diphenylisopropylsilyl and phenyldiisopropylsilyl; Lower alkoxymethyl groups such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, tert-butoxymethyl, 2-methoxyethoxy "Alkoxymethyl groups" such as lower alkoxylated lower alkoxymethyl groups such as methyl, 2,2,2-trichloroethoxymethyl, and halogeno lower alkoxymethyl such as bis (2-chloroethoxy) methyl; "Substituted ethyl groups" such as lower alkoxylated ethyl groups such as 1-ethoxyethyl and 1- (isopropoxy) ethyl, and halogen atomized ethyl groups such as 2,2,2-trichloroethyl; Lower alkyl groups substituted with 1 to 3 aryl groups such as benzyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl, 4-methyl Benzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, "Aralkyl groups" such as lower alkyl groups such as 4-bromobenzyl and 4-cyanobenzyl, lower alkoxy, nitro, halogen atoms, lower alkyl groups substituted with 1 to 3 aryl groups substituted with aryl rings with cyano groups; Lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, isobutoxycarbonyl, 2,2,2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl "Alkoxycarbonyl groups" such as lower alkoxycarbonyl groups substituted with halogen atoms or tri lower alkyl group silyl groups; "Alkenyloxycarbonyl groups" such as vinyloxycarbonyl and allyloxycarbonyl; 1-2 lower alkoxy, such as benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, or And an "aralkyloxycarbonyl group" in which an aryl ring may be substituted with a nitro group.
[72] On the other hand, as the "general protecting group" relating to "ester of the carboxy group", Preferably, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2 "Lower alkyl groups" such as -dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl; Ethenyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2 -Ethyl-2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-2-butenyl, 1-methyl-1-butenyl, 3-methyl-2-butenyl, 1-ethyl-2 -Butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, 1-pentenyl, 2-pentenyl, 1-methyl- 2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl "Alkenyl groups" such as 2-methyl-4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl; Ethynyl, 2-propynyl, 1-methyl-2-propynyl, 2-methyl-2-propynyl, 2-ethyl-2-propynyl, 2-butynyl, 1-methyl-2-butynyl, 2 -Methyl-2-butynyl, 1-ethyl-2-butynyl, 3-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-ethyl-3-butynyl, 2 -Pentynyl, 1-methyl-2-pentynyl, 2-methyl-2-pentynyl, 3-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 4-pentynyl, "Alkynyl groups" such as 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl; Trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-bro "Halogeno lower alkyl groups such as moethyl, 2-chloroethyl, 2-fluoroethyl, 2-iodineethyl, 3-chloropropyl, 4-fluorobutyl, 6-iodinehexyl, 2,2-dibromoethyl "; "Hydroxy lower alkyl groups" such as 2-hydroxyethyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, 3,4-dihydroxybutyl, 4-hydroxybutyl; "Aliphatic acyl"-"lower alkyl groups" such as acetylmethyl; 1 such as benzyl, phenethyl, 3-phenylpropyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, 6-phenylhexyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl "Lower alkyl groups" substituted with from 3 to aryl groups, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, 4-cyanobenzyldiphenylmethyl, bis (2-nitrophenyl) methyl, piperonyl, 4 "Aralkyl groups" such as lower alkyl groups such as methoxycarbonylbenzyl, lower alkoxy, nitro, halogen atoms, cyano, lower alkyl groups substituted with 1 to 3 aryl groups substituted with aryl rings with cyano, alkoxycarbonyl groups; Trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, tert-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-tert-butylsilyl, triisopropylsilyl, methyldiphenylsilyl, isopropyldiphenylsilyl, butyldi And "silyl groups" such as phenylsilyl and phenyldiisopropylsilyl.
[73] A "protecting group that can be cleaved by biological methods such as hydrolysis in living organisms" refers to a protecting group cleaved by a biological method such as hydrolysis in the human body to produce a free acid or a salt thereof, and whether the derivative is such a derivative. Whether or not can be determined by intravenous injection to an experimental animal, such as a rat or mouse, and by examining the body fluids of the animal afterwards to detect the underlying compound or a pharmacologically acceptable salt thereof.
[74] Examples of the "protecting group which can be cleaved by biological methods such as hydrolysis in vivo" for "ester of hydroxyl group" include, for example, formyloxymethyl, acetoxymethyl, dimethylaminoacetoxymethyl, propionyloxymethyl, Butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, isovaleryloxymethyl, hexanoyloxymethyl, 1-formyloxyethyl, 1-acetoxyethyl, 1-propionyloxyethyl, 1-buty Ryloxyethyl, 1-pivaloyloxyethyl, 1-valeryloxyethyl, 1-isovaleryloxyethyl, 1-hexanoyloxyethyl, 1-formyloxypropyl, 1-acetoxypropyl, 1-propy Onyloxypropyl, 1-butyryloxypropyl, 1-pivaloyloxypropyl, 1-valeryloxypropyl, 1-isovaleryloxypropyl, 1-hexanoyloxypropyl, 1-acetoxybutyl, 1-propy Onyloxybutyl, 1-butyryloxybutyl, 1-pivaloyloxybutyl, 1-acetoxypentyl, 1-propionyljade 1-("aliphatic acyl" oxy) "lower alkyl groups" such as cypentyl, 1-butyryloxypentyl, 1-pivaloyloxypentyl, 1-pivaloyloxyhexyl; Formylthiomethyl, acetylthiomethyl, dimethylaminoacetylthiomethyl, propionylthiomethyl, butyrylthiomethyl, pivaloylthiomethyl, valerylthiomethyl, isovalerylthiomethyl, hexanoylthiomethyl, 1-form Milthioethyl, 1-acetylthioethyl, 1-propionylthioethyl, 1-butyrylthioethyl, 1-pivaloylthioethyl, 1-valerylthioethyl, 1-isovalerylthioethyl, 1-hexa Noylthioethyl, 1-formylthiopropyl, 1-acetylthiopropyl, 1-propionylthiopropyl, 1-butyrylthiopropyl, 1-pivaloylthiopropyl, 1-valerylthiopropyl, 1-isovalle Ylthiopropyl, 1-hexanoylthiopropyl, 1-acetylthiobutyl, 1-propionylthiobutyl, 1-butyrylthiobutyl, 1-pivaloylthiobutyl, 1-acetylthiopentyl, 1-propionyl 1-("aliphatic acyl" thio) "lower alkyls such as thiopentyl, 1-butyrylthiopentyl, 1-pivaloylthiopentyl, 1-pivaloylthiohexyl group"; Cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, 1-cyclopentylcarbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl, 1-cyclohexylcarbonyloxypropyl, 1-("cycloalkyl" carbonyloxy) "lower alkyl groups" such as 1-cyclopentylcarbonyloxybutyl, 1-cyclohexylcarbonyloxybutyl, 1-("aromatic acyl" oxy) "such as benzoyloxymethyl 1- (acyloxy) "lower alkyl group" such as "lower alkyl group": methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyloxy Methyl, isobutoxycarbonyloxymethyl, pentyloxycarbonyloxymethyl, hexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxy (cyclohexyl) methyl, 1- (meth Toxi Levonyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, 1- (propoxycarbonyloxy) ethyl, 1- (isopropoxycarbonyloxy) ethyl, 1- (butoxycarbonyloxy) ethyl , 1- (isobutoxycarbonyloxy) ethyl, 1- (tert-butoxycarbonyloxy) ethyl, 1- (pentyloxycarbonyloxy) ethyl, 1- (hexyloxycarbonyloxy) ethyl, 1- (Cyclopentyloxycarbonyloxy) ethyl, 1- (cyclopentyloxycarbonyloxy) propyl, 1- (cyclohexyloxycarbonyloxy) propyl, 1- (cyclopentyloxycarbonyloxy) butyl, 1- ( Cyclohexyloxycarbonyloxy) butyl, 1- (cyclohexyloxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) propyl, 2- (methoxycarbonyloxy) ethyl, 2- (ethoxy Carbonyloxy) ethyl, 2- (propoxycarbonyloxy) ethyl, 2- (isopropoxycarbonyloxy) ethyl, 2- (butoxycarbonyloxy) ethyl, 2- (isobutoxycarbonyloxy) ethyl , 2- (pentyl Oxycarbonyloxy) ethyl, 2- (hexyloxycarbonyloxy) ethyl, 1- (methoxycarbonyloxy) propyl, 1- (ethoxycarbonyloxy) propyl, 1- (propoxycarbonyloxy) Propyl, 1- (isopropoxycarbonyloxy) propyl, 1- (butoxycarbonyloxy) propyl, 1- (isobutoxycarbonyloxy) propyl, 1- (pentyloxycarbonyloxy) propyl, 1- ( Hexyloxycarbonyloxy) propyl, 1- (methoxycarbonyloxy) butyl, 1- (ethoxycarbonyloxy) butyl, 1- (propoxycarbonyloxy) butyl, 1- (isopropoxycarbonyl Oxy) butyl, 1- (butoxycarbonyloxy) butyl, 1- (isobutoxycarbonyloxy) butyl, 1- (methoxycarbonyloxy) pentyl, 1- (ethoxycarbonyloxy) pentyl, 1- (Alkoxycarbonyloxy) alkyl groups such as (methoxycarbonyloxy) hexyl, 1- (ethoxycarbonyloxy) hexyl: "phthalidyl, dimethylphthalidyl, dimethoxyphthalidyl" Thalidil group ": (5- Nyl-2-oxo-1,3-dioxoren-4-yl) methyl, [5- (4-methylphenyl) -2-oxo-1,3-dioxorenyl] methyl, [5- (4-meth Methoxyphenyl) -2-oxo-1,3-dioxoren4-yl] methyl, [5- (4-fluorophenyl) -2-oxo-1,3-dioxoren-4-yl] methyl, [5- (4-Chlorophenyl) -2-oxo-1,3-dioxoren-4-yl] methyl, (2-oxo-1,3-dioxoren-4-yl) methyl, (5- Methyl-2-oxo-1,3-dioxoren4-yl) methyl, (5-ethyl-2-oxo-1,3-dioxoren-4-yl) methyl, (5-propyl-2-oxo -1,3-dioxoren-4-yl) methyl, (5-isopropyl-2-oxo-1,3-dioxoren-4-yl) methyl, (5-butyl-2-oxo-1, "Carbonyloxyalkyl groups" such as oxodioxorenylmethyl groups such as 3-dioxoren-4-yl) methyl; Said "aliphatic acyl group"; Said "aromatic acyl group": "half ester salt residue of succinic acid"; "Phosphate ester salt residues"; "Ester forming residues such as amino acids"; Carbamoyl groups; Carbamoyl groups substituted with 1 to 2 lower alkyl groups: 2-carboxylethyldithioethyl, 3-carboxylpropyldithioethyl, 4-carboxylbutyldithioethyl, 5-carboxylpentyldithioethyl, 6-carboxylhexylditi Carboxyl group "lower alkyl group" dithioethyl group such as oethyl; "Lower alkyl groups" dithioethyl groups such as methyldithioethyl, ethyldithioethyl, propyldithioethyl, butyldithioethyl, pentyldithioethyl and hexyldithioethyl;
[75] On the other hand, as the "protecting group which can be cleaved by biological methods such as hydrolysis in living organisms" relating to "ester of the carboxyl group", specifically, methoxymethyl, 1-ethoxyethyl, 1-methyl-1-methoxy Ethyl, 1- (isopropoxy) ethyl, 2-methoxyethyl, 2-ethoxyethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, lower alkoxy lower alkyl groups such as n-butoxymethyl, tert-butoxymethyl, lower alkoxylated lower alkoxy lower alkyl groups such as 2-methoxyethoxymethyl, "aryl groups" oxy "lower alkyl groups" such as phenoxymethyl, "Alkoxy lower alkyl groups" such as halogen atomized lower alkoxy lower alkyl groups such as 2,2,2-trichloroethoxymethyl and bis (2-chloroethoxy) methyl: "lower alkoxy" carbonyls such as methoxycarbonylmethyl "Lower alkyl group"; Cyano "lower alkyl groups" such as cyanomethyl, 2-cyanoethyl; "Lower alkyl groups" thiomethyl groups such as methylthiomethyl and ethylthiomethyl; "Aryl groups" thiomethyl groups such as phenylthiomethyl and naphthylthiomethyl; "Lower alkyl groups" sulfonyl "lower alkyl groups which may be substituted with halogen atoms such as 2-methanesulfonylethyl and 2-trifluoromethanesulfonylethyl; "Aryl groups" sulfonyl "lower alkyl groups" such as 2-benzenesulfonylethyl and 2-toluenesulfonylethyl; Formyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, isovaleryloxymethyl, hexanoyloxymethyl, 1-formyloxyethyl, 1- Acetoxyethyl, 1-propionyloxyethyl, 1-butyryloxyethyl, 1-pivaloyloxyethyl, 1-valeryloxyethyl, 1-isovaleryloxyethyl, 1-hexanoyloxyethyl, 2- Formyloxyethyl, 2-acetoxyethyl, 2-propionyloxyethyl, 2-butyryloxyethyl, 2-pivaloyloxyethyl, 2-valeryloxyethyl, 2-isovaleryloxyethyl, 2- Hexanoyloxyethyl, 1-formyloxypropyl, 1-acetoxypropyl, 1-propionyloxypropyl, 1-butyryloxypropyl, 1-pivaloyloxypropyl, 1-valeryloxypropyl, 1-iso Valeryloxypropyl, 1-hexanoyloxypropyl, 1-acetoxybutyl, 1-propionyloxybutyl, 1-butyryloxybutyl, 1-pivaloyloxybutyl, 1-acetoxypentyl, 1- "Aliphatic acyl" oxy "lower alkyl groups" such as lopionyloxypentyl, 1-butyryloxypentyl, 1-pivaloyloxypentyl, 1-pivaloyloxyhexyl, cyclopentylcarbonyloxymethyl, cyclohexylcarbonyl Oxymethyl, 1-cyclopentylcarbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl, 1-cyclohexylcarbonyloxypropyl, 1-cyclopentylcarbonyloxybutyl, 1- Acyloxy "lower alkyl groups" such as "cycloalkyl" carbonyloxy "lower alkyl groups" such as cyclohexylcarbonyloxybutyl and "aromatic acyl" oxy "lower alkyl groups" such as benzoyloxymethyl; Methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl, pentyloxycarbonyloxymethyl, Hexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxy (cyclohexyl) methyl, 1- (methoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) Ethyl, 1- (propoxycarbonyloxy) ethyl, 1- (isopropoxycarbonyloxy) ethyl, 1- (butoxycarbonyloxy) ethyl, 1- (isobutoxycarbonyloxy) ethyl, 1- ( tert-butoxycarbonyloxy) ethyl, 1- (pentyloxycarbonyloxy) ethyl, 1- (hexyloxycarbonyloxy) ethyl, 1- (cyclopentyloxycarbonyloxy) ethyl, 1- (cyclopentyl Oxycarbonyloxy) propyl, 1- (cyclohexyloxycarbonyloxy) propyl, 1- (cyclopentyloxy Levonyloxy) butyl, 1- (cyclohexyloxycarbonyloxy) butyl, 1- (cyclohexyloxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) propyl, 2- (methoxycarbonyl Oxy) ethyl, 2- (ethoxycarbonyloxy) ethyl, 2- (propoxycarbonyloxy) ethyl, 2- (isopropoxycarbonyloxy) ethyl, 2- (butoxycarbonyloxy) ethyl, 2 -(Isobutoxycarbonyloxy) ethyl, 2- (pentyloxycarbonyloxy) ethyl, 2- (hexyloxycarbonyloxy) ethyl, 1- (methoxycarbonyloxy) propyl, 1- (ethoxycarbon Carbonyloxy) propyl, 1- (propoxycarbonyloxy) propyl, 1- (isopropoxycarbonyloxy) propyl, 1- (butoxycarbonyloxy) propyl, 1- (isobutoxycarbonyloxy) propyl, 1- (pentyloxycarbonyloxy) propyl, 1- (hexyloxycarbonyloxy) propyl, 1- (methoxycarbonyloxy) butyl, 1- (ethoxycarbonyloxy) butyl, 1- (propoxy Carbonyloxy) butyl, 1- (this Propoxycarbonyloxy) butyl, 1- (butoxycarbonyloxy) butyl, 1- (isobutoxycarbonyloxy) butyl, 1- (methoxycarbonyloxy) pentyl, 1- (ethoxycarbonyloxy) (Alkoxycarbonyloxy) alkyl groups such as pentyl, 1- (methoxycarbonyloxy) hexyl, 1- (ethoxycarbonyloxy) hexyl; (5-phenyl-2-oxo-1,3-dioxoene 4 -Yl) methyl, [5- (4-methylphenyl) -2-oxo-1,3-dioxoren4-yl] methyl, [5- (4-methoxyphenyl) -2-oxo-1,3- Dioxoren4-yl] methyl, [5- (4-fluorophenyl) -2-oxo-1,3-dioxoren4-yl] methyl, [5- (4-chlorophenyl) -2-oxo -1,3-dioxoren4-yl] methyl, (2-oxo-1,3-dioxoren4-yl) methyl, (5-methyl-2-oxo-1,3-dioxoene4- Il) methyl, (5-ethyl-2-oxo-1,3-dioxoren4-yl) methyl, (5-propyl-2-oxo-1,3-dioxoren4-yl) methyl, (5 Oxodioxorenylmethyl groups such as isopropyl-2-oxo-1,3-dioxoren4-yl) methyl, (5-butyl-2-oxo-1,3-dioxoren4-yl) methyl, etc. "Carbonyloxyalkyl group": "Phthalidyl groups" such as thalidyl, dimethylphthalidyl and dimethoxyphthalidyl: "aryl groups" such as phenyl and indanyl: said "lower alkyl groups": methylthio, ethylthio, n-propylthio, iso Propylthio, n-butylthio, isobutylthio, s-butylthio, tert-butylthio, n-pentylthio, isopentylthio, 2-methylbutylthio, neopentylthio, 1-ethylpropylthio, n-hexyl Thio, isohexylthio, 4-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio, 1-methylpentylthio, 3,3-dimethylbutylthio, 2,2-dimethylbutylthio, 1,1- Linear or branched alkylthio groups having 1 to 6 carbon atoms, such as dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio, 2,3-dimethylbutylthio, and 2-ethylbutylthio; Preferably an "alkylthio group" having 1 to 4 carbon atoms: "carboxyalkyl group" such as carboxy group methyl: and "amide forming moiety of amino acid" such as phenylalanine The can.
[76] The term "other derivative" refers to an ether derivative or carbamoyloxy derivative in the case of having a "hydroxyl group" or an amide derivative in the case of having an "amino group". Refers to a group that produces a "hydroxyl group" or an "amino group", and whether or not it is a derivative thereof is administered to an experimental animal such as a mouse or mouse by intravenous injection, followed by investigation of the body fluids of the animal, or a compound thereof. It can be determined by being able to detect pharmacologically acceptable salts.
[77] The compound (I) of the present invention may have a subsidiary carbon in the molecule, and stereoisomers each of which is an R configuration and an S configuration exist, but each or a mixture of any ratio thereof is included in the present invention.
[78] In addition, the external preparation of the present invention includes at least one compound of the above nitroimidazole derivatives and antifungal agent, antibacterial agent, sulfa agent, immunosuppressant agent, anti-inflammatory agent, antibiotic substance, antiviral agent, metabolic antagonist, antihistamine drug, tissue repair accelerator, vitamins, anti- It is an external preparation for administering at least one of allergy medicines, local anesthetics, hair preparations or steroids simultaneously or separately.
[79] In the above description, the "simultaneous" administration is not particularly limited as long as it is a dosage form that can be administered at about the same time, but is preferably administered as a single composition.
[80] In the above, the "individually administered over time" is not particularly limited as long as it is a dosage form that can be administered separately at different times. For example, the nitroimidazole derivative is administered on the first day, and the antifungal agent on the second day, Drugs containing at least one of antimicrobial agents, sulfa drugs, immunosuppressants, anti-inflammatory agents, antibiotics, antiviral agents, metabolic antagonists, antihistamines, tissue repair accelerators, vitamins, antiallergic drugs, local anesthetics, hair preparations or steroids Or after first administering nitroimidazole derivatives, and after a predetermined time, antifungal agents, antibacterial agents, sulfa agents, immunosuppressants, anti-inflammatory agents, antibiotics, antiviral agents, metabolic antagonists, antihistamines, tissue repair accelerators, vitamins, Administration of a drug containing at least one of anti-allergic drugs, local anesthetics, hair preparations or steroids Says that.
[81] At least one of the above antifungal, antibacterial, sulfa, immunosuppressant, anti-inflammatory, antibiotic, antiviral, metabolic antagonist, antihistamine, tissue repair promoter, vitamins, antiallergic, local anesthetic, hair for use or steroid Among the pharmaceutical agents, in the external preparations for the treatment or prevention of atopic dermatitis, preferably, they are antifungal agents, immunosuppressants, steroids and combinations thereof, more preferably immunosuppressants, steroids and antifungal agents and steroid agents, and treatment of psoriasis. Or in the external preparation for prevention, preferably antifungal agents, immunosuppressive agents, vitamins, antiallergic drugs, steroid agents and combinations thereof, more preferably immunosuppressants, vitamins and steroid agents, and in the external preparation for the treatment or prevention of ringworm. Is preferably an antibacterial agent, for the treatment of purulent skin diseases or In the external preparation for prevention, it is preferably an antibiotic substance.
[82] In the above, at least one of antifungal, antimicrobial, sulfa, immunosuppressant, anti-inflammatory, antibiotic, antiviral, metabolic antagonist, antihistamine, tissue repair promoter, vitamins, antiallergic, local anesthetic, hair for use or steroid The concentration of the medicament of the medicament is preferably a concentration which does not show any efficacy by itself. Those skilled in the art can easily determine whether or not the concentration exhibits efficacy by itself, using known means (for example, comparative tests in humans or animals).
[83] Preparations for containing antifungal, antibacterial, sulfa, immunosuppressant, anti-inflammatory, antibiotic, antiviral, metabolic antagonist, antihistamine, tissue repair accelerator, vitamins, antiallergic, local anesthetic, hair or steroid The content in the solvent is not particularly limited as long as it is a concentration that does not exhibit adverse effects, but the antifungal agent is preferably 0.0005 to 2% by weight, more preferably 0.01 to 0.5% by weight based on the weight of the preparation; The antimicrobial agent is preferably 0.001 to 5% by weight, more preferably 0.01 to 0.5% by weight; The sulfa agent is preferably 0.001 to 5% by weight, more preferably 0.01 to 0.5% by weight; The immunosuppressant is preferably 0.001 to 5% by weight, more preferably 0.01 to 0.1% by weight; In anti-inflammatory agents, it is preferably 0.001 to 5% by weight, more preferably 0.005 to 0.5% by weight; The antibiotic substance is preferably 0.0001 to 5% by weight, more preferably 0.001 to 0.1% by weight; The antiviral agent is preferably 0.01 to 5% by weight, more preferably 0.1 to 1% by weight; The metabolic antagonist is preferably 0.01 to 5% by weight, more preferably 0.01 to 0.5% by weight; The antihistamine is preferably 0.001 to 10% by weight, more preferably 0.01 to 5% by weight; The tissue repair accelerator is preferably 0.1 to 20% by weight, more preferably 0.1 to 5% by weight; The vitamins are preferably 0.000001 to 0.005% by weight, more preferably 0.00001 to 0.001% by weight; The anti-allergic agent is preferably 0.001 to 5% by weight, more preferably 0.01 to 0.5% by weight; In local anesthetics, preferably 0.001 to 5% by weight, more preferably 0.01 to 1% by weight; The hair solvent is preferably 0.01 to 10% by weight, more preferably 0.1 to 2% by weight; The steroidal agent is preferably 0.001 to 1% by weight, more preferably 0.001 to 0.1% by weight.
[84] The antifungal agent is not particularly limited as long as it is a drug used for the treatment of pathogenic filamentous fungus and deep fungal disease. For example, croconazole hydrochloride, neticonazole hydrochloride, crotrimazole, ketoconazole, isoconazole nitrate , Imidazole compounds including nitrate econasol, oxyconazole nitrate, sulconazole nitrate, myconazole nitrate, thioconazole, bihonazole, lanconazole and the like, amorphine hydrochloride, terbinamate hydrochloride, butena hydrochloride Pin, cyclopyrocus oramin, tolciclate, tolnafite, and the like.
[85] The antimicrobial agent in the above is not particularly limited as long as it is a drug having an effect on pathogenic microorganisms (gram positive cocci and bacillus, negative cocci and bacillus), and examples thereof include enoxacin, methyllozaniline chloride, and cycloproploxine hydrochloride. , Lomefloxacin, opfloxacin, sinoxacin, sinoxacin, spalfloxacin, tosyl acid tosfloxacin, nalidixic acid, norfloxacin, pipemide trihydrate, pyromide acid, plexaxacin, levofloxacin, and the like, or their Derivatives; and the like.
[86] The sulfa agent in the above is not particularly limited as long as it is usually used, and examples thereof include acetyl sulfamethoxazole, sarazosulfypyridine, sulfadiazine, sulfadiazine silver, sulfadimethoxine, sulfatiazole, and sulfape. Nazol, Sulfamethoxazole, Sulfamethoxypyridazine, Sulfamethoxypyrazine, Sulfamethmidine, Sulfamethizol, Sulfameladin, Sulfamonothoxine, Sulphixazole, Sulfoisomidine, Sulfoisomidine Sodium, Homosulpa Min, etc., or derivatives thereof are mentioned.
[87] The immunosuppressant is not particularly limited as long as it is a drug that suppresses an immune rejection reaction. For example, pimeclolims, silolims, evelorims, cyclosporin, taclorims, glyferrim hydrochloride, mizoribin, FTY -720 [2-amino-2- (2- (4octylphenyl) ethyl) propane-1,3-diol hydrochloride] etc. are mentioned.
[88] There is no restriction | limiting in particular if it is a conventionally used anti-inflammatory agent, For example, acrotite, azrene, acemethacin, aspirin, alclofenac, aluminopropene, anfenac sodium, anpyroxycamp, ibpro Pens, ibuprofenpiconol, indomethacin, indomethacinpalnesyl, upenamat, etodra, epirisol, emolfazone, tiaramid hydrochloride, tinoridine hydrochloride, brprenol hydrochloride, pentazosin hydrochloride, en Phenam, Oxaprozin, Glytilechinic Acid, Crotamiton, Ketoprofen, Zaltpropene, Diflunisal, Diclofenac Sodium, Sprofen, Sulindak, Tiapropene, Tenoxycam, Trimethine Sodium, Nabu Metone, nafuroxen, nipric acid, pyroxicam, phenacetin, phenylbutazone, phenopropenecalcium, felbinac, fenbfen, bucolom, brecsamark, pranoprofen, fluluprofen, proctaphenin , Mesyl Dimethatothiine, Methiazine, Bendazar, Heparin Oil Substance, maleic acid Pro Glu meth sour methoxy penam chloride, mefenamic acid, sodium lock port and a pen, Robben place the agent, and the like of sodium, vaccinia virus inoculation rabbit inflamed skin extract and the like, or their derivatives.
[89] As said antibiotic substance, the substance which inhibits the growth of a microorganism is mentioned, For example, acetylkitasamycin, acetylspiramycin, amphotericin B, amoxicillin, ampicillin, kanamycin monoethyl succinic acid erythromycin, erythromycin, Erythromycin ester, hydrochloric acid hydrochloric acid, oxytetracycline hydrochloride, kulindamycin hydrochloride, cefetamethopic acid hydrochloride, ceftamihexetyl hydrochloride, cefecapfenpic hydrochloride, cephmenoxyl hydrochloride, deampicillin hydrochloride, tetra hydrochloride Cyclin, demethylchlorotetracycline hydrochloride, tetracycline hydrochloride, vancomycin hydrochloride, doxycycline hydrochloride, doxolic acid hydrochloride, bacampicillin hydrochloride, palmitic acid coolidamycin hydrochloride, vancomycin hydrochloride, skin mesilinic hydrochloride, bleomycin hydrochloride, Minocycline hydrochloride, lincomycin hydrochloride, renampicillin hydrochloride, sodium calbenicillin, Kitasamycin, potassium clavulanic acid, clarithromycin, glyceroflubin, sodium chlorxacin, chloramphenicol, sodium colistin methanesulfonate, cycloserine, midecamycin acetate, cyclolacillin, dicloxacillin sodium , Sitkanin, josamycin, erythromycin stearate, sodium sulfenicillin, cephachloro, cefazoline, cephatridine propylene glycol, cephadroxyl, cephapyrin, cefamandol sodium, ceparexin, cepharotin sodium, cephalori Dean, Sepiksim, Sepepsitin Sodium, Cytotaxin Sodium, Cythetane, Ceferrazon Sodium, Ceftitorenfixil, Ceftdinyl, Ceftsulodine Sodium, Ceftioxime Sodium, Ceftibbutene, Cefterrampican, Cefpyramid Sodium, Cefferrazone Sodium, Cefpodoximefuroxetyl, Cefmethazol Sodium, Cefradine, Cefroxadine, Cefroximexetyl, Cefroxime Sodium, Ticacillin Sodium, Tetracycline, tosylic acid sulfamicillin, tobramycin, trichomycin, nystatin, bariotin, palmitic acid chloramphenicol, piperacillin sodium, fimaricin, parophenem sodium, josamycin propenic acid, potassium peneticillin, phenoxy Potassium methylphenicillin, potassium benzylpenicillin, benzylpenicillinbenzatin, phosphomycin calcium, mitomycin C, midecamycin, metaphosphate tetracycline, latamoxef sodium, rifampicin, astoromycin sulfate, amikacin sulfate, Kanamycin Sulfate, Gentamicin Sulfate, Sisomycin Sulfate, Dibecassin Sulfate, Streptomycin Sulfate, Netylmycin Sulfate, Pradiomycin Sulfate, Bleomycin Sulfate, Becanamycin Sulfate, Pefuromycin Sulfate, Polymyric Sulfate B, Microno Sulfate Mycin, ribostomycin sulfate, kurindamycin phosphate, roxyslomycin, loctamycin and the like, or derivatives thereof Can be mentioned.
[90] The antiviral agent in the above refers to a specific drug for the virus, for example, acyclovir (caniclovir), cancyclovir, sanylbudine, zalcitabine, didanosine, dididobudine, nevirapine, mesylic acid sakinavill, Mesylic acid nelfinabil, lamivudine ritnabil, indinabil sulfate, and the like, and additions and substitutions of salts thereof; and the like can be given.
[91] There is no restriction | limiting in particular if it is a conventionally used metabolic antagonist, For example, actinomycin D, L-asparaginase, acegraton, ubenimex, uracil, etposide, enositabine, Hydrochloric acid hydrochloride, dalinocin hydrochloride, irinotecan hydrochloride, irinotecan hydrochloride, doplovic acid hydrochloride, donolvine hydrochloride, doxolybine hydrochloride, pyralbisine hydrochloride, padrosol hydrochloride, bleomycin hydrochloride, procarbazine hydrochloride, mitoxantol hydrochloride , Carbopratin, carmoful, citric acid tamoxifen, citric acid toremifene, cyclophosphamide, cisplatin, cyzopyran, cytarabine, cytarabine oak phosphate, dinostatin styrama, tartaric acid vinorelbine, sobuzoki acid, thiotepa, Tegaful, doxyplidine, docetaquicel hydrate, tretinoin, neokaltinostatin, nedapratin, paclitaxel, bicaltamide, hydroxycarbamide, phosphestrol, busulfan, pla Aurolausyl, flutamide, propylthiolausyl, pentstatin, porphymarium, methyltestosterone, mephithiostane, G-mercaptopurine liposide, mercaptopurine, methotrexite, melparan, lysobacterial extract, sulfuric acid Pefuromycin, vincristine sulfate, vinblastine sulfate, retinan, etc., or derivatives thereof, etc. are mentioned.
[92] The antihistamine drug described above is not particularly limited as long as it is a drug that antagonizes histamine specifically. For example, cifuroheptadine hydrochloride, diphenhydramine hydrochloride, triprolidine hydrochloride, hydroxydine hydrochloride, and promethadine hydrochloride are used. Homochloric acid hydrochloride, cimetidine, tartaric acid arimadine, tannic acid diphenhydramine, theoclate diphenylpyraline, famoic acid hydroxydine, pamotidine, maleic acid chlorpheniramine, fumaric acid cremastine, mech Tadine, or derivatives thereof.
[93] The tissue repair accelerator is not particularly limited as long as it is a drug that promotes tissue repair. Examples of the tissue repair accelerator include calf blood extract, EGF, and derivatives thereof.
[94] As said vitamins, what has a vitamin-like effect is mentioned, For example, Vitamin D3 flexible bodies, such as tacalcitol, makicalcalitol, calcipotriol, and perecalcitol; Vitamin A softeners such as adaparene, tazalotene, aritretinoin, etreninite; Vitamin A, B group, C, D, E etc. are mentioned.
[95] There is no restriction | limiting in particular if it is a conventionally used anti-allergic agent, For example, astemisol, anlexanox, Yvdylast, evastin, azelastine hydrochloride, efinastin hydrochloride, ozagrelic hydrochloride, hydrochloric acid Ceciridine, Oxatamide, Sodium Chromogrigate, Ceratlast, Tazanolast, Terpenadine, Tosyl Acid Spurastast, Trinilast, Fumarate Emedastine, Fumarate Ketotifen, Furan Lucas And trihydrate, potassium pillastil, repirinast, or derivatives thereof.
[96] As the anti-local anesthetic agent described above, it refers to a drug that paralyzes the applied local perception and exercise, and examples thereof include ethyl amine benzoate, oxybrofucaine hydrochloride, jibcaine hydrochloride, tetracaine hydrochloride and parabutylamine hydrochloride diethyl benzoate. And amino derivatives, procaine hydrochloride, mepivacaine hydrochloride, lycaine hydrochloride, oxase, lycaine, or derivatives thereof.
[97] There is no restriction | limiting in particular as it is normally used as said hair solvent, Asunaron, a calpronium chloride, minoxidil, etc. are mentioned.
[98] The steroidal agent in the above is not particularly limited as long as it is a drug that exhibits steroid hormone-like action secreted from the adrenal cortex, and includes, for example, amcinonoid, oxymetrone, potassium cannoate, prednisolone acetate and gluconate acetate. Diflucoltron, dexamethasone gilacetic acid, beta metazone of nitrate, succinic acid hydrocortisone, succinic acid prednisolone, chlormadinone acetate, cortizone, acetic acid diflorazone, acetic acid hydrocortisone, paramethasone acetate, Fludocortizone acetate, prednisolone acetate, methenolone acetate, diflupredonide, dipropionate beta metazone, dexamethasone, toriamcinolone, tritoriamcinolone acetonide, halogeninide, hydrocortisone, Pivalic acid flumetazone, prednisolone gel, palesonic acid, budesonide, furan carboxylic acid mometazone, fluorino De, fluorocinolone acetonide, fluoromethorone, fluoxycortide, prednisolone, propionic acid archrometazone, propionic acid clobetasol, propionic acid dexamethasone, propionic acid deprodone, propionic acid beclomethasone, beta metazone Zone, methyl prednisolone, butyric acid clobetazone, butyric acid hydrocortisone, butyric acid propionic acid hydrocortisone, butyric acid propionic acid beta metazone, phosphate hydrocortisone sodium, beta metazone sodium phosphate, or derivatives thereof, and the like. .
[99] As said nitroimidazole derivatives, Preferably it is the above-mentioned (1)-(9), More preferably, metronidazole and tinidazole.
[100] Moreover, the external preparation for skin diseases of this invention is an external preparation for skin diseases preferably containing crotamiton. By containing crotamiton, there exists an effect which shows anti-pruritic effect early, improves the solubility of a nitroimidazole derivative, and improves stability of an external preparation.
[101] Preferably as a skin disease of the external preparation for treatment, prevention or improvement of the skin disease of the present invention,
[102] (10) atopic dermatitis
[103] (11) facial atopic dermatitis
[104] (12) atopic dermatitis in children
[105] (13) blemishes, pigmentation or scars on the skin
[106] 14 psoriasis
[107] (15) Liquid odor, body odor or drunkenness
[108] (16) contact dermatitis, plant dermatitis or hyperemia
[109] (17) skin pruritus or weakness
[110] (18) Alumni
[111] (19) redness
[112] 20 ringworm
[113] 21 purulent skin disease
[114] (22) bedsores
[115] (23) trauma
[116] (24) Intestinal erythematosis, squamous thyroid, gloss thyroid, pore erythematous nasal gin, gibberous rosacea, erythematosis (polymorphic exudative erythema, nodular erythema, centrifugal annular erythema on the leg), chronic disc erythematous erythematous lupus erythematosus , Alopecia areata, lacerations (including scars, keloids), pemphigus, During herpes dermatitis (including rheumatic swelling), seborrheic dermatitis, skin stomatitis, candidiasis (liver erosion, interrogation / skin candidiasis, infant parasitic erythema, Prostheticitis, vulvar candidiasis) or electric wind, and (10), (11), (12), (13), (14) and (15) are more preferable. Further, in the treatment, prevention or amelioration of the above skin diseases, nitroimidazole derivatives are optionally selected, and at least one compound of the nitroimidazole derivatives, an antifungal agent, an antibacterial agent, a sulfa agent, an immunosuppressant, an anti-inflammatory agent, an antibiotic substance, an antiviral agent It is also preferable to use an external preparation for simultaneously or separately administering at least one of metabolic antagonists, antihistamines, tissue repair accelerators, vitamins, antiallergic drugs, local anesthetics, hair preparations or steroids. Let's say
[117] External preparation for the treatment or prevention of (10) atopic dermatitis, wherein the nitroimidazole derivative is metronidazole,
[118] External preparation for the treatment or prevention of facial atopic dermatitis, wherein the nitroimidazole derivative is metronidazole (11),
[119] External preparation for the treatment or prevention of atopic dermatitis in children, wherein the nitroimidazole derivative is metronidazole (12)
[120] (13) external preparations for improving the appearance of skin, pigmentation or scars, wherein the nitroimidazole derivative is metronidazole;
[121] (14) External preparation for the treatment or prevention of psoriasis, wherein the nitroimidazole derivative is metronidazole,
[122] (15) External preparations for the treatment or prophylaxis of liquid odor, body odor or odor, wherein the nitroimidazole derivative is metronidazole,
[123] (10) External preparations for the treatment or prophylaxis of atopic dermatitis, wherein the nitroimidazole derivative is metronidazole and is administered separately or simultaneously with metronidazole, an antifungal agent, an immunosuppressant, a steroid or a combination thereof,
[124] (10) External preparations for the treatment or prophylaxis of atopic dermatitis, wherein the nitroimidazole derivative is metronidazole, wherein metronidazole and an immunosuppressant, steroid, or a combination of antifungal and steroid agents are administered simultaneously or separately.
[125] The nitroimidazole derivative is metronidazole, the topical agent for the treatment or prophylaxis of psoriasis, in which metronidazole and antifungal agents, immunosuppressive agents, vitamins, antiallergic drugs, steroids, or combinations thereof are administered separately, either simultaneously or over time. ,
[126] The nitroimidazole derivative is metronidazole, the topical agent for the treatment or prophylaxis of psoriasis, wherein the metronidazole and the immunosuppressant, vitamins or steroids are administered simultaneously or separately, (14)
[127] (10) External preparation for the treatment or prevention of atopic dermatitis, wherein the nitroimidazole derivative is tinidazole,
[128] External preparation for the treatment or prevention of facial atopic dermatitis, wherein the nitroimidazole derivative is tinidazole (11),
[129] External preparation for the treatment or prevention of atopic dermatitis in children, wherein the nitroimidazole derivative is tinidazole (12)
[130] (13) external preparation for improving the appearance of skin, pigmentation or scars, wherein the nitroimidazole derivative is tinidazole;
[131] (14) External preparation for treating or preventing psoriasis, wherein the nitroimidazole derivative is tinidazole,
[132] (15) External preparations for the treatment or prophylaxis of liquid odor, body odor or odor, wherein the nitroimidazole derivative is tinidazole,
[133] (10) External preparations for the treatment or prevention of atopic dermatitis, wherein the nitroimidazole derivative is tinidazole and the tinidazole and the antifungal agent, the immunosuppressive agent, the steroid agent or a combination thereof are administered separately or simultaneously.
[134] (10) External preparations for the treatment or prophylaxis of atopic dermatitis, wherein the nitroimidazole derivative is tinidazole and the tinidazole and the immunosuppressant, steroid, or combination of antifungal and steroid agents are administered simultaneously or separately. ,
[135] (14) Treatment of psoriasis, in which the nitriimidazole derivative is tinidazole, in which tinidazole and antifungal agents, immunosuppressive agents, vitamins, antiallergic drugs, steroid agents, or a combination thereof are administered simultaneously or separately over time (14) Prophylactic external preparations,
[136] The nitroimidazole derivative is tinidazole and is an external preparation for the treatment or prevention of psoriasis in which tinidazole and an immunosuppressant, vitamins or steroids are administered simultaneously or separately over time.
[137] Subjects to improvement, treatment or prevention in the above include diseases in other mammals (eg dogs or cats) in addition to diseases of humans.
[138] The formulation of the external preparation for skin diseases of the present invention is not particularly limited as long as it is a commonly used formulation, but is preferably a cream, lotion, shampoo, gel, rinse, lotion, emulsion, pasta, shaving cream, foundation, colon, Packs, ointments, attachments, semisolids, solids or liquids. In particular, in the treatment of atopic dermatitis of the head, since a cream or ointment is difficult to use, external preparations such as shampoo, gel, rinse and the like are useful.
[139] In the external preparation for skin diseases of the present invention, the concentration of the nitroimidazole derivative is not particularly limited as long as it is a concentration exhibiting an effect, but preferably 0.1-20% by weight, more preferably 1.0-10% by weight based on the weight of the preparation. %, Still more preferably 1.5-10% by weight, most preferably 1.5-5% by weight.
[140] In the external preparations for skin diseases of the present invention, the pH of the entire formulation is not particularly limited as long as it is usually used, but is preferably 2.0 to 9.0, more preferably 3.0 to 9.0, still more preferably 4.0 to 9.0 to be.
[141] In the present invention, the nitroimidazole derivatives are external preparations for the treatment or prevention of atopic dermatitis, external preparations for the improvement of skin blemishes, pigmentation or scars, external preparations for the treatment or prophylaxis of psoriasis, and the treatment or prevention of odor, body odor or drunkenness. Used to prepare external preparations.
[142] In the present invention, the treatment or prevention of atopic dermatitis, improvement of the appearance of the skin, pigmentation or scarring, treatment or prevention of psoriasis and liquid odor, body odor or odor by using an external preparation for skin diseases containing nitroimidazole derivatives Treatment or prevention is done.
[143] Table 1 shows specific compounds included in the nitroimidazole derivatives of the present invention. However, the nitroimidazole derivative contained in this invention is not limited to these.
[144] In Table 1, Me represents a methyl group, Et represents an ethyl group, Pr represents a propyl group, iPr represents an isopropyl group, Bu represents a butyl group, Pn represents a pentyl group, Hx represents a hexyl group, and Ac Represents an acetyl group, Bn represents a benzyl group, Bz represents a benzoyl group, Car represents a carbamoyl group, and Mor represents a morpholino group.
[145]
[146] TABLE 1
[147]
[148]
[149]
[150]
[151] ㅓ
[152] ㅓ
[153]
[154]
[155]
[156]
[157]
[158]
[159]
[160] ㅓ
[161]
[162]
[163]
[164]
[165]
[166]
[167]
[168]
[169]
[170]
[171]
[172]
[173] In Table 1, preferred compounds are 1, 21, 23, 28, 29, 43, 50, 54, 55, 56, 57, 58, 135, 136, 137, 138, 139, 140, 141, 142, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 175, 176, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 191, 192, 193, 194, 195, 196, 197, 198, 209, 210, 268, 290, 291, 292, 293, 294, 295, 296, 308, 309, 316, 324, 401, 402, 403, 404, 405, 406, 459, 460, 461, 462, 493, 562, 568 or 673, more preferably 28, 29, 43, 54, 135, 136, 137, 138 , 139, 140, 141, 142, 157, 158, 159, 160, 161, 162, 163, 175, 177, 178, 179, 180, 181, 182, 183, 191, 196, 197, 198, 290, 291 , 292, 293, 294, 295, 296, 402, 459 or 673, more preferably
[174] 43) 4- (2-nitro-1H-imidazol-1-yl) ethyl morpholine (common name: nimorazol),
[175] 135) 1,2-dimethyl-5-nitro-1H-imidazole (common name: dimethidazole),
[176] 157) 2- (2-methyl-5-nitroimidazol-1-yl) ethanol (common name: metronidazole),
[177] 163) 1- (2-ethylsulfonylethyl) -2-methyl-5-nitroimidazole (common name: tinidazole),
[178] 176) (2- (2-methyl-5-nitroimidazol-1-yl) ethylthiocarbamic acid methyl ester (common name: carnidazole),
[179] 183) 1- (2-methyl-5-nitroimidazol-1-yl) propan-2-ol (common name: Cecnidazole),
[180] 191) 1-chloro-3-methyl-5-nitroimidazol-1-yl) propan-2-ol (common name: onidazol),
[181] 402) 2-carbamoyloxymethyl-1-methyl-5-nitro-1H-imidazole (common name: ronidazole),
[182] 459) α-methoxymethyl-2-nitroimidazole-1-ethanol (common name: misonidazole), or
[183] 673) 1-methyl-2- (1-methylethyl) -5-nitroimidazole (common name: ipronidazole), most preferably,
[184] 157) 2- (2-methyl-5-nitroimidazol-1-yl) ethanol (common name: metronidazole), or
[185] 163) 1- (2-ethylsulfonylethyl) -2-methyl-5-nitroimidazole (common name: tinidazole).
[186] The nitroimidazole derivative contained in the external preparation of the present invention is a known compound or can also be obtained by the following A to C methods.
[187]
[188] In said A method-C method, R <^1> -R <^4> represents the same meaning as the above-mentioned, R <^3> and R <^4> is the same or different, represents a hydrogen atom or arbitrary organic group, R <^1a> is R mentioned above ^The functional groups on ¹ or R ¹ are suitably protected according to known methods as required (e.g., "Protective Groups in Organic Synthesis", Greene, TW; Wuts, PGM John Wiley & Sons: New York, 1999., etc.). and, also, shows that it is substituted by a suitable functional group to obtain a functional group of interest by a known substitution reaction according to the need functional group on R ^1, R ² a is a necessary functional group on the above-mentioned R ² or R ² According to the known method according to the method, it is appropriately protected, and furthermore, the functional group on R ² is optionally substituted with a suitable functional group which can obtain a desired functional group by a known substitution reaction, and R ³ a represents R ³ And are properly protected according to known methods, depending on the required functional groups on R ^3, also, that it is substituted with an appropriate functional group that can be obtained a functional group of interest by a known substitution reaction according to the need to functional groups on R ³ R ⁴ a is R ⁴ , or a functional group on R ⁴ is suitably protected according to a known method as necessary, and a functional group on R ⁴ is optionally required by a known substitution reaction. It represents substituted by the appropriate functional group obtained, and Y represents a leaving group.
[189] Hereinafter, each process of A method-C method is explained in full detail.
[190] (A law)
[191] (A-1)
[192] This step is a step of producing compound (III) by reacting compound (II) obtained easily or from R ^2a -Y with a known catalyst or in the presence or absence of a base catalyst in an inert solvent.
[193] Solvents to be used include, for example, water; Aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; Aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; Esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; Ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone; Nitro compounds such as nitroethane and nitrobenzene; Nitriles such as acetonitrile and isobutyl nitrile; Amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone and hexamethylphosphotriamide; Sulfoxides such as sulfolane; Although pyridines are mentioned, Preferably they are water or pyridine.
[194] As a base catalyst used, For example, alkali metal hydroxides, such as sodium hydroxide and potassium hydroxide; Alkali metal carbonates such as sodium carbonate and potassium carbonate; Alkali metal alkoxides such as sodium methoxide, sodium ethoxide; Organic bases such as triethylamine, pyridine and dimethylaminopyridine; Ammonia water etc. are mentioned, Preferably it is alkali metal hydroxide.
[195] Although reaction temperature changes with raw material compounds, a solvent, a reagent, and a base catalyst used, they are 0 degreeC-200 degreeC normally, Preferably they are 20 degreeC-130 degreeC.
[196] Although reaction time changes with raw material compounds, a solvent, a reagent, a base catalyst, and reaction temperature used, they are normally 10 minutes-3 days, Preferably they are 1 hour-10 hours.
[197] After completion of the reaction, the target compound (III) of the reaction is, for example, neutralizing the reaction solution, the reaction mixture is concentrated, washed with water and an immiscible organic solvent such as ethyl acetate, and then washed with water. It is obtained by isolate | separating the organic layer or water layer containing and distilling a solvent off.
[198] If necessary, the obtained compound can be further purified by conventional methods such as recrystallization, silica gel column chromatography, and the like.
[199] Moreover, when the obtained compound is the target compound (Ia), and deprotection and conversion of a functional group are not needed, a compound (Ia) can be obtained without going through the A-2 process demonstrated below.
[200] (A-2 process)
[201] This step is a step of obtaining compound (Ia) by subjecting compound (III) obtained from a known or (A-1) to an inert solvent, if necessary, followed by a deprotection reaction, if necessary, or simultaneously. to be.
[202] Although the substitution reaction of this process differs according to the target substituent, there will be no limitation in particular if it is a reaction from which a desired functional group is obtained, and it is described in literature [for example, "Aliphatic Nucleophilic Substitution", Hartshorn, Cambridge University Press: Cambridge (1973), Chem . Soc. Rev., 19 , 83 (1990), Carbocation Chem., 1 , 121 (1989), etc.].
[203] In addition, although the deprotection reaction of this process changes with a protecting group, if a desired functional group is obtained, there will be no limitation in particular, and it is described in literature (for example, "Protective Groups in Organic Synthesis", Greene, TW; Wuts, PGM John Wiley & Sons). (New York, 1999., etc.).
[204] (B law)
[205] (B-1)
[206] This step is a step of producing compound (V) by reacting compound (IV) and R ^1a -Y which are easily obtained from known or known ones in the presence or absence of a base catalyst in an inert solvent.
[207] As a solvent used, For example, Water; Aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; Aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; Esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; Ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone; Nitro compounds such as nitroethane and nitrobenzene; Nitriles such as acetonitrile and isobutyl nitrile; Amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone and hexamethylphosphorotriamide; Sulfoxides such as sulfolane; Although pyridines are mentioned, Preferably they are water or pyridine.
[208] Base catalysts to be used include, for example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; Alkali metal carbonates such as sodium carbonate and potassium carbonate; Alkali metal alkoxides such as sodium methoxide, sodium ethoxide; Organic bases such as triethylamine, pyridine and dimethylaminopyridine; Ammonia water etc. are mentioned, Preferably it is alkali metal hydroxide.
[209] Although reaction temperature changes with raw material compounds, a solvent, a reagent, and a base catalyst used, they are 0 degreeC-200 degreeC normally, Preferably they are 20 degreeC-130 degreeC.
[210] Although reaction time changes with raw material compounds, a solvent, a reagent, a base catalyst, and reaction temperature used, they are normally 10 minutes-3 days, Preferably they are 1 hour-10 hours.
[211] After completion of the reaction, the target compound (V) of the present reaction includes, for example, neutralizing the reaction solution, concentrating the reaction mixture, washing with water and adding an immiscible organic solvent such as ethyl acetate, and then including the desired compound. It is obtained by isolate | separating the organic layer or aqueous layer to distill, and distilling a solvent off.
[212] If necessary, the obtained compound can be further purified according to conventional methods, for example, recrystallization, silica gel column chromatography, and the like.
[213] Moreover, when the obtained compound is a desired compound (Ia) and deprotection and a change of a functional group are not needed, a compound (Ia) can be obtained without going through the B-2 process demonstrated below.
[214] (B-2 process)
[215] This process is a well-known inert solvent, or the compound (V) obtained by (B-1) as needed is substituted by reaction, and, at the same time, a deprotection reaction is carried out as needed, and compound (Ia) is carried out. It is a process of obtaining.
[216] This process is performed similarly to the A-2 process.
[217] (C method)
[218] (C-1)
[219] This step is a step of producing compound (VII) by reacting compound (VI) and R ^2a -Y which are easily obtained from known or known ones in the presence or absence of a base catalyst in an inert solvent.
[220] This process is performed similarly to the process A-1.
[221] If necessary, the obtained compound can be further purified according to conventional methods, for example, recrystallization, silica gel column chromatography, and the like.
[222] Moreover, when the obtained compound is a desired compound (Ib) and deprotection and a change of a functional group are not needed, a compound (Ib) can be obtained without going through the C-2 process demonstrated below.
[223] (C-2 process)
[224] In this step, compound (Ib) is obtained by subjecting compound (VII) obtained from a known or (C-1) compound to an inert solvent, if necessary, followed by a deprotection reaction, if necessary, or simultaneously. It is a process.
[225] This process is performed similarly to the A-2 process.
[226] In addition, the compounds of the present invention are disclosed by a known method [for example, the method of preparing metronidazole by Jacob et al. (US Pat. No. US 2,944,061), and the method of preparing tinidazole is disclosed by Butler et al. (US Pat. 376,311). In addition, for example, the preparation of a derivative having a dihydropyridine ring is disclosed by Gorlitzer et al. [Pharmazie (1999), 54 (12), 889-892], and the preparation of the carbamate derivative is disclosed by Hay et al. [Bioorg . Med. Chem. Lett. (1999), 9 (15), 2237-2242, and the preparation of a derivative having an isoquinoline ring is disclosed by Parveen et al. [Bioorg. Med. Chem. Lett. (1999), 9 (15), 2031-2036, and a method for producing a derivative having a pyrrole ring is disclosed by Anadlu et al. [Eur. J. Med. Chem. (1999), 34 (3), 275-278, and a method for producing a derivative having a benzene ring substituted with a carboxy group is disclosed by Everett et al. [Bioorg. Med. Chem. Lett. (1999), 9 (9), 1267-1272, and the preparation of derivatives having halogen-substituted benzene rings and derivatives having pyridine rings is disclosed by Shafiee et al. Hetrocycl. Chem. (1998), 35 (3), 607-610, and the method for producing a derivative having an arylcarbonyloxy group is disclosed by Bowden et al. [Eur. J. Med. Chem. (1997), 32 (12), 995-1000, and a method for producing a derivative having a dioxolane ring is disclosed by Baji et al. [Eur. J. Chem. (1997), 32 (7-8), 637-650, and a method for producing a derivative having a hydroxyaryl group is disclosed by Arrendondo et al. [Bioorg. Med. Chem. Lett. (1996), 6 (15), 1781-1784, and a method for producing a derivative having a phenylamide group is disclosed by Shafiee et al. Sci. Islamic Repub. Iran (1995), 6 (1), 25-8], and the preparation of derivatives having alkylthio groups is disclosed by Rao et al. Chem. Soc. Perkin Trans. 1 (1994), (17), 2399-2402, the preparation method of the derivative which has a hydroxyalkyl aryl group is disclosed by Furlan etc. (European Patent No. EP535528), and the manufacturing method of the derivative which has (beta) lactam ring is Bertola (European Patent Publication No. EP490450), the preparation method of the aminoalkylphenyl acyl derivative is disclosed by Bundgaargd et al. (International Patent Publication No. WO90 / 08128), and the production method of the derivative having an aralkylcarbonyloxy group is described in Rao et al. Initiated by Indian J. Chem., Sect. B (1990), 29B (11), 1034-40, and the preparation of N-substituted aminomethylbenzoate derivatives is disclosed by Jansen et al. [Int. J. Pharm. (1990), 58 (2), 143-53, and the preparation of derivatives having a pyridine ring is disclosed by Alcalde et al. (Farmaco (1989), 44 (11), 1095-107). The manufacturing method of metronidazole / secnidazole following the transition reaction of nitro group is disclosed by Buforn et al. (US Pat. No. US492591), and the preparation of dimethidazole using dimethyl sulfate is disclosed by Buforn et al. (US Pat. No. US4925952). The method for producing metronidazole and cecindazole using alkylene sulfate is disclosed by Bonnamas et al. (US Pat. No. US4925949), and the method for preparing derivatives having alkylcarbonyloxy groups is disclosed by Johansen et al. [Int. J. Pharm. (1986), 32 (2-3), 199-206, and a method for producing a derivative having a dextran ring is disclosed by Vermeersch et al. [Bull. Soc. Chim. Belg. (1985), 94 (8), 591-6, the preparation of L-cysteine derivatives is disclosed by Reiner (European Patent Publication EP140395), and the preparation of ester derivatives of amino acid residues is carried out by Cho. The preparation method of the derivative which has been disclosed (European Patent Publication No. EP127274) and has a hydroxyalkylaryl group is disclosed by Tessitore (European Patent Publication No. EP11657), and the manufacturing method of the derivative which has a hydroxyalkylaryl group is disclosed by Scalesciani ( European Patent Publication No. EP103100, which discloses the preparation of ester derivatives of amino acid residues by Bundgaard et al. [Int. J. Pharm. (1984), 18 (1-2), 67-77, the preparation of ester derivatives of dimethylglycine residues is disclosed by Thorbek et al. (European Patent Publication No. EP96870), and 2-nitroimi having an aryloxy ring. The preparation method of the dazole derivative is disclosed by Hofheinz (European Patent Publication EP81719), and the production method of the platinum salt derivative is disclosed by Bales et al. [J. Chem. Soc., Chem. Comm. (1983), (8), 432-3, the preparation of retinoic acid derivatives is disclosed by Whitefield et al. (UK Patent Publication No. GB2097783), and the production of derivatives having a hydroxyalkylaryl group is disclosed by Bononi. (US Pat. No. US4463012), the preparation of derivatives having alkylsulfonylphenyloxy groups and derivatives having alkylthiophenyloxy groups is disclosed by Winkelmann et al. (UK Patent Publication No. GB1541280, GB1590974), and acetamido-substituted phenyloxy The preparation of derivatives having groups is disclosed by Winkelmann et al. [Arzneim. -Forsch. (1978), 28 (5), 739-49, and the preparation of derivatives having a phenylcarbamate group and derivatives having a hydrazinecarboxyl group is disclosed by Cavalleri et al. Med. Chem. (1978), 21 (8), 781-4, and the preparation of derivatives having hydrazine groups is disclosed by Winkelmann et al. [Arzneim. -Forsch. (1977), 27 (12), 2251-63, the preparation of 2-nitroimidazole derivatives having a phenyl carbamate group is disclosed by Cavalleri et al. (US Pat. No. US4113953), and 2 having an allen group. -The preparation of nitroimidazole derivatives is disclosed by Cavalleri et al. [J. Med. Chem. (1977), 20 (11), 1522-5, the preparation method of the derivative which has a substituted phenoxy group was disclosed by Winkelmann etc. (US Pat. No. US4031232), and the 2-nitroimidazole derivative which has a hydroxyl group The production method is disclosed by Assandri et al. (UK Patent Publication No. GB1480192), the production method of a derivative having an alkylcarbonyloxy group is disclosed by Hoffer (UK Patent Publication No. GB1453417), and the production method of a derivative having a quinoline ring is disclosed by Kreider et al. (US Pat. No. US3910925, US3828056), the method for producing dimethidazole using formic acid as a solvent is disclosed by Frank et al. (UK Patent Publication No. GB1493496), and the method for producing metronidazole using alkylene oxide is Frank et al. (UK Patent Publication No. GB1481349), and the production method of a derivative having a phenylamide group is disclosed by Heeres et al. (US Patent Call and is US3928374), epichlorohydrin disclosed sludge the preparation of imidazole such as by using a Hoffer Hi gave [J. Med. Chem. (1974), 17 (9), 1019-20, the preparation of 1-methyl-5-isopropyl-2-nitroimidazole is disclosed by Martin et al. (US Pat. No. US3828064), and carboxyimidamide The preparation of derivatives having groups is disclosed by Rufer et al. (US Pat. No. US3966732), and the preparation of derivatives having carbamate groups and 2-nitroimidazole derivatives is disclosed by Challier et al. (UK Patent Publication No. GB1352288). The preparation of metronidazole using sulfuric acid is disclosed by Muhlbrod (UK Patent Publication No. GB1301225), and the preparation of 2-nitroimidazole derivatives having a phenylhydrazone group or an alkenyl group is disclosed by Cavalleri et al. [J. Hetrocycle Chem. (1972), 9 (5), 979-84; the preparation of derivatives having carbooxymidyl groups is disclosed by Papaioannou (US Pat. No. US3694452), and the preparation of derivatives having alkenyl groups is carried out by Hoffer et al. Disclosed (US Patent No. US3652579), the preparation method of 2-benzyl derivative is disclosed by Hoff et al. (UK Patent Publication No. GB1336228), and the manufacturing method of cecindazole by nitrification with nitric acid and subsequent hydrolysis is Jeanmart (UK Patent Publication No. GB1278757), and the preparation of cecnidazole and 1- (2-methyl-5-nitroimidazol-1-yl) 2-propanol is disclosed by Jeanmart et al. (UK Patent Publication No. GB1278758), the preparation of 1,5-dimethyl-2-nitroimidazole and 1,4,5-trimethyl-2-nitroimidazole is disclosed by Lancini et al. (UK Patent Publication No. GB1114154), and a nitroso group Preparation of derivatives Kulsa (US Pat. No. US3711495), the preparation method of the derivative having a hydroxyl group is disclosed by Chemerda et al. (US Pat. No. US3584007), and the preparation method of the 2-nitroimidazole derivative substituted with an alkyl group is disclosed by Lancini et al. South African Patent Publication No. ZA6905670, a method for producing a derivative (including tinidazole) having a sulfonyl group is disclosed by Miller et al. Med. Chem. (1970), 13 (5), 849-52, the preparation method of 2-nitroimidazole derivatives having a hydroxy group is disclosed by Lancini et al. (UK Patent Publication No. GB1229170), and the production method of derivatives having a halogenated alkyl group Initiated by Kajfez et al. [Farm. Glas. (1969), 25 (2), 49-54, and the preparation of 4-iodine-1,2-dimethyl-5-nitroimidazole is disclosed by Hoffer et al., J. Heterocycle Chem. (1966), 3 (4), 454-8].
[227] As the dosage form of the external preparation for skin diseases of the present invention, for example, an ointment, a cream, a lotion, a functional attachment or a non-functional attachment, a shampoo, a gel, a rinse, a lotion, an emulsion, a pasta, Shaving creams, foundations, colons, packs, semi-solids, solids or liquids, and these preparations can be used as needed, including antioxidants (e.g., carboxylic acids such as ascorbic acid, citric acid; tocopherol, dibutylhydroxy). Phenols such as toluene), preservatives (for example, carboxylic acids such as dehydroacetic acid, salicylic acid, disodium edetate; ethyl paraoxybenzoate, methyl paraoxybenzoate, isopropyl paraoxybenzoate and thymol); Same phenols), wetting agents (e.g., glycols such as glycerin, propylene glycol, dipropylene glycol, 1,3-butylene glycol; organic salts such as hyaluronic acid; And the like; viscous agents (e.g., high molecular compounds such as polyethylene glycol; celluloses such as sodium carboxymethyl cellulose, carboxypropyl cellulose), buffers (e.g., citric acid, lactic acid, tartaric acid, Organic acids such as hydrochloric acid, boric acid; inorganic acids such as sodium dihydrogen phosphate, sodium citrate; organic bases such as triethanolamine; inorganic bases such as sodium hydroxide, potassium hydroxide), adsorbents (e.g. Hydrous aluminum silicates such as kaolin, bentonite; inorganic salts such as alumina magnesium hydroxide, aluminum hydroxide), bases (for example, white petrolatum, Tween60, Tween80, liquid paraffin, beeswax, petrolatum, castor oil, Silicone oil, hardened castor oil, natural rubber, palm oil fatty acid diethanolamide, polyoxyethylene hardened castor oil, natural rubber Organic materials such as tex, 1,3-pentadiene copolymer resins; polybutene, synthetic rubber SBR, monostearic acid polyethylene glycol, monostearic acid polyoxyethylene glycol, polyoxyethylene setstearyl ether, polyoxyethylene oleyl High molecular compounds such as methyl ether, silicone, starch acrylate 300, sodium polyacrylate, n-butyl copolymer of methacrylic acid and acrylic acid, and carboxyvinyl polymer; Fatty acids such as stearic acid; Alcohols such as cetanol and myristyl alcohol; Fatty acid esters such as myristic acid octadodecyl, myristic acid isopropyl, octanoic acid cetyl), solvents (e.g. ethanol, isopropanol, 1,3-butylene glycol, n-octadecyl alcohol Carbohydrates such as crotamiton, tri (caprylic acid and capuron) glycerin, stabilizers (for example, inorganic salts such as sodium metaphosphate, zinc oxide and titanium oxide; polyoxyethylene lauryl sulfate) Organic salts such as ether sodium sulfate, sodium lauryl sulfate), pressure sensitive adhesives (e.g., high molecular compounds such as sodium polyacrylate, dipropylene glycol), emulsifiers (e.g., monoolefin acid sorbitan) , Carbohydrates such as monoolefinic polyoxyethylene sorbitan, D-sorbitol, monolauric acid polyglycerine, polyoxyethylene lauryl ether sodium sulfate), surfactants (e.g., High molecular compounds such as polyglycerin monolauric acid, polyoxyethylene oleyl alcohol ether), squalene, diluent, span 60, span 80, gelatin, propylparaben, methylparaben, lauryldimethylaminoacetic acid betaine, palm oil For example, the following is described using additives such as fatty acid diethanolamide, N- [alkyl (12,14) oxy-2-hydroxypropyl] -L-arginine hydrochloric acid solution, silicone oil, jojoba oil, flavoring agent, and the like. As can be produced by a conventional method.
[228] "Fragrance" which can be used should just be what can be generally used, such as food, cosmetics, and medicines, As a natural fragrance, for example, rose, lavender, orange, etc. can be mentioned as a fragrance obtained from a plant, The fragrance obtained from an animal Examples thereof include civet oil (scented) obtained from musk deer and castium oil (smelted oil) obtained from dissociation. Examples of the synthesized fragrance include limonene, β-cariopyrene, and farnesol (farnesol). ), Citral, γ-undecalactone, indole, riral and the like.
[229] The ointment is prepared by, for example, warming and stirring the active ingredient and the substrate, and then cooling the mixture to room temperature under stirring.
[230] Creams are prepared, for example, by first preparing a substrate under heat stirring, adding the active ingredient itself or a solution containing the same under heat stirring, and cooling the resulting emulsion to room temperature.
[231] The lotion agent is added, for example, the active ingredient itself or a solution containing the same to an oily substrate or a mixed substrate of a heated molten oily substrate and an aqueous substrate under heating and stirring, and then an aqueous substrate is added to bring the resulting liquid to room temperature. It is prepared by cooling.
[232] The waterborne additive is, for example, added to the mixed substrate of the heated melted oil-based base material and the aqueous base material with stirring, and the active ingredient itself or a solution containing the same is added to the nonwoven fabric by heating and stirring. Introduce and cut to moderate size.
[233] The non-functional attachment agent is added, for example, to the mixed substrate of the warm-melted oil-based substrate by heating stirring with the active ingredient itself or a solution containing the same, followed by adding it to the warm-fused mixture of synthetic resin with stirring, The obtained solid is spread on a nonwoven fabric or a woven fabric, and is cut into an appropriate size.
[234] The gel was dissolved, for example, by dissolving the gel base material, followed by the addition of a hydrophilic organic solvent, followed by the addition of the active ingredient. The solvent was added to this under warming. Subsequently, the mixture is neutralized under stirring, and then cooled to room temperature to prepare.
[235] The shampoo is prepared by, for example, warming purified water, adding an active ingredient, anionic surfactant, moisturizer, etc., if necessary, dissolving it uniformly and then dissolving it uniformly.
[236] For example, the pasta agent is prepared by adding fats and oils to beeswax, heating and melting to add pigments, hydrocarbons, and active ingredients, adding a moisturizer and the like to make it homogeneous, and then cooling the product.
[237] The rinse agent is heated and melted, for example, by adding an aqueous component such as an active ingredient, a humectant, and a cationic surfactant to purified water. Heat-melted things of oily components, such as a higher alcohol and a hydrocarbon, are added to this, stirred, and made uniform, and cooled and manufactured.
[238] The liquid preparation is prepared by, for example, adding and mixing an active ingredient, a humectant, a lower alcohol, and the like into purified water, and adding a water-soluble polymer if necessary. If necessary, the mixture may be prepared by heating and melting the mixture of oily components such as fatty acids, fats and oils and fatty acid esters.
[239] Soap agents can be produced by, for example, adding alkali to a heated fat or oil. Moreover, lower alcohol is added and stirred to fats and oils, and it manufactures by adding alkali, purified water, and a moisturizer. It can also be manufactured by adding a polysaccharide to it, mixing it well, adding a dye, a fragrance, and an active ingredient, making it uniform, and then cooling and drying.
[240] The milky solution is melted by adding an active ingredient, a moisturizing agent, etc. to purified water, and heat-melting it, and adding it to the heat-melted thing of oily components, such as surfactant and a higher alcohol, and stirring it uniformly, and manufacturing it by cooling.
[241] Shaving cream is heat-melted, for example by adding an active ingredient, a moisturizer, an alkali, etc. to purified water. This is added to the heat-melted thing by adding necessary things, such as a fatty acid, fatty acid ester, fats and oils, and after mixing uniformly, it cools and manufactures.
[242] For example, the lotion is prepared by adding an active ingredient, a thickener, a humectant, and the like to purified water, followed by adding a mixture of oily ingredients such as alcohols, surfactants, and fats and oils.
[243] The foundation is prepared by, for example, mixing finely pulverized clay mineral pigments and colored pigments, adding fatty acids, higher alcohols and the like, fats and oils, esters and the like, and mixing them uniformly.
[244] The colon is prepared by, for example, adding and mixing an active ingredient, a humectant, a lower alcohol, and the like into purified water, adding a water-soluble polymer if necessary, and then adding a flavoring agent after cooling. If necessary, the mixture may be prepared by heating and melting them to a mixture of oily components such as fatty acids, fats and oils and fatty acid esters, and adding flavors after cooling.
[245] Packs vary in their raw materials, depending on the formulation. If it is a jelly type, an active ingredient, a moisturizer, an alkali, etc. are melt | dissolved in purified water, for example, a thickener, water-soluble polymer, etc. are added and stirred. Next, alcohols, surfactants, etc. are added and dissolved, and it cools and manufactures.
[246] Moreover, in manufacturing the external preparation for skin diseases of this invention, unless it inhibits the dermatologically applicable effect which combined these chemical | medical agents, it may also add other drug active ingredients in addition to these. As these active ingredients, for example, known refreshing ingredients, exfoliants, cortical inhibitors, anti-ginus agents, fungicides, antiseptics, and the like can be exemplified, and specifically, menthol and salicylic acid can be exemplified. Estradiol, glytilinic acid, benzalconium chloride, phenol, camphor and the like; Narcotics and stimulants such as ethyl morphine hydrochloride, oxycodine hydrochloride, cocaine hydrochloride, pettidine hydrochloride, methane petamine hydrochloride, dl-methyl ephedrine hydrochloride, morphine hydrochloride, fentanyl citrate, levalollate, and the like; Topical fungicides such as forbidden iodine, iodine form and the like; Enzyme preparations such as lysozyme chloride, streptokinase, streptornase tripucine, deoxyribonuclease and the like; Herbal medicines such as syconx, lotex and the like; Hemorrhoidal medicines, such as E. coli, Epidihydrocholesterin, and tribenoside; Hemostatic agents such as thrombin, cellulose oxide, sodium alginate, and the like.
[247] Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples.
[248] EXAMPLE
[249] Example 1 External Ointment
[250] Prescription: Metronidazole (2g), Tween80 (1g), Propylene Glycol (28g), White Vaseline (69g)
[251] Preparation Method: A mixture of Tween 80, propylene glycol and metronidazole was added to white petroleum jelly with warm stirring. It was warmly dispersed with continuous stirring. Then, the mixture was slowly cooled to a temperature of about 25 ° C. and collected in a suitable container.
[252] Example 2 External Ointment
[253] Prescription: Metronidazole (2g), Propylene Glycol (5g), Polyoxyethylene Glycol Monostearate (4g), Liquid Paraffin (10g), White Vaseline (60g), Distilled Water (total amount of 100g)
[254] Method of preparation: Distilled water, propylene glycol, and metronidazole were heated and dispersed with stirring to a temperature of about 70 ° C, and polyoxyethylene glycol monostearate, liquid paraffin, and white petrolatum were slowly added at a temperature of about 70 ° C. did. This was slowly cooled to a temperature of about 25 ° C. with continuous stirring and collected in a suitable container.
[255] Example 3 External Cream
[256] Prescription: metronidazole (2g), stearic acid (5g), polyoxyethylenecetostearyl ether (12E.O.) (0.5g), polyoxyethylenecetostearyl ether (20E.O.) (0.5g), theta Knoll (5g), cetyl octanoate (5g), liquid paraffin (5g), beeswax (1g), glycerin (5g), 1,3-butylene glycol (5g), triethanolamine (5g), hydrochloric acid (2.7g) , Distilled water (amount that becomes 100 g)
[257] Preparation method: about 70-75 polyoxyethylenecetostearyl ether (20E.O.), polyoxyethylenecetostearyl ether (12E.O.), stearic acid, cetanol, cetane octanoate, liquid paraffin and beeswax While stirring the solution melt | dissolved at the temperature of ° C, the solution which melt | dissolved distilled water, glycerin, 1, 3- butylene glycol, and triethanolamine was added slowly, maintaining the temperature of about 70 degreeC. Then, the dissolved solution of distilled water, metronidazole and hydrochloric acid was slowly heated to about 70 ° C. The resulting emulsion was cooled to a temperature of about 25 ° C. with continuous stirring. The resulting cream was collected in a suitable container.
[258] Example 4 External Cream
[259] Prescription: metronidazole (1.8g), stearic acid (2g), monostearate glycol (12g), monostearic acid polyoxyethylene glycol (3g), polyoxyethylenecetostearyl ether (12E.O.) (1g), Polyoxyethylenecetostearyl ether (20E.O.) (1 g), cetanol (2 g), liquid paraffin (5 g), cetyl octanoate (5 g), ethyl paraoxybenzoate (0.3 g), silicone (1 g), Beeswax (1.5g), 1,3-butylene glycol (7g), glycerin (5g), sodium hydroxide (suitable), hydrochloric acid (suitable), distilled water (total amount 100g)
[260] Method of preparation: Metronidazole was added to a solution of distilled water, 1,3-butylene glycol and glycerin, and hydrochloric acid was added until the metronidazole was completely dissolved. The solution was warmed to about 70 ° C. and adjusted to pH6.9 with sodium hydroxide. This is an oily stearic acid, monostearic acid glycol, monostearic acid polyoxyethylene glycol, polyoxyethylene cetostearyl ether (12E.O.), polyoxyethylene cetostearyl ether (20E.O.), cetanol, Liquid paraffin, cetyl octanoate, silicon, ethyl paraoxybenzoate and beeswax were slowly added to the liquid which had been adjusted and melted to a temperature of about 70 to 75 ° C. The resulting emulsion was cooled to a temperature of about 25 ° C. with continuous stirring, and the resulting cream was collected in a suitable container.
[261] Example 5 External Cream
[262] Prescriptions: metronidazole (1.8g), n-octadecyl alcohol (5g), stearic acid (5g), triethanolamine (5g), liquid paraffin (10g), disodium edate (0.25g), glycerin (10g), thymol (0.25 g), hydrochloric acid (amount), distilled water (amount of 100 g)
[263] Method of preparation: A mixture of n-octadecyl alcohol, stearic acid and liquid paraffin is heated and melted while stirring to maintain a temperature of about 70 ° C., followed by addition of metronidazole, and the dissolution mixture of distilled water, glycerin and triethanolamine is about 70 It was added slowly while maintaining at a temperature of ℃ while stirring. Then disodium edetate and thymol were added. The resulting emulsion was adjusted to pH 6.8 with hydrochloric acid, then cooled to a temperature of about 25 ° C. with continuous stirring and collected in a suitable container.
[264] Example 6 External lotion
[265] Prescriptions: metronidazole (2g), stearic acid (4g), cetanol (1g), polyoxyethylenecetostearyl ether (20E.O.) (1g), triethanolamine (0.2g), glycerin (5g), isopropanol ( 10 g), distilled water (amount of which becomes 100 g)
[266] Preparation Method: Cetanol, polyoxyethylenecetostearyl ether (20E.O.), stearic acid and metronidazole were heated and melted with stirring, and a mixed melt of triethanolamine, distilled water and glycerin was added. Next, it cooled to the temperature of 40 degreeC, isopropanol was added, and it quenched to the temperature of about 25 degreeC, stirring continuously. After cooling, the sample was collected in a suitable container.
[267] Example 7 External lotion
[268] Prescriptions: metronidazole (1.8g), n-octadecyl alcohol (1g), cetanol (1g), polyoxyethylenecetostearyl ether (12E.O.) (1g), 1,3-butylene glycol (10g) , Tween 80 (1 g), sodium carboxymethyl cellulose (1 g), isopropanol (10 g), distilled water (amount of 100 g total)
[269] Method of preparation: The dissolution mixture of 1,3-butylene glycol and distilled water was adjusted to a temperature of about 70 ° C. and continuously stirred, to which n-octadecyl alcohol, cetanol and polyoxyethylenecetostearyl ether (12E) were added. The material which adjusted the heated melt of .O.) To about 70 degreeC was added slowly. While stirring, the substance which heated and mixed metronidazole, carboxymethyl cellulose sodium, and Tween80 was added. After cooling to a temperature of about 40 ° C., isopropanol was slowly added, cooled to a temperature of about 25 ° C. while stirring, and collected in a suitable container.
[270] Example 8 Functional Attachment
[271] Prescriptions: metronidazole (2 g), kaolin (5 g), liquid paraffin (10 g), glycerin (15 g), sodium carboxymethyl cellulose (5 g), crotamiton (1.5 g), zinc oxide (2 g), Tween 80 (1 g), Gelatin (5 g), sodium polyacrylate (5 g), distilled water (amount of 100 g)
[272] Manufacturing method: Distilled water, carboxymethyl cellulose sodium, and gelatin were heated and melt | dissolved, and this was added, stirring, to what stirred and dispersed zinc oxide, sodium polyacrylate, and a liquid paraffin. Kaolin is added to this, stirring. Subsequently, metronidazole, crotamiton, glycerin, and Tween80 were stirred and warmed to mix, and those adjusted to a temperature of about 60 ° C. were added while stirring and warming. The resulting ointment is spread on a nonwoven fabric at 1000 g per 1 m 2 and cut into a size of 10 cm x 14 cm (containing 280 mg of metronidazole per 14 g of ointment).
[273] Example 9 Functional Attachment
[274] Prescription: metronidazole (2g), sorbitan monooleate (0.5g), polyoxyethylene sorbitan monooleate (0.5g), castor oil (1g), crotamiton (1g), gelatin (1g), kaolin ( 12 g), sodium metaphosphate (0.15 g), 1,3-butylene glycol (5 g), starch acrylate 300 (1 g), sodium polyacrylate (5 g), methacrylic acid and n-butyl copolymer (3 g), D Sorbitol solution (70%) (50g), tartaric acid (1.5g), titanium oxide (1g), alumina magnesium hydroxide (0.25g), dibutylhydroxytoluene (0.2g), distilled water (amount of 100g total)
[275] Production method: A mixture of the distilled water and the appropriate amount of D-sorbitol solution was melted, titanium oxide was added while stirring continuously, followed by addition of appropriate amount of kaolin and D-sorbitol solution. A melt of sodium metaphosphate and distilled water was added to this, a melt of gelatin and distilled water was then added, and a methacrylic acid acrylic acid n-butyl copolymer was further added. To this, a mixed melt of sodium polyacrylate, starch acrylate 300, magnesium alumina hydroxide, 1,3-butylene glycol and castor oil, sorbitan monomonate and polyoxyethylene sorbitan monomonate are added, and metronidazole and crotami A warm mixture of tonnes and dibutylhydroxytoluene was added. Finally, the mixture adjusted to the temperature of 60 degreeC of the remaining D-sorbitol liquid and tartaric acid was added with stirring. The obtained ointment was inverted at 1000 g / m 2 on a nonwoven fabric and cut into a size of 10 cm × 14 cm (containing 280 mg of metronidazole per 14 g of ointment).
[276] (Example 10) Attachment (product made from plaster) which does not contain water
[277] Prescriptions: metronidazole (2 g), liquid paraffin (8 g), dibutylhydroxytoluene (0.2 g), crotamiton (1 g), monostearic acid polyoxyethylene glycol (2 g), polyoxyethylene cetostearyl ether (20E) .O.) (1.8 g), methacrylic acid-acrylic acid n-butyl copolymer (5 g), myristyl alcohol (8 g), natural rubber (20 g), synthetic rubber SBR (37 g), polybutene (15 g)
[278] Method of preparation: Metronidazole, dibutylhydroxytoluene and crotamitone are heated and mixed with stirring, followed by addition of polyoxyethylene glycol monopolystearate, polyoxyethylenecetostearyl ether (20E.O.) and myristyl alcohol. Mix by heating. This was added to the hot melt mixture of natural rubber latex, methacrylic acid acrylic acid n-butyl copolymer, and SBR synthetic latex with continuous stirring. Moreover, liquid paraffin and polybutene were added to this, stirring continuously. The obtained ointment was inverted at 100 g per m 2 on a nonwoven fabric or woven fabric, dried and cut into a size of 10 cm x 14 cm (containing 28 mg of metronidazole per 1.4 g of ointment).
[279] Example 11 External Ointment
[280] Prescription: Tinidazole (2g), Propylene Glycol (28g), Cetyl Octane (5g), White Vaseline (65g)
[281] Production method: To the white petrolatum, propylene glycol was added while stirring and stirring, and the substance which mixed the tinidazole and the cetyl octanoate was added, and it heated and disperse | distributed with continuous stirring. Then, after cooling slowly to the temperature of about 25 degreeC, it put into the suitable container and obtained the external ointment.
[282] Example 12 External Ointment
[283] Prescriptions: tinidazole (2 g), propylene glycol (10 g), monooxystearate polyoxyethylene glycol (5 g), liquid paraffin (20 g), white petrolatum (60 g), distilled water (amount of 100 g total)
[284] Manufacturing method: The thing which mixed and adjusted the temperature of 70 degreeC of distilled water and propylene glycol was stirred, The thing which mixed and adjusted the monostearic acid polyoxyethylene glycol, tinidazole, liquid paraffin, and white petrolatum to the temperature of 70 degreeC was added. After slowly cooling to a temperature of about 25 ° C. with continuous stirring, it was placed in a suitable container to obtain an external ointment.
[285] Example 13 External Cream
[286] Prescriptions: tinidazole (1.8 g), stearic acid (5 g), polyoxyethylenecetostearyl ether (12E.O.) (0.5g), polyoxyethylenecetostearyl ether (20E.O.) (0.5g ), Cetanol (5 g), cetyl octanoate (5 g), liquid paraffin (5 g), beeswax (1 g), glycerin (5 g), 1,3-butylene glycol (5 g), triethanolamine (5 g), hydrochloric acid ( 2.7 g), distilled water (amount of which becomes 100 g)
[287] Preparation method: about 70 oily stearic acid, polyoxyethylenecetostearyl ether (12E.O.), polyoxyethylenecetostearyl ether (20E.O.), cetanol, cetyl octanoate, liquid paraffin and beeswax It melted and stirred at the temperature of -75 degreeC. In this mixture, a solution in which distilled water, glycerin, 1,3-butylene glycol and triethanolamine were dissolved was kept at a temperature of about 70 ° C. and slowly added. Then, a solution in which distilled water, tinidazole and hydrochloric acid were dissolved was slowly added by warming to a temperature of about 70 ° C. The resulting emulsion was cooled to a temperature of about 25 ° C. with continuous stirring, and then collected in a suitable container to obtain a cream.
[288] Example 14 External Cream
[289] Prescriptions: tinidazole (1.8 g), stearic acid (3 g), monostearate glycol (4 g), monostearic acid polyoxyethylene glycol (1 g), polyoxyethylene cetostearyl ether (12E.O.) (0.5 g), polyoxyethylenecetostearyl ether (20E.O.) (0.5 g), cetanol (5 g), liquid paraffin (10 g), cetyl octanoate (5 g), ethyl paraoxybenzoate (0.3 g), silicone (1 g), beeswax (1.5 g), 1,3-butylene glycol (7 g), glycerin (5 g), sodium hydroxide (appropriate), hydrochloric acid (appropriate), distilled water (total amount 100g)
[290] Preparation method: Tinidazole was added to the melt | dissolution of distilled water, 1, 3- butylene glycol, and glycerin, and hydrochloric acid was further added until the tinidazole dissolves completely. The solution is warmed to a temperature of about 70 ° C. and brought to pH6.9 with sodium hydroxide. These are stearic acid, monostearic acid glycol, monostearic acid polyoxyethylene glycol, polyoxyethylene cetostearyl ether (12E.O.), polyoxyethylenecetostearyl ether (20E.O.), cetanol, liquid paraffin , Cetyl octanoate, ethyl paraoxybenzoate, silicon and beeswax were slowly added to the liquid which had been adjusted and melted at a temperature of about 70 to 75 ° C. The resulting emulsion was cooled to a temperature of about 25 ° C. with continuous stirring, and then collected in a suitable container to obtain a cream.
[291] Example 15 External Cream
[292] Prescriptions: tinidazole (2 g), n-octadecyl alcohol (5 g), stearic acid (5 g), triethanolamine (5 g), liquid paraffin (8 g), disodium edate (0.2 g), glycerin (10 g), Thymol (0.2 g), hydrochloric acid (property), distilled water (amount of 100 g)
[293] Method of preparation: A mixture of n-octadecyl alcohol, stearic acid and liquid paraffin is heated and melted while stirring to adjust to a temperature of about 70 ° C., followed by addition of tinidazole, to which a dissolved product of distilled water, glycerin and triethanolamine is added. Was adjusted to a temperature of about 70 ° C. and slowly added while stirring. After adjusting to pH6.8 with hydrochloric acid, disodium edetate and thymol were added continuously with stirring, and it cooled to the temperature of about 25 degreeC, and then collected in the suitable container and obtained the external cream agent.
[294] Example 16 External lotion
[295] Prescriptions: tinidazole (2 g), stearic acid (3 g), cetanol (1 g), polyoxyethylenecetostearyl ether (20E.O.) (0.5 g), triethanolamine (0.2 g), glycerin (5 g) , Isopropanol (10 g), distilled water (amount that becomes 100 g)
[296] Preparation Method: Cetanol, polyoxyethylenecetostearyl ether (20E.O.), stearic acid and tinidazole were heated and melted while stirring, and a mixed melt of triethanolamine, distilled water and glycerin was added. Next, after cooling to a temperature of 40 ° C, isopropanol is added and quenched to a temperature of about 25 ° C with continuous stirring. After cooling, the sample was collected in a suitable container to obtain an external lotion.
[297] Example 17 External lotion
[298] Prescriptions: tinidazole (1.8 g), isopropanol (10 g), n-octadecyl alcohol (10 g), cetanol (5 g), Tween 80 (2 g), 1,3-butylene glycol (10 g), carboxymethyl cellulose sodium (3 g), distilled water (amount that total quantity becomes 100 g)
[299] Production method: n-octadecyl alcohol and cetanol were warmed and melted, which was slowly added to a warm mixture of distilled water, carboxymethyl cellulose sodium, Tween80, 1,3-butylene glycol and tinidazole. Then, it cooled to the temperature of about 40 degreeC, and cooled to about 25 degreeC, adding isopropanol and stirring continuously. It collected in the suitable container and obtained the external lotion agent.
[300] Example 18 Functional Patch
[301] Prescriptions: tinidazole (2 g), kaolin (5 g), liquid paraffin (10 g), glycerin (15 g), sodium carboxymethyl cellulose (5 g), crotamiton (1.5 g), zinc oxide (2 g), Tween 80 (2 g) ), Gelatin (5 g), sodium polyacrylate (5 g), distilled water (amount of 100 g)
[302] Production method: After adding the hot melt of carboxymethyl cellulose and gelatin to distilled water, kaolin was added and disperse | distributed, and this was added, stirring, stirring zinc oxide, sodium polyacrylate, and liquid paraffin. Moreover, tinidazole, crotamiton, glycerin, and Tween80 were stirred and heated, and the thing adjusted to the temperature of about 60 degreeC was added, stirring and heating. The obtained ointment was inverted at 1000 g per m 2 on a nonwoven fabric, and cut into a size of 10 cm x 14 cm (containing 280 mg of tinidazole per 14 g of ointment) to obtain a patch.
[303] Example 19 Functional Patch
[304] Prescription: tinidazole (2g), sorbitan monooleate (0.5g), polyoxyethylene sorbitan monooleate (0.5g), castor oil (1g), crotamiton (1g), gelatin (1g), Kaolin (12 g), sodium metaphosphate (0.15 g), 1,3-butylene glycol (5 g), starch acrylate 300 (2 g), sodium polyacrylate (5 g), methacrylic acid, n-butyl copolymer (4 g) , D-sorbitol solution (70%) (50g), tartaric acid (1.7g), titanium oxide (1g), alumina magnesium hydroxide (0.25g), dibutylhydroxytoluene (0.2g), distilled water (total amount 100g amount)
[305] Production method: A mixture of distilled water and a suitable amount of D-sorbitol liquid was melted, titanium oxide was added, and then a proper amount of kaolin and D-sorbitol liquid were added while stirring. To this is added gelatin, followed by n-butyl copolymer of methacrylic acid and acrylic acid, followed by a mixed melt of sodium polyacrylate, starch acrylate 300, alumina magnesium hydroxide, 1,3-butylene glycol and castor oil. A mixture of a sol, a warm dispersion of crotamiton and dibutylhydroxytoluene, and a mixture of sorbitan monoolefin acid and polyoxyethylene sorbitan monoolefin was added with stirring. Next, what dissolved sodium metaphosphate in the distilled water small amount was added, and finally, the mixture which adjusted to the temperature of about 60 degreeC of the remaining D-sorbitol liquid and tartaric acid was added stirring. The obtained ointment was inverted at 1000 g per m 2 on a nonwoven fabric, and cut into a size of 10 cm x 14 cm (containing 280 mg of tinidazole per 14 g of ointment) to obtain a patch.
[306] Example 20 Patch (Plaster)
[307] Prescriptions: tinidazole (2 g), liquid paraffin (8 g), dibutylhydroxytoluene (0.2 g), crotamiton (1 g), monostearic acid polyoxyethylene glycol (2 g), polyoxyethylene cetostearyl ether (20E.O.) (1.8g), methacrylic acid / acrylic acid n-butyl copolymer (5g), myristyl alcohol (8g), natural rubber latex (solid) (20g), synthetic rubber SBR latex (solid) (37g ), Polybutene (15 g)
[308] Method of preparation: Tinidazole, dibutylhydroxytoluene and crotamiton are warmly dispersed while stirring, and polyoxyethylene glycol monopolystearate, polyoxyethylene cetostearyl ether (20E.O.) and myristyl alcohol are added thereto. Mix by heating. This was added to the heated melted mixture of the methacrylic acid acrylic n-butyl copolymer, natural rubber latex, and SBR synthetic latex with continuous stirring. Moreover, liquid paraffin and polybutene are added to this, stirring continuously. The obtained ointment was spread on a nonwoven fabric or woven fabric at 100 g per m 2, dried, and then cut into a size of 10 cm x 14 cm (containing 28 mg of tinidazole per 1.4 g of ointment) to obtain a plaster agent.
[309] Example 21 External Cream
[310] Prescriptions: metronidazole (2g), clotrimazole (0.1g), chloropropionate (0.005g), glycol monostearate (10g), cetanol (7g), liquid paraffin (9g), white petrolatum (3.5g), Propylene glycol (6.5 g), sodium lauryl sulfate (1 g), purified water (amount of 100 g total)
[311] Method of preparation: Glycol monostearate, cetanol, liquid paraffin and white petrolatum were stirred with warming at about 85 ° C., and propylene glycol, sodium lauryl sulfate and purified water were stirred with warming at about 85 ° C., and metronidazole was stirred. , Clotrimazole and propionate clobetasol were added. The resulting cream was collected into a suitable container by cooling to about 25 ° C. with continuous stirring.
[312] Example 22 External Cream
[313] Prescriptions: (a) metronidazole (2 g), lidocaine (0.05 g), gluconate acetate prednisolone (0.005 g); (b) glycol monostearate (10 g), cetanol (7 g), liquid paraffin (9 g), white petrolatum (3.5 g); (c) Propylene glycol (6.5 g), sodium lauryl sulfate (1 g), purified water (amount of 100 g total)
[314] Production method: (b) was stirred while warming to about 85 ° C., (c) was stirred while warming to about 85 ° C., and (a) was added while stirring. The resulting cream was collected in a suitable container with cooling at about 25 ° C. with continuous stirring.
[315] Example 23 External Cream
[316] Prescriptions: tinidazole (2 g), clotrimazole (0.1 g), chloropropate (0.002 g), glycol monostearate (10 g), cetanol (7 g), liquid paraffin (9 g), white petrolatum (3.5 g) ), Propylene glycol (6.5 g), sodium lauryl sulfate (1 g), purified water (amount of 100 g)
[317] Method of preparation: Glycol monostearate, cetanol, liquid paraffin and white petrolatum were stirred with warming to about 85 ° C., and propylene glycol, sodium lauryl sulfate and purified water were stirred with warming to about 85 ° C., followed by Nidazole, clotrimazole and propionate clobetasol were added. It cooled to about 25 degreeC with continuous stirring, and produced cream was extract | collected to the suitable container.
[318] Example 24 External Cream
[319] Prescriptions: tinidazole (2 g), chloramphenicol (0.001 g), acetic acid hydrocortisone (0.001 g), monostearate glycol (8 g), cetanol (7 g), liquid paraffin (10 g), white petrolatum (3.5 g) , Propylene glycol (6.5 g), sodium lauryl sulfate (0.8 g), purified water (amount of 100 g)
[320] Preparation method: Glycol monostearate, cetanol, liquid paraffin and white petrolatum were stirred while warming to about 85 ° C, and propylene glycol, sodium lauryl sulfate and purified water were added while warming to about 85 ° C, and stirred while stirring Nidazole, chloramphenicol and acetic acid hydrocortisone were added. It cooled to about 25 degreeC with continuous stirring, and produced cream was extract | collected to the suitable container.
[321] Example 25 Gel
[322] Prescriptions: (a) tinidazole (3 g), diphenhydramine hydrochloride (0.2 g), beta mesazone (0.01 g), carpronium chloride (0.2 g); (b) polyoxyethylene oleyl alcohol ether (1 g); (c) polyethylene glycol 1500 (6 g), polyoxyethylene glycol 400 (2 g), EDTA disodium (0.2 g); (d) dipropylene glycol (8 g); (e) awards; Potassium hydroxide (0.1 g); (f) Carboxyvinyl Polymer (0.5g), Methyl Cellulose (0.2g), Purified Water
[323] Manufacturing method: After dissolving (f) uniformly, (c) was added, (a) was added, it heated, it melt | dissolved, and was disperse | distributed. Then, (b) was added to (d), and what melt | dissolved at the temperature of about 60 degreeC was added. While stirring this, (e) is added and neutralized, and it cools to the temperature of about 25 degreeC. The resulting gel was collected in a suitable container.
[324] Example 26 External Cream
[325] Prescriptions: metronidazole (2 g), monostearate glycol (10.4 g), cetanol (7.3 g), liquid paraffin (9 g), propylparaben (0.05 g), white petrolatum (3.5 g), propylene glycol (6.5 g), Sodium lauryl sulfate (1 g), methyl paraben (0.05 g), urea (2 g), purified water (amount of 100 g total)
[326] Preparation method: Glycol monostearate, cetanol, liquid paraffinpropylparaben and white petrolatum were stirred with warming to about 85 ° C, and propylene glycol, sodium lauryl sulfate, methylparaben, urea and purified water were stirred with warming to about 85 ° C. Was added and metronidazole was added while stirring. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[327] Example 27 Shampoo
[328] Prescription: metronidazole (2g), polyglycerin monolauric acid (4g), sodium polyoxyethylenelauryl ether sulfate (7g), lauryldimethylaminoacetate betaine (2.5g), palm oil fatty acid diethanolamide (4g), polyethylene Glycol (5g), 1,3-butylene glycol (3g), citric acid (proper), purified water (the amount becomes 100g)
[329] Manufacturing method: Metronidazole is added to a mixture of polyethylene glycol and purified water in an appropriate amount, and then melted. In a separate container weigh the balance of polyglycerol monolauryl acid, sodium polyoxyethylene lauryl ether sulfate, lauryl dimethyl acetate, palm oil fatty acid diethanolamide, polyethylene glycol, 1,3-butylene glycol and purified water, Warm to about 70 ° C. with stirring, add to a mixture of metronidazole, polyethylene glycol and purified water, and adjust the pH to about 6.5 with citric acid. Cool down to a temperature of about 25 ° C. while stirring.
[330] Example 28 Gel
[331] Prescriptions: metronidazole (1 g), polyethylene glycol (8 g), carboxyvinyl polymer (0.5 g), methyl cellulose (0.2 g), propylene glycol (5 g), glycerin (2 g), polyoxyethylene oleylcetyl ether (1 g), Isopropanol (5 g), sodium hydroxide (appropriate amount), purified water (the amount becomes 100 g)
[332] Manufacturing method; Polyethyleneglycol is added and dissolved in purified water, and metronidazole is added and dissolved in warm water. It is cooled to about 50 ° C, polyoxyethylenecetyl ether is added to propylene glycol and glycerin with stirring, and the one heated to about 50 ° C is added. In addition, sodium hydroxide is added while stirring continuously, and pH is adjusted to about 6.8. After cooling to about 40 ° C., isopropanol was added, cooled to about 25 ° C., and collected in a suitable container.
[333] Example 29 Ointment
[334] Prescription: (a) metronidazole (2 g), crotamiton (2 g); (b) stearic acid (2 g), monostearine glycol (12 g), monostearic acid polyoxyethylene glycol (3 g), polyoxyethylene cetostearyl ether (12E.O.) (1 g), polyoxyethylene cetostearyl Ether (20E.O.) (1 g), cetanol (2 g), liquid paraffin (8 g); (c) 1,3-butylene glycol (7 g), glycerin (5 g), purified water (amount of which total amount becomes 100 g)
[335] Manufacturing method: (b) was melt | dissolved and adjusted to about 75 degreeC. The thing which melt | dissolved and adjusted (c) at about 75 degreeC was added to this, stirring, and (a) was then added continuously. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[336] Example 30 External Cream
[337] Prescriptions: (a) metronidazole (2 g), lidocaine (0.05 g), gluconate acetate prednisolone (0.005 g); (b) glycol monostearate (10 g), cetanol (7 g), liquid paraffin (9 g), white petrolatum (3.5 g); (c) Propylene glycol (6.5 g), sodium lauryl sulfate (1 g), purified water (amount of 100 g)
[338] Manufacturing method: (b) was melt | dissolved and adjusted to about 85 degreeC. The thing which melt | dissolved and adjusted (c) at about 85 degreeC was added to this, stirring, and (a) was then added. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[339] Example 31 External Cream
[340] Prescription: (a) metronidazole (2.5 g), ketoconazole (0.1 g); (b) stearic acid (5 g), stearyl alcohol (5 g), liquid paraffin (5 g), myristic acid isopropyl (1 g), span 60 (1 g), thymol (0.2 g); (c) Tween 60 (0.5 g), propylene glycol (5 g), triethanolamine (0.4 g), distilled water (amount of 100 g total)
[341] Manufacturing method: (b) was melt | dissolved and adjusted to about 85 degreeC. The thing which melt | dissolved and adjusted (c) at about 85 degreeC was added to this, stirring, and then (a) was added. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[342] Example 32 External Cream
[343] Prescriptions: (a) metronidazole (3 g), pipemic acid trihydrate (0.1 g), prednisolone (0.001 g); (b) glycol monostearate (5 g), polyoxyethylene (23) cetyl ether (2 g), cetanol (6 g), white petrolatum (5 g), liquid paraffin (5 g), tri (capuric acid capric acid) glycerin ( 5 g), octylate dodecyl (3 g), propyl paraoxybenzoate (0.1 g); (c) propylene glycol (5 g), methyl paraoxybenzoate (0.1 g), distilled water (amount of which the total amount is 100 g)
[344] Manufacturing method: (b) was melt | dissolved and adjusted to about 85 degreeC. The thing which melt | dissolved and adjusted (c) at about 85 degreeC was added to this, stirring, and (a) was then added. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[345] Example 33 External Ointment
[346] Prescriptions: (a) metronidazole (2 g), crotamiton (1 g), fluorocinolone acetonide (0.001 g); (b) white petrolatum (45 g), cetanol (20 g), polyoxyethylene hardened castor oil (5 g), Tween 80 (2 g), liquid paraffin (5 g), paraoxybenzoic acid propyl (0.1 g); (c) methyl paraoxybenzoate (0.1 g), distilled water (amount of which the total amount is 100 g)
[347] Manufacturing method: (b) was melt | dissolved and adjusted to about 85 degreeC. The thing which melt | dissolved and adjusted (c) at about 85 degreeC was added to this, stirring, and (a) was then added. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[348] Example 34 External Ointment
[349] Prescriptions: (a) metronidazole (2 g), diphenhydramine hydrochloride (0.2 g), lidocaine (0.1 g); (b) stearyl alcohol (7 g), cetanol (3 g), white petrolatum (30 g), monostearate glycol (10 g), span 80 (1.5 g), liquid paraffin (5 g); (c) Propylene glycol (5 g), Tween 80 (1 g), distilled water (amount of which becomes 100 g)
[350] Manufacturing method: (c) was melt | dissolved and adjusted to about 85 degreeC. The thing which made (b) into about 85 degreeC was added to this, stirring, and then (a) was added. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[351] Example 35 External Ointment
[352] Prescription: (a) metronidazole (2 g), gentamicin sulfate (0.005 g); (b) monostearic acid glycol (15 g), monostearic acid polyoxyethylene glycol (3 g), polyoxyethylene cetostearyl ether (2 g), cetanol (5 g), beeswax (5 g), white petrolatum (20 g) ( c) distilled water (amount of which is 100 g)
[353] Preparation method: (c) was adjusted to about 85 degreeC. The thing which made (b) into about 85 degreeC was added to this, stirring, and then (a) was added. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[354] Example 36 Lotion Agent
[355] Prescriptions: (a) metronidazole (2 g), betaacetazone (0.005 g), bihonazole (0.05 g); (b) stearic acid (2 g), cetanol (1.5 g), petrolatum (4 g), squalene (5 g), tri (caprylic acid and capronic acid) glycerin (2 g), sorbitan monoolefin (2 g), polyethylene Glycol (5 g); (c) dipropylene glycol (5 g), triethanolamine (0.7 g), purified water (60 g); (d) Isopropanol (10 g), purified water (amount of which total amount becomes 100 g)
[356] Manufacturing method: (c) was melt | dissolved and adjusted to about 75 degreeC. The thing which melt | dissolved and adjusted (b) at about 75 degreeC was added to this, stirring, and then (a) was added. After rapidly cooling to a temperature of about 40 ° C. while stirring continuously, (d) is added and cooled to about 25 ° C. while stirring. The resulting lotion agent was collected in a suitable airtight container.
[357] Example 37 Patch
[358] Prescriptions: (a) metronidazole (3 g), crotamiton (1 g), prednisolone (0.05 g); (b) D-sorbitol (70%) (30 g), purified water (9 g), kaolin (13 g), titanium oxide (1 g); (c) gelatin (1 g), purified water (4 g); (d) sodium metaphosphate (0.1 g), purified water (1 g); (e) Sodium polyacrylate (5 g), acrylate starch 300 (1 g), propylene glycol (5 g), castor oil (1 g), alumina magnesium hydroxide (0.25 g), monoolefin acid sorbitan (0.5 g), monoolefin acid Polyoxyethylene sorbitan (0.5 g); (f) D-sorbitol (70%) (14 g), dibutylhydroxytoluene (0.2 g); (g) methacrylic acid acrylic acid n-butyl copolymer (3 g); (h) D-sorbitol (70%) (4.9 g), tartaric acid (1.5 g)
[359] Manufacturing method: (b) was melt | dissolved and adjusted to about 40 degreeC. The thing which melt | dissolved and adjusted (d) at about 60 degreeC was added to this, stirring (c) and (g) were then added further. The thing which mixed well (a) and (e) was added to this, Then, (h) was added little by little, adding (f) and stirring. The obtained ointment 14g was uniformly apply | coated to 10 cm x 14 cm nonwoven fabric, and the patch was obtained.
[360] Example 38 Patch (Plaster)
[361] Prescription: (a) metronidazole (3 g), indomethacin (1 g); (b) liquid paraffin (7 g), isopropyl myristin (3 g), polybutene (15 g), 1,3-pentadiene copolymer resin (26 g); (c) polyoxyethylene sorbitan monostearate (1.5 g), zinc oxide (3 g), titanium oxide (2 g), dibutylhydroxytoluene (0.2 g), crotamitone (1 g); (d) kaolin (6 g); (e) natural rubber latex (solid) (15 g), synthetic rubber SBR (solid) (17 g); (f) Glycerin (0.25 g), purified water (1 g), sodium polyacrylate (0.05 g)
[362] Manufacturing method: (b) was melted and mixed at about 110 ° C, and adjusted to about 90 ° C. After adding (a) to this and adjusting to about 70 degreeC, the thing which mixed (c) and (d) was added. (F) was further added while stirring, and (e) was added at about 70 degreeC. The obtained ointment 14g was uniformly apply | coated to 10 cm x 14 cm nonwoven fabric, and the patch was obtained.
[363] Example 39 Gel
[364] Prescription: (a) metronidazole (3 g), diphenhydramine hydrochloride (0.5 g), beta mesazone (0.01 g); (b) polyoxyethylene oleyl alcohol ether (1 g); (c) polyethylene glycol 1500 (6 g), polyoxyethylene glycol 400 (2 g), EDTA disodium (0.2 g); (d) dipropylene glycol (8 g); (e) potassium hydroxide (0.1 g); (f) Carboxyvinyl Polymer (0.5g), Methyl Cellulose (0.2g), Purified Water
[365] Manufacturing method: After dissolving (f) uniformly, (c) was added, Then, (a) was added, it heated, it melt | dissolved and dispersed. To this, (b) was added (b), and what was mixed and melted at about 60 ° C was added. Furthermore, while stirring (e) was added and neutralized, it cooled to about 25 degreeC. The resulting gel was collected in a suitable container.
[366] Example 40 External Cream
[367] Prescriptions: (a) Tinidazole (1 g), Gilniacetic acid prednisolone (0.005 g); (b) glycol monostearate (8 g), cetanol (7 g), liquid paraffin (10 g), white petrolatum (3.5 g); (c) Propylene glycol (6.5 g), sodium lauryl sulfate (1 g), purified water (amount of which is 100 g).
[368] Manufacturing method: (b) was melt | dissolved and adjusted to about 85 degreeC. The thing which melt | dissolved and adjusted (c) at about 85 degreeC was added to this, stirring, and (a) was then added. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[369] Example 41 External Cream
[370] Prescription: (a) tinidazole (2.5 g), azelastine hydrochloride (0.02 g), prednisolone acetate (0.001); (b) glycol monostearate (5 g), polyoxyethylene (23) cetyl ether (2 g), cetanol (5 g), white petrolatum (3.5 g), liquid paraffin (5 g), isopropyl myripropyl acid (5 g) , Octylate dodecyl (3 g), propyl paraoxybenzoate (0.15 g); (c) Propylene glycol (7 g), methyl paraoxybenzoate (0.15 g), distilled water (amount of which total amount becomes 100 g).
[371] Manufacturing method: (b) was melt | dissolved and adjusted to about 85 degreeC. The thing which melt | dissolved and adjusted (c) at about 85 degreeC was added to this, stirring, and (a) was then added. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[372] Example 42 Cream
[373] Prescription: (a) tinidazole (2.0 g), tolnaftate (0.05 g), (b) stearic acid (5 g), stearyl alcohol (5 g), liquid paraffin (5 g), isopropyl myripropyl acid (1 g) ), Span 60 (1.2 g), thymol (0.2 g); (c) Tween 60 (0.7 g), propylene glycol (6 g), triethanolamine (0.4 g), purified water (amount of which total amount is 100 g).
[374] Manufacturing method: (b) was melt | dissolved and adjusted to about 85 degreeC. The thing which melt | dissolved and adjusted (c) at about 85 degreeC was added to this, stirring, and (a) was then added. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[375] Example 43 Cream
[376] Prescription: (a) Tinidazole (2.0 g), Acylcloville (0.2 g); (b) stearic acid (5 g), stearyl alcohol (5 g), liquid paraffin (5 g), isopropyl myristin (1 g), span 60 (1.2 g), thymol (0.2 g); (c) Tween 60 (0.7 g), propylene glycol (6 g), triethanolamine (0.4 g), purified water (amount of which total amount is 100 g).
[377] Manufacturing method: (b) was melt | dissolved and adjusted to about 85 degreeC. The thing which melt | dissolved and adjusted (c) to about 85 degreeC was added to this, stirring, and (a) was then added. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[378] Example 44 External Ointment
[379] Prescriptions: (a) Tinidazole (2 g), Diclofenac Sodium (0.05 g), Crotamiton (1 g), Fluorcinolone Acetonide (0.001 g); (b) white petrolatum (45 g), cetanol (20 g), polyoxyethylene hardened castor oil (5 g), Tween 80 (2 g), liquid paraffin (5 g), paraoxybenzoic acid propyl (0.1 g); (c) Methyl paraoxybenzoate (0.1 g) and distilled water (amount whose total quantity becomes 100 g).
[380] Manufacturing method: (b) was melt | dissolved and adjusted to about 85 degreeC. The thing which melt | dissolved and adjusted (c) at about 85 degreeC was added to this, stirring, and (a) was then added. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[381] Example 45 External Ointment
[382] Prescription: (a) tinidazole (2 g), calf blood extract (1 g), diphenhydramine hydrochloride (0.2 g), lidocaine (0.1 g); (b) stearyl alcohol (7 g), cetanol (3 g), white petrolatum (30 g), monostearate glycol (10 g), span 80 (1.5 g), liquid paraffin (5 g); (c) Propylene glycol (5 g), Tween 80 (1 g), distilled water (amount of which total amount is 100 g).
[383] Manufacturing method: (c) was melt | dissolved and adjusted to about 85 degreeC. The thing which made (b) into about 85 degreeC was added to this, stirring, and then (a) was added. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[384] Example 46 External Ointment
[385] Prescription: (a) tinidazole (2 g), gentamicin sulfate (0.005 g); (b) monostearic acid glycol (15 g), monostearic acid polyoxyethylene glycol (3 g), polyoxyethylene cetostearyl ether (2 g), cetanol (5 g), beeswax (5 g), white petrolatum (20 g); (c) distilled water (amount of which becomes 100 g).
[386] Preparation method: (c) was adjusted to about 85 degreeC. The thing which made (b) into about 85 degreeC was added to this, stirring, and then (a) was added. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[387] Example 47 Lotion Agent
[388] Prescriptions: (a) tinidazole (2 g), nofloxacin (0.005 g), clotrimazole (0.05 g); (b) stearic acid (2 g), cetanol (1.5 g), white petrolatum (4 g), squalene (5 g), tri (caprylic acid and capronic acid) glycerin (2 g), monoolefin sorbitan (2 g), Polyethylene glycol (5 g); (c) dipropylene glycol (5 g), triethanolamine (0.7 g), purified water (60 g); (d) isopropanol (10 g) and purified water (amount of which total amount is 100 g).
[389] Manufacturing method: (c) was melt | dissolved and adjusted to about 70 degreeC. The thing which melt | dissolved and adjusted (b) at about 70 degreeC was added to this, stirring, and then (a) was added. After quenching to the temperature of about 40 degreeC, stirring continuously, (d) was added and it cooled to about 25 degreeC, stirring. The resulting lotion agent was collected in a suitable airtight container.
[390] Example 48 Patch
[391] Prescriptions: (a) Tinidazole (3g), Crotamiton (1g), Prednisolone (0.05g); (b) D-sorbitol (70%) (30 g), purified water (9 g), kaolin (13 g), titanium oxide (1 g); (c) gelatin (1 g), purified water (4 g); (d) sodium metaphosphate (0.1 g), purified water (1 g); (e) Sodium polyacrylate (5 g), acrylic acid starch 300 (1 g), propylene glycol (5 g), castor oil (1 g), alumina magnesium hydroxide (0.25 g), monoolefin acid sorbitan (0.5 g), monoolefin acid Polyoxyethylene sorbitan (0.5 g); (f) D-sorbitol (70%) (14 g), dibutylhydroxytoluene (0.2 g); (g) methacrylic acid acrylic acid n-butyl copolymer (3 g); (h) D-sorbitol (70%) (4.9 g), tartaric acid (1.5 g).
[392] Manufacturing method: The thing which adjusted (d) to the temperature of about 60 degreeC was added, adjusting (b) to the temperature of about 40 degreeC, stirring. Subsequently, (c) was added and (g) was added stirring. The thing which mixed well (a) and (e) is added to this, and (f) is added, adding (f), stirring. 14 g of the produced ointment was weighed and uniformly applied to a 10 cm x 14 cm nonwoven fabric to obtain a patch.
[393] Example 49 Patch (Plaster)
[394] Prescription: (a) Tinidazole (3g), Indomethacin (1g); (b) liquid paraffin (7 g), isopropyl myristin (3 g), polybutene (15 g), 1,3-pentadiene copolymer resin (26 g); (c) polyoxyethylene sorbitan monostearate (1.5 g), zinc oxide (3 g), titanium oxide (2 g), dibutylhydroxytoluene (0.2 g), crotamitone (1 g); (d) kaolin (6 g); (e) natural rubber latex (solid) (15 g), synthetic rubber SBR (solid) (17 g); (f) Glycerin (0.25 g), purified water (1 g), sodium polyacrylate (0.05 g).
[395] Manufacturing method: After melt | dissolving and mixing (b) at the temperature of about 110 degreeC, it adjusted to about 90 degreeC, added (a), and adjusted to the temperature of about 70 degreeC. The thing which mixed (c) and (d) was added to this. Furthermore, (f) was added and (e) was added at the temperature of about 70 degreeC. The resulting ointment was extended to 100 g per m 2 in a nonwoven fabric or woven fabric, and cut into a size of 10 cm x 14 cm.
[396] Example 50 External Cream
[397] Prescriptions: (a) Tinidazole (1 g), Fluorouracil (0.02 g), Gyl Acetate Prednisolone (0.005 g); (b) glycol monostearate (8 g), cetanol (7 g), liquid paraffin (10 g), white petrolatum (3.5 g); (c) Propylene glycol (6.5 g), sodium lauryl sulfate (1 g), purified water (amount of which is 100 g).
[398] Manufacturing method: (b) was melt | dissolved and adjusted to about 85 degreeC. The thing which melt | dissolved and adjusted (c) at about 85 degreeC was added to this, stirring, and (a) was then added. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[399] Example 51 External Cream
[400] Prescriptions: metronidazole (2 g), monostearate glycol (10 g), cetanol (7 g), liquid paraffin (9 g), white petrolatum (3.5 g), propylene glycol (6.5 g), sodium lauryl sulfate (1 g), purified water ( The quantity becomes 100g)
[401] Method of preparation: Glycol monostearate, cetanol, liquid paraffin and white petrolatum were stirred with warming to about 85 ° C., and propylene glycol, sodium lauryl sulfate and purified water were added with warming to about 85 ° C. and metronidazole was stirred. Was added. The resulting cream was collected in a suitable container.
[402] Example 52 External Cream
[403] Prescription: (a) metronidazole (0.5 g); (b) glycol monostearate (10 g), cetanol (7 g), liquid paraffin (9 g), white petrolatum (3.5 g); (c) Propylene glycol (6.5 g), sodium lauryl sulfate (1 g), purified water (amount of 100 g)
[404] Manufacturing method: (b) was melt | dissolved and adjusted to about 85 degreeC. The thing which melt | dissolved and adjusted (c) at about 85 degreeC was added to this, stirring, and (a) was then added. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[405] Example 53 External Cream
[406] Prescription: (a) Tinidazole (0.5 g); (b) glycol monostearate (10 g), cetanol (7 g), liquid paraffin (9 g), white petrolatum (3.5 g); (c) Propylene glycol (6.5 g), sodium lauryl sulfate (1 g), purified water (amount of 100 g)
[407] Manufacturing method: (b) was melt | dissolved and adjusted to about 85 degreeC. The thing which melt | dissolved and adjusted (c) at about 85 degreeC was added to this, stirring, and (a) was then added. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[408] Example 54 External Cream
[409] Prescription: (a) metronidazole (1.5 g), ketoconazole (0.1 g); (b) glycol monostearate (5 g), polyoxyethylene (23) cetyl ether (2 g), stearic acid (0.5 g), cetanol (5 g), white petrolatum (3.5 g), liquid paraffin (5 g), in advance Isopropyl stinate (5 g), octylate dodecyl (3 g), propyl paraoxybenzoate (0.15 g); (c) Propylene glycol (7 g), methyl paraoxybenzoate (0.15 g), distilled water (amount of total amount of 100 g)
[410] Manufacturing method: (b) was melt | dissolved and adjusted to about 85 degreeC. The thing which melt | dissolved and adjusted (c) at about 85 degreeC was added to this, stirring, and (a) was then added. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[411] Example 55 External Cream
[412] Prescription: (a) tinidazole (1.5 g), ketoconazole (0.1 g); (b) glycol monostearate (5 g), polyoxyethylene (23) cetyl ether (2 g), stearic acid (0.5 g), cetanol (5 g), white petrolatum (3.5 g), liquid paraffin (5 g), in advance Isopropyl stinate (5 g), octylate dodecyl (3 g), propyl paraoxybenzoate (0.15 g); (c) Propylene glycol (7 g), methyl paraoxybenzoate (0.15 g), distilled water (amount of total amount of 100 g)
[413] Manufacturing method: (b) was melt | dissolved and adjusted to about 85 degreeC. The thing which melt | dissolved and adjusted (c) at about 85 degreeC was added to this, stirring, and (a) was then added. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[414] Example 56 External Cream
[415] Prescriptions: (a) metronidazole (3 g), norfloxacin (0.2 g); (b) stearic acid (5 g), stearyl alcohol (5 g), liquid paraffin (5 g), isopropyl myristin (1 g), span 60 (1.2 g), thymol (0.2 g); (c) Tween 60 (0.7 g), propylene glycol (6 g), triethanolamine (0.4 g), purified water (amount of 100 g total)
[416] Manufacturing method: (b) was melt | dissolved and adjusted to about 85 degreeC. The thing which melt | dissolved and adjusted (c) at about 85 degreeC was added to this, stirring, and (a) was then added. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[417] Example 57 External Cream
[418] Prescription: (a) tinidazole (3 g), norfloxacin (0.2 g); (b) stearic acid (5 g), stearyl alcohol (5 g), liquid paraffin (5 g), isopropyl myristin (1 g), span 60 (1.2 g), thymol (0.2 g); (c) Tween 60 (0.7 g), propylene glycol (6 g), triethanolamine (0.4 g), purified water (amount of 100 g total)
[419] Manufacturing method: (b) was melt | dissolved and adjusted to about 85 degreeC. The thing which melt | dissolved and adjusted (c) at about 85 degreeC was added to this, stirring, and (a) was then added. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[420] Example 58 External Ointment
[421] Prescription: (a) metronidazole (2 g), diclofenac sodium (0.1 g); (b) White Vaseline (45 g), Cetanol (20 g), Polyoxyethylene Cured Castor Oil (5 g), Tween 80 (2 g), Crotamiton (3 g), Liquid Paraffin (5 g), Paraoxybenzoic Acid Profile (0.1 g) ); (c) Methyl paraoxybenzoate (0.1 g), distilled water (amount of which total amount becomes 100 g)
[422] Manufacturing method: (b) was melt | dissolved and adjusted to about 85 degreeC. The thing which melt | dissolved and adjusted (c) at about 85 degreeC was added to this, stirring, and (a) was then added. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[423] Example 59 External Ointment
[424] Prescription: (a) Tinidazole (2 g), Diclofenac Sodium (0.1 g); (b) White petrolatum (45 g), cetanol (20 g), polyoxyethylene cured castor oil (5 g), Tween 80 (2 g), crotamiton (3 g), liquid paraffin (5 g), paraoxybenzoic acid propyl (0.1 g) ); (c) methyl paraoxybenzoate (0.1 g), distilled water (amount of which the total amount is 100 g)
[425] Manufacturing method: (b) was melt | dissolved and adjusted to about 85 degreeC. The thing which melt | dissolved and adjusted (c) to about 85 degreeC was added to this, stirring, and (a) was then added. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[426] Example 60 External Cream
[427] Prescription: (a) metronidazole (10 g); (b) monostearate glycol (7 g), monostearate polyoxyethylene glycol (3 g), polyoxyethylene cetostearyl ether (2 g), polyoxyethylene hardened castor oil (1 g), cetanol (5 g), beeswax (1 g), liquid paraffin (3 g); (c) polyethylene glycol (5 g), 1,3-butylene glycol (4 g), distilled water (amount of which the total amount is 100 g)
[428] Manufacturing method: (c) was melt | dissolved and adjusted to about 85 degreeC. The thing which melt | dissolved and adjusted (b) at about 85 degreeC was added to this, stirring, and then (a) was added. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[429] Example 61 External Cream
[430] Prescription: (a) tinidazole (10 g); (b) Monostearate glycol (7 g), monostearate polyoxyethylene glycol (3 g), polyoxyethylene cetostearyl ether (2 g), polyoxyethylene hardened castor oil (1 g), cetanol (5 g), beeswax (1 g), liquid paraffin (3 g); (c) polyethylene glycol (5 g), 1,3-butylene glycol (4 g), distilled water (amount of which the total amount is 100 g)
[431] Manufacturing method: (c) was melt | dissolved and adjusted to about 85 degreeC. The thing which melt | dissolved and adjusted (b) at about 85 degreeC was added to this, stirring, and then (a) was added. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[432] Example 62 Lotion Agent
[433] Prescription: (a) metronidazole (5 g); (b) stearic acid (2 g), cetanol (1.5 g), white petrolatum (4 g), squalene (5 g), tri (caprylic acid and capronic acid) glycerin (2 g), monoolefin acid sorbitan (2 g), Polyethylene glycol (5 g); (c) dipropylene glycol (5 g), triethanolamine (0.7 g), purified water (60 g); (d) isopropanol (10 g), purified water (amount of which becomes 100 g)
[434] Manufacturing method: (c) was melt | dissolved and adjusted to about 70 degreeC. The thing which melt | dissolved and adjusted (b) at about 70 degreeC was added to this, stirring, and then (a) was added. After cooling to the temperature of about 40 degreeC continuously stirring, it cooled to the temperature of about 25 degreeC, adding (d) and stirring. The resulting lotion agent was collected in a suitable airtight container.
[435] Example 63 Lotion Agent
[436] Prescription: (a) metronidazole (5 g), tranilast (0.4 g); (b) stearic acid (2 g), cetanol (1.5 g), white petrolatum (4 g), squalene (5 g), tri (caprylic acid and capronic acid) glycerin (2 g), monoolefin sorbitan (2 g), Polyethylene glycol (5 g); (c) dipropylene glycol (5 g), triethanolamine (0.7 g), purified water (60 g); (d) isopropanol (10 g), purified water (amount of which becomes 100 g)
[437] Manufacturing method: (c) was melt | dissolved and adjusted to about 70 degreeC. The thing which melt | dissolved and adjusted (b) at about 70 degreeC was added to this, stirring, and then (a) was added. After cooling to the temperature of about 40 degreeC continuously stirring, it cooled to the temperature of about 25 degreeC, adding (d) and stirring. The resulting lotion agent was collected in a suitable airtight container.
[438] Example 64 Lotion Agent
[439] Prescription: (a) tinidazole (3 g), clotrimazole (0.1 g), prednisolone acetate (0.005 g); (b) stearic acid (2 g), cetanol (1.5 g), white petrolatum (4 g), squalene (5 g), tri (caprylic acid and capronic acid) glycerin (2 g), sorbitan monoolefin (2 g), Polyethylene glycol (5 g); (c) dipropylene glycol (5 g), triethanolamine (0.7 g), purified water (60 g); (d) isopropanol (10 g), purified water (amount of which becomes 100 g)
[440] Manufacturing method: (c) was melt | dissolved and adjusted to about 70 degreeC. The thing which melt | dissolved and adjusted (b) at about 70 degreeC was added to this, stirring, and then (a) was added. After cooling to the temperature of about 40 degreeC continuously stirring, it cooled to the temperature of about 25 degreeC, adding (d) and stirring. The resulting lotion agent was collected in a suitable airtight container.
[441] Example 65 External Cream
[442] Prescription: (a) metronidazole (2 g); (b) glycol monostearate (10 g), cetanol (7 g), liquid paraffin (9 g), white petrolatum (3.5 g); (c) urea (2 g), propylene glycol (6.5 g), sodium lauryl sulfate (1 g), purified water (amount of 100 g total)
[443] Manufacturing method: (b) was melt | dissolved and adjusted to about 85 degreeC. The thing which melt | dissolved and adjusted (c) at about 85 degreeC was added to this, stirring, and (a) was then added. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[444] Example 66 External Cream
[445] Prescription: (a) tinidazole (2 g); (b) glycol monostearate (10 g), cetanol (7 g), liquid paraffin (9 g), white petrolatum (3.5 g); (c) urea (2 g), propylene glycol (6.5 g), sodium lauryl sulfate (1 g), purified water (amount of 100 g total)
[446] Manufacturing method: (b) was melt | dissolved and adjusted to about 85 degreeC. The thing which melt | dissolved and adjusted (c) to about 85 degreeC was added to this, stirring, and (a) was then added. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[447] Example 67 External Cream
[448] Prescription: (a) metronidazole (10 g); (b) glycol monostearate (10 g), cetanol (7 g), liquid paraffin (9 g), white petrolatum (2.5 g); (c) urea (2 g), polyethylene glycol (7 g), Tween 80 (1 g), purified water (amount of which becomes 100 g)
[449] Manufacturing method: (b) was melt | dissolved and adjusted to about 85 degreeC. The thing which melt | dissolved and adjusted (c) at about 85 degreeC was added to this, stirring, and (a) was then added. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[450] Example 68 External Cream
[451] Prescription: (a) tinidazole (10 g); (b) glycol monostearate (10 g), cetanol (7 g), liquid paraffin (9 g), white petrolatum (2.5 g); (c) Urea (2 g), polyethylene glycol (7 g), Tween 80 (1 g), purified water (amount of 100 g total)
[452] Manufacturing method: (b) was melt | dissolved and adjusted to about 85 degreeC. The thing which melt | dissolved and adjusted (c) at about 85 degreeC was added to this, stirring, and (a) was then added. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[453] Example 69 External Ointment
[454] Prescriptions: (a) metronidazole (3 g); (b) white petrolatum (45 g), cetanol (20 g), polyoxyethylene hardened castor oil (5 g), liquid paraffin (5 g), paraoxybenzoic acid propyl (0.1 g); (c) Methyl paraoxybenzoate (0.1 g), Tween 80 (2 g), polyethylene glycol (5 g), distilled water (amount of 100 g total)
[455] Manufacturing method: (b) was melt | dissolved and adjusted to about 85 degreeC. The thing which melt | dissolved and adjusted (c) at about 85 degreeC was added to this, stirring, and (a) was then added. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[456] Example 70 External Ointment
[457] Prescription: (a) tinidazole (3 g); (b) white petrolatum (45 g), cetanol (20 g), polyoxyethylene hardened castor oil (5 g), liquid paraffin (5 g), paraoxybenzoic acid propyl (0.1 g); (c) Methyl paraoxybenzoate (0.1 g), Tween 80 (2 g), polyethylene glycol (5 g), distilled water (amount of 100 g total)
[458] Manufacturing method: (b) was melt | dissolved and adjusted to about 85 degreeC. The thing which melt | dissolved and adjusted (c) at about 85 degreeC was added to this, stirring, and (a) was then added. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[459] Example 71 Lotion Agent
[460] Prescription: (a) metronidazole (3 g); (b) stearic acid (2 g), cetanol (1.5 g), white petrolatum (4 g), squalene (5 g), tri (caprylic acid and capronic acid) glycerin (2 g), and sorbitan monooleate (2 g); (c) polyethylene glycol (5 g), dipropylene glycol (5 g), triethanolamine (0.2 g), purified water (60 g); (d) Isopropanol (10 g), purified water (amount of which total amount becomes 100 g)
[461] Manufacturing method: (c) was melt | dissolved and adjusted to about 70 degreeC. The thing which melt | dissolved and adjusted (b) at about 70 degreeC was added to this, stirring, and then (a) was added. It cooled to the temperature of about 40 degreeC, stirring continuously, and then cooled to the temperature of about 25 degreeC, adding (d) and stirring. The resulting lotion agent was collected in a suitable airtight container.
[462] Example 72 Lotion Agent
[463] Prescription: (a) tinidazole (3 g); (b) stearic acid (2 g), cetanol (1.5 g), white petrolatum (4 g), squalene (5 g), tri (caprylic acid and capronic acid) glycerin (2 g), and sorbitan monooleate (2 g); (c) polyethylene glycol (5 g), dipropylene glycol (5 g), triethanolamine (0.2 g), purified water (60 g); (d) isopropanol (10 g), purified water (amount of which becomes 100 g)
[464] Manufacturing method: (c) was melt | dissolved and adjusted to about 70 degreeC. The thing which melt | dissolved and adjusted (b) at about 70 degreeC was added to this, stirring, and then (a) was added. It cooled to the temperature of about 40 degreeC, stirring continuously, and then cooled to the temperature of about 25 degreeC, adding (d) and stirring. The resulting lotion agent was collected in a suitable airtight container.
[465] Example 73 External Cream
[466] Prescription: (a) metronidazole (2 g), tranilast (0.1 g); (b) glycol monostearate (5 g), polyoxyethylene (23) cetyl ether (2 g), stearic acid (0.5 g), cetanol (5 g), white petrolatum (3.5 g), liquid paraffin (5 g), in advance Isopropyl stinate (5 g), octylate dodecyl (3 g), propyl paraoxybenzoate (0.15 g); (c) Propylene glycol (7 g), methyl paraoxybenzoate (0.15 g), distilled water (amount of total amount of 100 g)
[467] Manufacturing method: (b) was melt | dissolved and adjusted to about 75 degreeC. The thing which melt | dissolved and adjusted (c) at about 75 degreeC was added to this, stirring, and then (a) was added. After cooling to a temperature of about 25 ° C. with continuous stirring, the sample was collected in a suitable container.
[468] Example 74 External Cream
[469] Prescription: (a) tinidazole (2 g), tranilast (0.1 g); (b) glycol monostearate (5 g), polyoxyethylene (23) cetyl ether (2 g), stearic acid (0.5 g), cetanol (5 g), white petrolatum (3.5 g), liquid paraffin (5 g), in advance Isopropyl stinate (5 g), octylate dodecyl (3 g), propyl paraoxybenzoate (0.15 g); (c) Propylene glycol (7 g), methyl paraoxybenzoate (0.15 g), distilled water (amount of total amount of 100 g)
[470] Manufacturing method: (b) was melt | dissolved and adjusted to about 75 degreeC. The thing which melt | dissolved and adjusted (c) at about 75 degreeC was added to this, stirring, and then (a) was added. After cooling to a temperature of about 25 ° C. with continuous stirring, the sample was collected in a suitable container.
[471] Example 75 External Cream
[472] Prescription: (a) metronidazole (1.5 g); (b) stearic acid (5 g), cetanol (5 g), polyoxyethylene stearyl ether (3 g); (c) Glycerin (6g), 1,3-butylene glycol (4g), triethanolamine (0.3g), purified water (the amount becomes 100g)
[473] Manufacturing method: (a) was dissolved in a suitable amount of purified water. Subsequently, (c) which was heated to about 80 ° C was added, and (b) was added to what was heated and dissolved at about 75 ° C to emulsify with stirring. It cooled to the temperature of about 30 degreeC, stirring continuously, and collected in the suitable container.
[474] Example 76 External Cream
[475] Prescription: (a) metronidazole (3.0 g); (b) stearic acid (5 g), cetanol (5 g), polyoxyethylene stearyl ether (3 g); (c) glycerin (6 g), 1,3-butylene glycol (4 g), triethanolamine (0.3 g), purified water (amount of 100 g total)
[476] Manufacturing method: (a) was dissolved in a suitable amount of purified water. Subsequently, (c) which was heated to about 80 ° C was added, and (b) was added to what was heated and dissolved at about 75 ° C to emulsify with stirring. It cooled to the temperature of about 30 degreeC, stirring continuously, and collected in the suitable container.
[477] Example 77 External Cream
[478] Prescription: (a) Tinidazole (1.5); (b) stearic acid (5 g), cetanol (5 g), polyoxyethylene stearyl ether (3 g); (c) Glycerin (6g), 1,3-butylene glycol (4g), triethanolamine (0.3g), purified water (the amount becomes 100g)
[479] Manufacturing method: (a) was dissolved in a suitable amount of purified water. Subsequently, (c) which was heated to about 80 ° C was added, and (b) was added to what was heated and dissolved at about 75 ° C to emulsify with stirring. It cooled to the temperature of about 30 degreeC, stirring continuously, and collected in the suitable container.
[480] Example 78 External Cream
[481] Prescription: (a) Tinidazole (3.0 g); (b) stearic acid (5 g), cetanol (5 g), polyoxyethylene stearyl ether (3 g); (c) glycerin (6 g), 1,3-butylene glycol (4 g), triethanolamine (0.3 g), purified water (amount of 100 g total)
[482] Manufacturing method: (a) was dissolved in a suitable amount of purified water. Subsequently, (c) which was heated to about 80 ° C was added, and (b) was added to what was heated and dissolved at about 75 ° C to emulsify with stirring. It cooled to the temperature of about 30 degreeC, stirring continuously, and collected in the suitable container.
[483] Example 79 External Cream
[484] Prescription: (a) metronidazole (1.0 g); (b) stearic acid (0.5 g), monostearate glycol (8 g), stearyl alcohol (5 g), liquid paraffin (8 g); (c) propylene glycol (6 g), glycerin (4 g), polyoxyethylene lauryl ether sodium sulfate (1 g), purified water (amount of 100 g total)
[485] Manufacturing method: (a) was dissolved in a suitable amount of purified water. Subsequently, (c) which was heated to about 80 ° C was added, and (b) was added to what was heated and dissolved at about 75 ° C to emulsify with stirring. It cooled to the temperature of about 30 degreeC, stirring continuously, and collected in the suitable container.
[486] Example 80 External Cream
[487] Prescription: (a) metronidazole (2.5 g); (b) stearic acid (0.5 g), monostearate glycol (8 g), stearyl alcohol (5 g), liquid paraffin (8 g); (c) propylene glycol (6 g), glycerin (4 g), polyoxyethylene lauryl ether sodium sulfate (1 g), purified water (amount of 100 g total)
[488] Manufacturing method: (a) was dissolved in a suitable amount of purified water. Subsequently, (c) which was heated to about 80 ° C was added, and (b) was added to what was heated and dissolved at about 75 ° C to emulsify with stirring. It cooled to the temperature of about 30 degreeC, stirring continuously, and collected in the suitable container.
[489] Example 81 External Cream
[490] Prescription: (a) Tinidazole (1.0 g); (b) stearic acid (0.5 g), monostearate glycol (8 g), stearyl alcohol (5 g), liquid paraffin (8 g); (c) propylene glycol (6 g), glycerin (4 g), polyoxyethylene lauryl ether sodium sulfate (1 g), purified water (amount of 100 g total)
[491] Manufacturing method: (a) was dissolved in a suitable amount of purified water. Subsequently, (c) which was heated to about 80 ° C was added, and (b) was added to what was heated and dissolved at about 75 ° C to emulsify with stirring. It cooled to the temperature of about 30 degreeC, stirring continuously, and collected in the suitable container.
[492] Example 82 External Cream
[493] Prescription: (a) Tinidazole (2.5 g); (b) stearic acid (0.5 g), monostearate glycol (8 g), stearyl alcohol (5 g), liquid paraffin (8 g); (c) propylene glycol (6 g), glycerin (4 g), polyoxyethylene lauryl ether sodium sulfate (1 g), purified water (amount of 100 g total)
[494] Manufacturing method: (a) was dissolved in a suitable amount of purified water. Subsequently, (c) which was heated to about 80 ° C was added, and (b) was added to what was heated and dissolved at about 75 ° C to emulsify with stirring. It cooled to the temperature of about 30 degreeC, stirring continuously, and collected in the suitable container.
[495] Example 83 External Cream
[496] Prescription: (a) metronidazole (1.0 g); (b) glycol monostearate (10.4 g), cetanol (7.3 g), liquid paraffin (9 g), white petrolatum (3.5 g), propylparaben (0.05 g); (c) Propylene glycol (6.5 g), methyl paraben (0.05 g), sodium lauryl sulfate (1 g), purified water (amount of 100 g total)
[497] Manufacturing method: (a) was dissolved in a suitable amount of purified water. Subsequently, (c) which was heated to about 80 ° C was added, and (b) was added to what was heated and dissolved at about 75 ° C and emulsified while stirring. It cooled to the temperature of about 30 degreeC, stirring continuously, and collected in the suitable container.
[498] Example 84 External Cream
[499] Prescription: (a) metronidazole (1.8 g); (b) glycol monostearate (10.4 g), cetanol (7.3 g), liquid paraffin (9 g), white petrolatum (3.5 g), propylparaben (0.05 g); (c) Propylene glycol (6.5 g), methyl paraben (0.05 g), sodium lauryl sulfate (1 g), purified water (amount of 100 g total)
[500] Manufacturing method: (a) was dissolved in a suitable amount of purified water. Subsequently, (c) which was heated to about 80 ° C was added, and (b) was added to what was heated and dissolved at about 75 ° C to emulsify with stirring. It cooled to the temperature of about 30 degreeC, stirring continuously, and collected in the suitable container.
[501] Example 85 External Cream
[502] Prescription: (a) Tinidazole (1.0 g); (b) glycol monostearate (10.4 g), cetanol (7.3 g), liquid paraffin (9 g), white petrolatum (3.5 g), propylparaben (0.05 g); (c) Propylene glycol (6.5 g), methyl paraben (0.05 g), sodium lauryl sulfate (1 g), purified water (amount of 100 g total)
[503] Manufacturing method: (a) was dissolved in a suitable amount of purified water. Subsequently, (c) which was heated to about 80 ° C was added, and (b) was added to what was heated and dissolved at about 75 ° C to emulsify with stirring. It cooled to the temperature of about 30 degreeC, stirring continuously, and collected in the suitable container.
[504] Example 86 External Cream
[505] Prescription: (a) Tinidazole (2.0 g); (b) glycol monostearate (10.4 g), cetanol (7.3 g), liquid paraffin (9 g), white petrolatum (3.5 g), propylparaben (0.05 g); (c) Propylene glycol (6.5 g), methyl paraben (0.05 g), sodium lauryl sulfate (1 g), purified water (amount of 100 g total)
[506] Manufacturing method: (a) was dissolved in a suitable amount of purified water. Subsequently, (c) which was heated to about 80 ° C was added, and (b) was added to what was heated and dissolved at about 75 ° C to emulsify with stirring. It cooled to the temperature of about 30 degreeC, stirring continuously, and collected in the suitable container.
[507] Example 87 External Cream
[508] Prescription: (a) Tinidazole (1.0 g); (b) glycol monostearate (10.4 g), cetanol (7.3 g), liquid paraffin (9 g), white petrolatum (3.5 g), propylparaben (0.05 g); (c) Propylene glycol (6.5 g), methyl paraben (0.05 g), sodium lauryl sulfate (1 g), purified water (amount of 100 g total)
[509] Manufacturing method: (a) was dissolved in a suitable amount of purified water. Subsequently, (c) which was heated to about 85 ° C was added, and (b) was added to what was heated and dissolved at about 85 ° C to emulsify with stirring. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[510] Example 88 External Cream
[511] Prescription: (a) metronidazole (2.0 g); (b) glycol monostearate (10.4 g), cetanol (7.3 g), liquid paraffin (9 g), white petrolatum (3.5 g), propylparaben (0.05 g); (c) Propylene glycol (6.5 g), methyl paraben (0.05 g), sodium lauryl sulfate (1 g), purified water (amount of 100 g total)
[512] Manufacturing method: (a) was dissolved in a suitable amount of purified water. Subsequently, (c) which was heated to about 85 ° C was added, and (b) was added to what was heated and dissolved at about 85 ° C to emulsify with stirring. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[513] Example 89 External Cream
[514] Prescription: (a) metronidazole (1.8 g); (b) glycol monostearate (10.4 g), cetanol (7.3 g), liquid paraffin (9 g), white petrolatum (3.5 g), propylparaben (0.05 g); (c) Propylene glycol (6.5 g), methyl paraben (0.05 g), sodium lauryl sulfate (1 g), purified water (amount of 100 g total)
[515] Manufacturing method: (a) was dissolved in a suitable amount of purified water. Subsequently, (c) which was heated to about 85 ° C was added, and (b) was added to what was heated and dissolved at about 85 ° C to emulsify with stirring. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[516] Example 90 External Cream
[517] Prescription: (a) Tinidazole (1.5 g); (b) glycol monostearate (10.4 g), cetanol (7.3 g), liquid paraffin (9 g), white petrolatum (3.5 g), propylparaben (0.05 g); (c) Propylene glycol (6.5 g), methyl paraben (0.05 g), sodium lauryl sulfate (1 g), purified water (amount of 100 g total)
[518] Manufacturing method: (a) was dissolved in a suitable amount of purified water. Subsequently, (c) which was heated to about 85 ° C was added, and (b) was added to what was heated and dissolved at about 85 ° C to emulsify with stirring. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[519] Example 91 External Cream
[520] Prescription: (a) Tinidazole (2.0 g); (b) glycol monostearate (7 g), stearyl alcohol (7 g), liquid paraffin (5 g), polyoxyethylenecetostearyl ether (3 g); (c) Glycerin (5 g), 1,3-butylene glycol (7 g), sodium carboxymethyl cellulose (0.4 g), Tween 80 (1 g), purified water (amount of 100 g total)
[521] Manufacturing method: (a) was dissolved in a suitable amount of purified water. Subsequently, (c) which was heated to about 85 ° C was added, and (b) was added to what was heated and dissolved at about 80 ° C and emulsified while stirring. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[522] Example 92 External Cream
[523] Prescription: (a) metronidazole (2.0 g); (b) glycol monostearate (7 g), stearyl alcohol (7 g), liquid paraffin (5 g), polyoxyethylenecetostearyl ether (3 g); (c) Glycerin (5 g), 1,3-butylene glycol (7 g), sodium carboxymethyl cellulose (0.4 g), Tween 80 (1 g), purified water (amount of 100 g total)
[524] Manufacturing method: (a) was dissolved in a suitable amount of purified water. Subsequently, (c) which was heated to about 85 ° C was added, and (b) was added to what was heated and dissolved at about 80 ° C and emulsified while stirring. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[525] Example 93 External Cream
[526] Prescription: (a) metronidazole (5.0 g); (b) glycol monostearate (7 g), stearyl alcohol (4 g), white petrolatum (3.5 g), isopropyl myristin (3 g), span 60 (1 g), Tween 60 (0.5 g); (c) Propylene glycol (7 g), glycerin (2 g), Tween 80 (0.1 g), purified water (amount of 100 g total)
[527] Manufacturing method: (a) was dissolved in a suitable amount of purified water. Subsequently, (c) which was heated to about 80 ° C was added, and (b) was added to what was heated and dissolved at about 75 ° C to emulsify with stirring. It cooled to the temperature of about 30 degreeC, stirring continuously, and collected in the suitable container.
[528] Example 94 External Cream
[529] Prescription: (a) Tinidazole (3.0 g); (b) glycol monostearate (7 g), stearyl alcohol (4 g), white petrolatum (3.5 g), isopropyl myristin (3 g), span 60 (1 g), Tween 60 (0.5 g); (c) Propylene glycol (7 g), glycerin (2 g), Tween 80 (0.1 g), purified water (amount of 100 g total)
[530] Manufacturing method: (a) was dissolved in a suitable amount of purified water. Subsequently, (c) which was heated to about 80 ° C was added, and (b) was added to what was heated and dissolved at about 75 ° C to emulsify with stirring. It cooled to the temperature of about 30 degreeC, stirring continuously, and collected in the suitable container.
[531] Example 95 External Cream
[532] Prescription: (a) Tinidazole (1.5 g); (b) glycol monostearate (7.28 g), monostearate sorbitan (3.12 g), cetanol (7.3 g), white petrolatum (3.5 g), liquid paraffin (9 g), propylparaben (0.05 g); (c) Propylene glycol (6.5 g), sodium lauryl sulfate (1 g), methyl paraben (0.05 g), purified water (amount of 100 g total)
[533] Manufacturing method: (a) was dissolved in a suitable amount of purified water. Subsequently, (c) which was heated to about 80 ° C was added, and (b) was added to what was heated and dissolved at about 85 ° C to emulsify with stirring. It cooled to the temperature of about 30 degreeC, stirring continuously, and collected in the suitable container.
[534] Example 96 External Cream
[535] Prescription: (a) Tinidazole (2.0 g); (b) glycol monostearate (7.28 g), sorbitan monostearate (3.12 g), cetanol (7.3 g), white petrolatum (3.5 g), liquid paraffin (9 g), propylparaben (0.05 g); (c) Propylene glycol (6.5 g), sodium lauryl sulfate (1 g), methyl paraben (0.05 g), purified water (amount of 100 g total)
[536] Manufacturing method: (a) was dissolved in a suitable amount of purified water. Subsequently, (c) which was heated to about 80 ° C was added, and (b) was added to what was heated and dissolved at about 85 ° C to emulsify with stirring. It cooled to the temperature of about 30 degreeC, stirring continuously, and collected in the suitable container.
[537] Example 97 External Cream
[538] Prescription: (a) metronidazole (2.0 g); (b) glycerin monostearate (6 g), stearyl alcohol (5 g), cetanol (6 g), isopropyl myristin (1 g), span 60 (1.5 g), Tween 60 (1 g); (c) Sodium carboxymethyl cellulose (0.2 g), propylene glycol (4 g), purified water (amount of total amount of 100 g)
[539] Production method: (b) was heated and dissolved at about 75 ° C., and (c) heated to about 75 ° C. was added with stirring, and then (a) was added and stirred. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[540] Example 98 External Cream
[541] Prescription: (a) metronidazole (1.0 g); (b) glycol monostearate (7 g), stearyl alcohol (4 g), white petrolatum (3 g), isopropyl myristin (3 g), span 60 (1 g), Tween 60 (0.5 g); (c) Propylene glycol (7 g), glycerin (2 g), Tween 80 (0.1 g), purified water (amount of 100 g total)
[542] Manufacturing method: (b) was heated and dissolved at about 75 degreeC, (c) heated at about 75 degreeC was added stirring, Then, (a) was added and stirred. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[543] Example 99 External Cream
[544] Prescription: (a) Tinidazole (1.0 g); (b) glycol monostearate (7 g), stearyl alcohol (4 g), white petrolatum (3 g), isopropyl myristin (3 g), span 60 (1 g), Tween 60 (0.5 g); (c) Propylene glycol (7 g), glycerin (2 g), Tween 80 (0.1 g), purified water (amount of 100 g total)
[545] Production method: (b) was heated and dissolved at about 75 ° C., and (c) heated to about 75 ° C. was added with stirring, and then (a) was added and stirred. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[546] Example 100 External Cream
[547] Prescription: (a) metronidazole (2.0 g), norfloxacin (0.05 g); (b) glycerin monostearate (2 g), stearyl alcohol (5 g), white petrolatum (3 g), isopropyl myristin (3 g), span 60 (1 g), Tween 60 (0.5 g); (c) Propylene glycol (7 g), glycerin (2 g), Tween 80 (0.1 g), purified water (amount of 100 g total)
[548] Production method: (b) was heated and dissolved at about 75 ° C., and (c) heated to about 75 ° C. was added with stirring, and then (a) was added and stirred. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[549] Example 101 External Cream
[550] Prescription: (a) tinidazole (2.0 g), tranilast (0.2 g); (b) Monostearine glycol (4 g), cetanol (4 g), stearyl alcohol (3 g), polyoxyethylene cetyl alcohol (2 g), myristic acid isopropyl (3 g), span 60 (1 g), Tween 60 (0.5) g); (c) propylene glycol (5 g), purified water (amount of which becomes 100 g)
[551] Production method: (b) was heated and dissolved at about 75 ° C., and (c) heated to about 75 ° C. was added with stirring, and then (a) was added and stirred. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[552] Example 102 External Cream
[553] Prescription: (a) tinidazole (2.0 g), ketoprofen (0.5 g); (b) Monostearine glycol (4 g), cetanol (4 g), stearyl alcohol (3 g), polyoxyethylene cetyl alcohol (2 g), myristic acid isopropyl (3 g), span 60 (1 g), Tween 60 (0.5) g); (c) propylene glycol (5 g), purified water (amount of which becomes 100 g)
[554] Production method: (b) was heated and dissolved at about 75 ° C., and (c) heated to about 75 ° C. was added with stirring, and then (a) was added and stirred. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[555] Example 103 External Cream
[556] Prescription: (a) metronidazole (2.5 g), procaine hydrochloride (0.2 g); (b) glycerin monostearate (2 g), stearyl alcohol (5 g), white petrolatum (3 g), isopropyl myristin (3 g), span 60 (1 g), Tween 60 (0.5 g); (c) Propylene glycol (7 g), glycerin (2 g), Tween 80 (0.1 g), purified water (amount of 100 g total)
[557] Production method: (b) was heated and dissolved at about 75 ° C., and (c) heated to about 75 ° C. was added with stirring, and then (a) was added and stirred. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[558] Example 104 External Cream
[559] Prescriptions: (a) Tinidazole (3.0 g), Citric Acid Moxifene (0.05 g); (b) Monostearine glycol (4 g), cetanol (4 g), stearyl alcohol (3 g), polyoxyethylene cetyl alcohol (2 g), myristic acid isopropyl (3 g), span 60 (1 g), Tween 60 (0.5) g); (c) propylene glycol (5 g), purified water (amount of which becomes 100 g)
[560] Production method: (b) was heated and dissolved at about 75 ° C., and (c) heated to about 75 ° C. was added with stirring, and then (a) was added and stirred. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[561] Example 105 External Cream
[562] Prescription: (a) Tinidazole (2.0 g), Carpronium chloride (0.5 g); (b) stearic acid (0.5 g), monostearate glycol (12 g), stearyl alcohol (7 g), white petrolatum (2 g), liquid paraffin (5 g); (c) polyethylene glycol (5 g), 1,3-butylene glycol (5 g), purified water (amount of which becomes 100 g)
[563] Production method: (b) was heated and dissolved at about 75 ° C., and (c) heated to about 75 ° C. was added with stirring, and then (a) was added and stirred. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[564] Example 106 External Cream
[565] Prescription: (a) tinidazole (2.0 g), calf blood extract (0.5 g); (b) stearic acid (0.5 g), monostearate glycol (12 g), stearyl alcohol (7 g), white petrolatum (2 g), liquid paraffin (5 g); (c) polyethylene glycol (5 g), 1,3-butylene glycol (5 g), purified water (amount of which becomes 100 g)
[566] Production method: (b) was heated and dissolved at about 75 ° C., and (c) heated to about 75 ° C. was added with stirring, and then (a) was added and stirred. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[567] (Example 107) External cream
[568] Prescription: (a) metronidazole (0.5 g); (b) stearic acid (0.5 g), monostearate glycol (10 g), cetanol (5 g), white petrolatum (3 g); (c) Propylene glycol (7 g), sodium lauryl sulfate (1 g), purified water (amount of 100 g total)
[569] Production method: (b) was heated and dissolved at about 75 ° C., and (c) heated to about 75 ° C. was added with stirring, followed by addition of (a) and stirring. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[570] Example 108 External Cream
[571] Prescription: (a) Tinidazole (0.5 g); (b) stearic acid (0.5 g), monostearate glycol (10 g), cetanol (5 g), white petrolatum (3 g); (c) Propylene glycol (7 g), sodium lauryl sulfate (1 g), purified water (amount of 100 g total)
[572] Production method: (b) was heated and dissolved at about 75 ° C., and (c) heated to about 75 ° C. was added with stirring, followed by addition of (a) and stirring. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[573] (Example 109) External Cream
[574] Prescription: (a) metronidazole (5 g); (b) stearic acid (0.5 g), monostearate glycol (10 g), cetanol (5 g), white petrolatum (3 g); (c) Propylene glycol (7 g), sodium lauryl sulfate (1 g), purified water (amount of 100 g total)
[575] Production method: (b) was heated and dissolved at about 75 ° C., and (c) heated to about 75 ° C. was added with stirring, and then (a) was added and stirred. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[576] Example 110 External Cream
[577] Prescription: (a) Tinidazole (5 g); (b) stearic acid (0.5 g), monostearate glycol (10 g), cetanol (5 g), white petrolatum (3 g); (c) Propylene glycol (7 g), sodium lauryl sulfate (1 g), purified water (amount of 100 g total)
[578] Production method: (b) was heated and dissolved at about 75 ° C., and (c) heated to about 75 ° C. was added with stirring, and then (a) was added and stirred. It cooled to the temperature of about 25 degreeC, stirring continuously, and collected in the suitable container.
[579] Example 111 Ointment
[580] Prescription: (a) metronidazole (2 g); (b) stearic acid (2 g), monostearine glycol (12 g), monostearic acid polyoxyethylene glycol (3 g), polyoxyethylene cetostearyl ether (12E.O.) (1 g), polyoxyethylene cetostearyl Ether (20E.O.) (1 g), cetanol (2 g), liquid paraffin (8 g); (c) 1,3-butylene glycol (7 g), glycerin (5 g), purified water (amount of which total amount becomes 100 g)
[581] Manufacturing method: (b) was melt | dissolved and adjusted to about 75 degreeC. The thing which melt | dissolved and adjusted (c) at about 75 degreeC was added to this, stirring, and then (a) was added. After cooling to a temperature of about 25 ° C. with continuous stirring, the sample was collected in a suitable container.
[582] (Example 112) External preparation
[583] Prescription: (a) metronidazole (2 g), ketoconazole (0.2 g); (b) glycerin monostearate (7.5 g), sorbitan monostearate (3 g), stearyl alcohol (7 g), liquid paraffin (8 g), white petrolatum (5 g), span 80 (1 g); (c) Propylene glycol (5 g), 1,3-butylene glycol (3 g), Tween 80 (1 g), purified water (amount of 100 g total)
[584] Manufacturing method: (b) was melt | dissolved and adjusted to about 75 degreeC. The thing which melt | dissolved and adjusted (c) at about 75 degreeC was added to this, stirring, and then (a) was added. After cooling to a temperature of about 25 ° C. with continuous stirring, the sample was collected in a suitable container.
[585] Example 113 External preparation
[586] Prescription: (a) metronidazole (2 g); (b) glycerin monostearate (7.5 g), sorbitan monostearate (3 g), stearyl alcohol (7 g), liquid paraffin (8 g), white petrolatum (5 g), span 80 (1 g); (c) Propylene glycol (5 g), 1,3-butylene glycol (3 g), Tween 80 (1 g), purified water (amount of 100 g total)
[587] Manufacturing method: (b) was melt | dissolved and adjusted to about 75 degreeC. The thing which melt | dissolved and adjusted (c) at about 75 degreeC was added to this, stirring, and then (a) was added. After cooling to a temperature of about 25 ° C. with continuous stirring, the sample was collected in a suitable container.
[588] Example 114 External preparation
[589] Prescription: (a) Tinidazole (2 g), Isoconazole nitrate (0.2 g); (b) glycerin monostearate (7.5 g), sorbitan monostearate (3 g), stearyl alcohol (7 g), liquid paraffin (8 g), white petrolatum (5 g), span 80 (1 g); (c) Propylene glycol (5 g), 1,3-butylene glycol (3 g), Tween 80 (1 g), purified water (amount of 100 g total)
[590] Manufacturing method: (b) was melt | dissolved and adjusted to about 75 degreeC. The thing which melt | dissolved and adjusted (c) at about 75 degreeC was added to this, stirring, and then (a) was added. After cooling to a temperature of about 25 ° C. with continuous stirring, the sample was collected in a suitable container.
[591] (Example 115) External preparation
[592] Prescription: (a) tinidazole (2 g); (b) glycerin monostearate (7.5 g), sorbitan monostearate (3 g), stearyl alcohol (7 g), liquid paraffin (8 g), white petrolatum (5 g), span 80 (1 g); (c) Propylene glycol (5 g), 1,3-butylene glycol (3 g), Tween 80 (1 g), purified water (amount of 100 g total)
[593] Manufacturing method: (b) was melt | dissolved and adjusted to about 75 degreeC. The thing which melt | dissolved and adjusted (c) at about 75 degreeC was added to this, stirring, and then (a) was added. After cooling to a temperature of about 25 ° C. with continuous stirring, the sample was collected in a suitable container.
[594] Example 116 Shampoo
[595] Prescriptions: tinidazole (1.5 g), polyglycerol monolaurate (4 g), sodium polyoxyethylene lauryl ether sulfate (7 g), lauryl dimethylamino beta acetate (2.5 g), palm oil fatty acid diethanolamide (4 g) ), Polyethylene glycol (5 g), 1,3-butylene glycol (3 g), citric acid (appropriate amount), purified water (the amount becomes 100 g)
[596] Manufacturing method: Metronidazole is added to a mixture of polyethylene glycol and purified water in an appropriate amount, and then melted. In a separate container, weighing a polyglycerol monolauric acid, sodium polyoxyethylene lauryl ether sulfate, lauryl dimethyl acetate beta, palm oil fatty acid diethanolamide, polyethylene glycol, 1,3-butylene glycol and purified water, Warm to about 70 [deg.] C. with stirring and add it to a mixture of tinidazole, polyethylene glycol and purified water and adjust the pH to about 6.5 with citric acid. Cool down to a temperature of about 25 ° C. while stirring.
[597] (Example 117) Rinse agent
[598] Prescription: (a) metronidazole (2 g); (b) isopropyl myristic acid (1 g), butyl myristic acid (1 g), silicone oil (2 g), liquid paraffin (1 g), N- [alkyl (12,14) oxy-2-hydroxypropyl]- L-arginic acid hydrochloric acid solution (2 g); (c) lactic acid (0.05 g), polyethylene glycol (6 g), purified water (amount of 100 g)
[599] Manufacturing method: (b) was heated to about 80 degreeC, (a) was added to (c), stirring, and the thing melt | dissolved by heating to about 80 degreeC was added. It cooled to about 25 degreeC, stirring, and extract | collected into the suitable container.
[600] Example 118 Rinse Agent
[601] Prescription: (a) tinidazole (2 g); (b) isopropyl myristic acid (1 g), butyl myristic acid (1 g), silicone oil (2 g), liquid paraffin (1 g), N- [alkyl (12,14) oxy-2-hydroxypropyl]- L-arginic acid hydrochloric acid solution (2 g); (c) lactic acid (0.05 g), polyethylene glycol (6 g), purified water (amount of 100 g)
[602] Manufacturing method: (a) was added to (c), heating (b) to about 80 degreeC, stirring, and what melt | dissolved by heating to about 80 degreeC was added. It cooled to about 25 degreeC, stirring, and extract | collected into the suitable container.
[603] Example 119 Soap
[604] Prescription: metronidazole (3g), monoglycerol laurate (75g), sodium monoglyceryl sulfate (7g), stearyl alcohol (8g), silicone oil (1g), glycerin (3g), polyethylene glycol (5g), carboxy Sodium methyl cellulose (0.4 g), purified water (10 g), fragrance (appropriate amount)
[605] Manufacturing method: The component except the fragrance was heated and melted while stirring. The fragrance was added while cooling started and it did not harden. It dried over time in the dark, and obtained soap.
[606] Example 120 Soap
[607] Prescription: tinidazole (2g), lauric acid monoglycerin (75g), fatty acid monoglyceryl sodium sulfate (7g), stearyl alcohol (8g), silicone oil (1g), glycerin (3g), polyethylene glycol (5g) , Sodium carboxymethyl cellulose (0.4g), purified water (10g), flavoring (appropriate amount)
[608] Manufacturing method: The component except the fragrance was heated and melted while stirring. The fragrance was added while cooling started and it did not harden. It dried over time in the dark, and obtained soap.
[609] (Example 121) Lotion
[610] Prescription: (a) metronidazole (1 g); (b) propylene glycol (3 g), polyethylene glycol (5 g), sodium carboxymethyl cellulose (0.4 g); (c) polyoxyethylene oleylcetyl ether (1 g), jojoba oil (0.5 g); (d) perfume (suitable), ethanol (8 g); (e) Purified water (amount of which total quantity is 100 g)
[611] Production method: (b) was added to (e) to be heated and melted. (A) was added to this, it melt | dissolved, it cooled to room temperature, and the thing which melt | dissolved and disperse | distributed (c) was added to (d), and it stirred and homogenized.
[612] (Example 122) Lotion
[613] Prescription: (a) Tinidazole (0.5 g); (b) propylene glycol (3 g), polyethylene glycol (5 g), sodium carboxymethyl cellulose (0.4 g); (c) polyoxyethylene oleylcetyl ether (1 g), jojoba oil (0.5 g); (d) perfume (suitable), ethanol (8 g); (e) Purified water (amount of which total quantity is 100 g)
[614] Production method: (b) was added to (e) to be heated and melted. (A) was added to this, it melt | dissolved, it cooled to room temperature, and the thing which melt | dissolved and disperse | distributed (c) was added to (d), and it stirred and homogenized.
[615] Example 123 Gel
[616] Prescriptions: tinidazole (1 g), polyethylene glycol (8 g), carboxyvinyl polymer (0.5 g), methyl cellulose (0.2 g), propylene glycol (5 g), glycerin (2 g), polyoxyethylene oleylcetyl ether (1 g) ), Isopropanol (5 g), sodium hydroxide (proper) and purified water (total amount 100 g)
[617] Manufacturing method; Polyethyleneglycol is added to the purified water for melting, and tinidazole is added to dissolve the mixture. This is cooled to about 50 ° C, and polyoxyethylenecetyl ether is added to propylene glycol and glycerin while stirring, and then heated to about 50 ° C. Further, sodium hydroxide is added while stirring continuously to prepare a pH of about 6.8. After cooling to about 40 ° C., isopropanol was added, cooled to about 25 ° C. and collected in a suitable container.
[618] Example 124 Cream
[619] Prescription: (a) Secnidazole (2 g); (b) glycol monostearate (10 g), polyoxyethylene glycol monostearate (3 g), polyoxyethylene cetostearyl ether (2 g), cetanol (4 g), beeswax (1 g), octystinate octylate (7g), isopropyl myristin (2g); (c) polyethylene glycol (3 g), carboxyvinyl polymer (0.2 g), purified water (amount of which total amount is 100 g); (d) sodium hydroxide aqueous solution (appropriate amount)
[620] Production method: (b) was heated to about 75 ° C, (c) was heated to about 75 ° C was added while stirring, then (a) was added while stirring. Thereafter, the pH was adjusted to about 6.8 in (d). Thereafter, after cooling to a temperature of about 25 ° C, the resulting cream was collected in a suitable container.
[621] Example 125 Cream
[622] Prescription: (a) panidazol (2 g); (b) glycol monostearate (10 g), polyoxyethylene glycol monostearate (3 g), polyoxyethylene cetostearyl ether (2 g), cetanol (4 g), beeswax (1 g), octystinate octylate (7g), isopropyl myristin (2g); (c) polyethylene glycol (3 g), carboxyvinyl polymer (0.2 g), purified water (amount of which total amount is 100 g); (d) sodium hydroxide aqueous solution (appropriate amount)
[623] Production method: (b) was heated to about 75 ° C, (c) was heated to about 75 ° C was added while stirring, then (a) was added while stirring. Thereafter, the pH was adjusted to about 6.8 in (d). Thereafter, after cooling to a temperature of about 25 ℃, the resulting cream was taken in a suitable container.
[624] Example 126 Cream
[625] Prescription: (a) dimethidazole (2 g); (b) glycol monostearate (10 g), polyoxyethylene glycol monostearate (3 g), polyoxyethylene cetostearyl ether (2 g), cetanol (4 g), beeswax (1 g), octystinate octylate (7g), isopropyl myristin (2g); (c) polyethylene glycol (3 g), carboxyvinyl polymer (0.2 g), purified water (amount of which total amount is 100 g); (d) sodium hydroxide aqueous solution (appropriate amount)
[626] Production method: (b) was heated to about 75 ° C, (c) was heated to about 75 ° C was added while stirring, then (a) was added while stirring. Thereafter, the pH was adjusted to about 6.8 in (d). Thereafter, after cooling to a temperature of about 25 ° C, the resulting cream was collected in a suitable container.
[627] Example 127 Cream
[628] Prescription: (a) Ronidazole (2 g); (b) glycol monostearate (10 g), polyoxyethylene glycol monostearate (3 g), polyoxyethylene cetostearyl ether (2 g), cetanol (4 g), beeswax (1 g), octystinate octylate (7g), isopropyl myristin (2g); (c) polyethylene glycol (3 g), carboxyvinyl polymer (0.2 g), purified water (amount of which total amount is 100 g); (d) sodium hydroxide aqueous solution (appropriate amount)
[629] Production method: (b) was heated to about 75 ° C, (c) was heated to about 75 ° C was added while stirring, then (a) was added while stirring. Thereafter, the pH was adjusted to about 6.8 in (d). Thereafter, after cooling to a temperature of about 25 ℃, the resulting cream was taken in a suitable container.
[630] Example 128 Cream
[631] Prescription: (a) Ipronidazole (2 g); (b) glycol monostearate (10 g), polyoxyethylene glycol monostearate (3 g), polyoxyethylene cetostearyl ether (2 g), cetanol (4 g), beeswax (1 g), octystinate octylate (7g), isopropyl myristin (2g); (c) polyethylene glycol (3 g), carboxyvinyl polymer (0.2 g), purified water (amount of which total amount is 100 g); (d) sodium hydroxide aqueous solution (appropriate amount)
[632] Production method: (b) was heated to about 75 ° C., and (c) was heated to about 75 ° C. while stirring was added, and then (a) was added while stirring. Thereafter, the pH was adjusted to about 6.8 in (d). Thereafter, after cooling to a temperature of about 25 ° C, the resulting cream was collected in a suitable container.
[633] Example 129 Cream
[634] Prescription: (a) onidazol (2 g); (b) glycol monostearate (10 g), polyoxyethylene glycol monostearate (3 g), polyoxyethylene cetostearyl ether (2 g), cetanol (4 g), beeswax (1 g), octystinate octylate (7g), isopropyl myristin (2g); (c) polyethylene glycol (3 g), carboxyvinyl polymer (0.2 g), purified water (amount of which total amount is 100 g); (d) sodium hydroxide aqueous solution (appropriate amount)
[635] Production method: (b) was heated to about 75 ° C, (c) was heated to about 75 ° C was added while stirring, then (a) was added while stirring. Thereafter, the pH was adjusted to about 6.8 in (d). Thereafter, after cooling to a temperature of about 25 ℃, the resulting cream was taken in a suitable container.
[636] Example 130 External Cream
[637] Prescription: (a) metronidazole (5 g); (b) glycol monostearate (10 g), cetanol (7 g), liquid paraffin (9 g), white petrolatum (2.5 g); (c) urea (2 g), polyethylene glycol (7 g), Tween 80 (1 g), purified water (amount of which becomes 100 g)
[638] Manufacturing method: (b) was melt | dissolved and adjusted to about 85 degreeC. The thing which melt | dissolved and adjusted (c) at about 85 degreeC was added to this, stirring, and (a) was then added. After cooling to a temperature of about 25 ° C. with continuous stirring, the sample was collected in a suitable container.
[639] (Example 131) External cream
[640] Prescription: (a) Tinidazole (5 g); (b) glycol monostearate (10 g), cetanol (7 g), liquid paraffin (9 g), white petrolatum (2.5 g); (c) urea (2 g), polyethylene glycol (7 g), Tween 80 (1 g), purified water (amount of which becomes 100 g)
[641] Manufacturing method: (b) was melt | dissolved and adjusted to about 85 degreeC. The thing which melt | dissolved and adjusted (c) at about 85 degreeC was added to this, stirring, and (a) was then added. After cooling to a temperature of about 25 ° C. with continuous stirring, the sample was collected in a suitable container.
[642] [Test Example]
[643] Test Example 1 Treatment of Atopic Dermatitis
[644] The ointment prepared in Example 1 was applied to atopic dermatitis patients to examine the therapeutic effect.
[645] It applied to the following patients as a subject patient.
[646] Target patient A: A child (aged boy) of age 1 with atopic dermatitis
[647] Target patient B: 2 years old child (male) suffering from atopic dermatitis
[648] Patient C: A 40-year-old woman suffering from atopic dermatitis
[649] Patient D: A 60-year-old woman suffering from atopic dermatitis
[650] Patient E: Male 27 years of age with atopic dermatitis
[651] For subjects A and B, the external ointment prepared in Example 1 was applied twice a day for 4 consecutive weeks on the face of severe atopic dermatitis, and the state of inflammation was observed.
[652] In addition, subjects C, D, and E applied the external ointment prepared in Example 1 twice a day over 4 consecutive weeks to the affected area from the lower thigh to the astragalus with severe atopic dermatitis and observed the state of inflammation. did.
[653] The treatment effect was evaluated by rating the symptoms of dermatitis such as redness and eczema at the start of treatment, and the timely healing situation after 3 days, 1 week, 2 weeks, 3 weeks, and 4 weeks later. Done. In addition, the presence or absence of pruritus on the surface of the skin after 4 weeks was evaluated.
[654] In addition, the evaluation grade is as follows.
[655] 5: Symptoms of dermatitis such as redness, eczema, etc. are severe, there is a lot of pruritus and the surface of the skin is unconsciously scratched, and the presence of a wound is also seen.
[656] 4: Symptoms of dermatitis such as redness, eczema, etc. are severe and pruritic, but none of evaluation is about 5.
[657] 3: Redness, eczema and other dermatitis symptoms can be confirmed, the degree of worry about pruritus.
[658] 2: Symptoms of dermatitis such as redness, eczema, etc. can be seen a little, but not so different from normal skin.
[659] 1: No dermatitis symptoms such as redness or eczema, no pruritus, normal skin condition.
[660] The results are shown in Table 2 below.
[661] TABLE 2
[662] 3 weeks after start, 1 week after 2 weeks, 3 weeks after 4 weeks
[663] Patient pruritus skin surface
[664] A 5 5 3 1 1 1 None Normal
[665] B 5 4 3 2 1 1 None Normal
[666] C 5 5 4 1 1 1 None Normal
[667] D 5 5 4 3 2 1 None Normal
[668] E 3 3 1 1 1 1 None Normal
[669] As apparent from the above results, the external preparation of the present invention showed an improvement in the symptoms of dermatitis 3 to 7 days after the start of the application when treating atopic dermatitis, and was not completely different from normal skin after 3 to 4 weeks. . Moreover, there was no irritation by the formulation also in application | coating. Moreover, even after discontinuation of administration, no rebound or the like such as side effects appearing in the external preparation of the steroid system was confirmed.
[670] Test Example 2 Treatment of Atopic Dermatitis
[671] The cream prepared in Example 4 was applied to atopic skin inflammation patients, and the therapeutic effect was examined. It applied to the following patients as a subject patient.
[672] Patient F: Child 2 years old (a boy) suffering from atopic dermatitis
[673] Target patient G: Child (male) of 8 years of age suffering from atopic dermatitis
[674] Target patient H: Woman 50 years old with atopic dermatitis
[675] Patient I: A 40-year-old woman suffering from atopic dermatitis
[676] Patient J: Male 27 years old with atopic dermatitis
[677] For the subjects F, G, H, I and J, the external cream prepared in Example 4 was applied twice a day for 4 consecutive weeks on the face with severe atopic dermatitis, and the state of inflammation was observed.
[678] As in Experiment 1, the therapeutic effect was evaluated by 3 days, 1 week, 2 weeks, 3 weeks, and 4 weeks after dermatitis symptoms such as redness and eczema at the start of treatment, and the timely healing situation thereafter. Evaluated. In addition, the presence or absence of pruritus on the surface of the skin after 4 weeks was evaluated. In addition, the evaluation rating used the evaluation rating in the said Test Example 1.
[679] The results are shown in Table 3 below.
[680] TABLE 3
[681] 3 weeks after start, 1 week after 2 weeks, 3 weeks after 4 weeks
[682] Patient pruritus skin surface
[683] F 5 4 2 1 1 1 None Normal
[684] G 5 4 3 2 1 1 None Normal
[685] H 5 5 3 1 1 1 None Normal
[686] I 3 2 2 1 1 1 None Normal
[687] J 3 2 1 1 1 1 None Normal
[688] As apparent from the above results, the external preparation of the present invention showed an improvement in the symptoms of dermatitis 3 to 7 days after the start of the application when treating atopic dermatitis, and was not completely different from normal skin after 3 to 4 weeks. . Moreover, there was no irritation by the formulation also in application | coating. Moreover, even after discontinuation of administration, no rebound or the like such as side effects appearing in the external preparation of the steroid system was confirmed.
[689] Test Example 3 Treatment of Atopic Dermatitis
[690] The ointment prepared in Example 11 was applied to atopic skin inflammation patients to examine the therapeutic effect.
[691] As a subject patient, it applied to the following patients.
[692] Target patient K: A child of 1 year old (male) suffering from atopic dermatitis
[693] Target patient L: 2 years old child (male) affected by atopic dermatitis
[694] Subject patient M: Woman 35 years old with atopic dermatitis
[695] Target patient N: Woman 54 years old with atopic dermatitis
[696] Subject patient O: Male 27 years old with atopic dermatitis
[697] For the subjects K and L, the external ointment prepared in Example 11 was applied twice a day over 4 consecutive weeks to the face with severe atopic dermatitis, and the state of the inflammation was observed.
[698] Subjects M, N, and O also applied the external ointment prepared in Example 11 twice daily for 4 consecutive weeks to the affected area from the lower thigh to the astragalus, where atopic dermatitis was severe. Observed.
[699] As in Experiment 1, the therapeutic effect was evaluated by 3 days, 1 week, 2 weeks, 3 weeks, and 4 weeks after dermatitis symptoms such as redness and eczema at the start of treatment, and the timely healing situation thereafter Evaluated. In addition, the presence or absence of pruritus on the surface of the skin after 4 weeks was evaluated. In addition, the evaluation rating used the evaluation rating in the said Test Example 1.
[700] The results are shown in Table 4 below.
[701] TABLE 4
[702] 3 weeks after start, 1 week after 2 weeks, 3 weeks after 4 weeks
[703] Patient pruritus skin surface
[704] K 5 5 3 1 1 1 None Normal
[705] L 5 4 3 2 1 1 None Normal
[706] M 5 5 4 1 1 1 None Normal
[707] N 5 5 4 3 2 1 None Normal
[708] O 4 3 1 1 1 1 None Normal
[709] As apparent from the above results, the external preparation of the present invention showed an improvement in the symptoms of dermatitis 3 to 7 days after the start of the application when treating atopic dermatitis, and was not completely different from normal skin after 3 to 4 weeks. . Moreover, there was no irritation by the formulation also in application | coating. Moreover, even after discontinuation of administration, no rebound or the like such as side effects appearing in the external preparation of the steroid system was confirmed.
[710] Test Example 4 Treatment of Atopic Dermatitis
[711] The cream prepared in Example 14 was applied to atopic dermatitis patients, and its therapeutic effect was examined. It applied to the following patients as a subject patient.
[712] Target patient P: 2 years old child (male) affected by atopic dermatitis
[713] Target patient Q: A child (male) of 6 years of age suffering from atopic dermatitis
[714] Target patient R: Woman 53 years old with atopic dermatitis
[715] Patient S: 58-year-old woman suffering from atopic dermatitis
[716] Patient T: 35-year-old male with atopic dermatitis
[717] To the subjects P, Q, R, S, and T, the external cream prepared in Example 14 was applied twice a day to the face with severe atopic dermatitis over four consecutive weeks, and the state of inflammation was observed.
[718] The therapeutic effect is evaluated after 3 days, 1 week, 2 weeks, 3 weeks, and 4 weeks after dermatitis symptoms such as redness and eczema at the start of treatment, and the timely healing situation thereafter as in Test Example 1 Was evaluated. In addition, the presence or absence of pruritus on the surface of the skin after 4 weeks was evaluated. In addition, the evaluation rating used the evaluation rating in the said Test Example 1.
[719] The results are shown in Table 5 below.
[720] TABLE 5
[721] 3 weeks after start, 1 week after 2 weeks, 3 weeks after 4 weeks
[722] Patient pruritus skin surface
[723] P 5 5 3 1 1 1 None Normal
[724] Q 5 4 3 3 1 1 None Normal
[725] R 5 5 3 2 1 1 None Normal
[726] S 5 4 2 1 1 1 None Normal
[727] T 5 4 2 1 1 1 None Normal
[728] As apparent from the above results, the external preparation of the present invention showed an improvement in the symptoms of dermatitis 3 to 7 days after the start of the application when treating atopic dermatitis, and was not completely different from normal skin after 3 to 4 weeks. . Moreover, there was no irritation by the formulation also in application | coating. Moreover, even after discontinuation of administration, no rebound or the like such as side effects appearing in the external preparation of the steroid system was confirmed.
[729] Test Example 5 Treatment of Atopic Dermatitis
[730] The cream prepared in Example 21 was applied to atopic dermatitis patients to examine the therapeutic effect.
[731] As a subject patient, it applied to the following patients.
[732] Target patient U: Woman 40 years old with atopic dermatitis
[733] Patient V: A 38-year-old woman suffering from atopic dermatitis
[734] Target patient W: Woman 55 years old suffering from atopic dermatitis
[735] Way:
[736] For the patients V and W, the external cream prepared in Example 21 was applied twice a day over the face of atopic dermatitis for 4 consecutive weeks, and the state of the inflammation was observed.
[737] About the subject U, the external cream of metronidazole monotherapy was applied twice a day to the face of atopic dermatitis over 4 consecutive weeks, and the state of the inflammation was observed.
[738] The treatment effect was evaluated by rating the symptoms of dermatitis such as redness and eczema at the start of treatment, and the timely healing situation thereafter after 3 days, 1 week, 2 weeks, 3 weeks, and 4 weeks. In addition, the presence or absence of pruritus on the surface of the skin after 4 weeks was evaluated.
[739] In addition, the evaluation grade is as follows.
[740] Condition of the skin
[741] 5: Symptoms of dermatitis, such as redness, eczema, severe pain, even pain.
[742] 4: Dermatitis symptoms such as redness and eczema are severe, but not about 5 degrees.
[743] 3: Symptoms of dermatitis such as redness, eczema, etc. can be confirmed, but not about 4.
[744] 2: Symptoms of dermatitis such as redness, eczema, etc. can be seen a little, but not so different from normal skin.
[745] 1: No dermatitis symptoms such as redness, eczema and normal skin condition.
[746] Skin sensation
[747] 3: Severe pruritus, unconsciously scratching the skin.
[748] 2: A feeling of literacy, but can stop scratching the skin.
[749] 1: A state of no prism at all.
[750] The results are summarized in Table 6 below.
[751] In Table 6, S1 represents the grade of the state of the skin, and S2 represents the grade of the pruritus.
[752] TABLE 6
[753] 3 weeks after start, 1 week after 2 weeks, 3 weeks after 4 weeks
[754] Patient S1: S2 S1: S2 S1: S2 S1: S2 S1: S2 S1: S2 S1: S2
[755] U 5: 3 5: 3 3: 3 2: 2 2: 2 1: 1 1: 1
[756] V 5: 3 4: 2 3: 1 2: 1 2: 1 1: 1 1: 1
[757] W 5: 3 4: 1 3: 1 1: 1 1: 1-:-1: 1
[758] As described above, after 4 weeks, patients U, V, and W all had skin conditions that were not different from those of healthy people, but patients V, who applied the external cream of Example 21, which was a combination agent, than patients U, who applied the external preparation of metronidazole alone, and W's patients lost pruritus early and skin improvement was quick. In addition, since the patient W was not able to confirm the symptoms of atopic dermatitis at the time of the third week, the application was terminated at the time of the third week at his or her wish.
[759] Test Example 6 Treatment of Atopic Dermatitis
[760] The creams prepared in Examples 22 and 51 were applied to patients with atopic dermatitis, and their therapeutic effects were examined.
[761] Test Methods:
[762] The external cream prepared in Example 22 was applied twice a day over four consecutive weeks to the right arm of atopic dermatitis of the patient U of the test example 5, and the state of the inflammation was observed. In addition, the external cream prepared in Example 51 was applied twice a day to the left arm of atopic dermatitis of the patient U of Test Example 5 over four consecutive weeks, and the state of inflammation was observed.
[763] The treatment effect was evaluated by rating the symptoms of dermatitis such as redness and eczema at the start of treatment, and the timely healing situation thereafter after 3 days, 1 week, 2 weeks, 3 weeks, and 4 weeks. In addition, the presence or absence of pruritus on the surface of the skin after 4 weeks was evaluated.
[764] Moreover, the grade of evaluation is the same as that of the test example 5.
[765] The results are summarized in Table 7 below.
[766] In Table 7, S1 represents the grade of the state of the skin and S2 represents the grade of the pruritus.
[767] TABLE 7
[768] 3 weeks after start, 1 week after 2 weeks, 3 weeks after 4 weeks
[769] Target S1: S2 S1: S2 S1: S2 S1: S2 S1: S2 S1: S2 S1: S2
[770] Right arm 4: 3 3: 1 2: 1 2: 1 1: 1 1: 1 1: 1
[771] Left arm 4: 3 4: 3 3: 2 2: 2 2: 1 1: 1 1: 1
[772] As described above, the skin condition of the left arm and right arm was improved after 4 weeks in the same symptoms of the patient U who was the same person. The right arm to which the external cream agent of Example 22 which is a composite agent was applied earlier than the left arm to which the external agent of Example 51 which is a metronidazole sole external agent disappeared early, and the improvement of skin was also quick.
[773] Test Example 7 Treatment of Atopic Dermatitis
[774] The cream prepared in Example 23 was applied to atopic dermatitis patients, and the therapeutic effect was examined.
[775] As a subject patient, it applied to the following patients.
[776] Target patient X: A woman 30 years of age with atopic dermatitis
[777] Patient Y: Female 28 years of age with atopic dermatitis
[778] Subject patient Z: Woman 26 years old with atopic dermatitis
[779] Target patient a: A 50 year old female with head disease affected by atopic dermatitis.
[780] Way:
[781] For the subject patient X, the external cream of the tinidazole monosaccharide was applied twice a day to the face with severe atopic dermatitis over 4 consecutive weeks, and the state of the inflammation was observed.
[782] For the subjects Y and Z, the topical atopic dermatitis was applied twice daily, and the external cream prepared in Example 23 was applied for 4 consecutive weeks to observe the state of the inflammation.
[783] About the target patient a, the gel preparation prepared in Example 25 was applied until symptoms improved 2-3 times a day, and the effect was observed.
[784] The treatment effect was evaluated by rating the symptoms of dermatitis such as redness and eczema at the start of treatment, and the timely healing situation thereafter after 3 days, 1 week, 2 weeks, 3 weeks, and 4 weeks. In addition, the presence or absence of pruritus on the surface of the skin after 4 weeks was evaluated.
[785] Moreover, the grade of evaluation is the same as that of the test example 5.
[786] The results are summarized in Table 8 below.
[787] In Table 8, S1 represents the grade of the state of the skin, and S2 represents the grade of the pruritus.
[788] TABLE 8
[789] 3 weeks after start, 1 week after 2 weeks, 3 weeks after 4 weeks
[790] Patient S1: S2 S1: S2 S1: S2 S1: S2 S1: S2 S1: S2 S1: S2
[791] X 5: 3 5: 3 4: 2 3: 2 2: 1 2: 1 2: 1
[792] Y 5: 3 4: 1 3: 1 2: 1 1: 1 1: 1 1: 1
[793] Z 4: 3 3: 1 2: 1 1: 1-:--:-1: 1
[794] a 4: 3 3: 1 3: 1 2: 1 2: 1 1: 1 1: 1
[795] As described above, after 4 weeks, patients X, Y, Z, and a all had a skin condition no different from that of healthy people, but the external cream or the embodiment 23 of Example 23, which was a combination agent than the patient X, which applied an external agent of tinidazole alone. The patients Y, Z, and a who applied the gel of Example 25 had no prurisiness early, and the improvement of the skin was quick. In addition, since the symptoms of atopic dermatitis could not be confirmed at the time of the second week, patient Z terminated the application at the time of the second week at his or her wish.
[796] Test Example 8 Treatment of Atopic Dermatitis
[797] The therapeutic effect was examined by applying the external preparation of the present invention to a patient with actual atopic dermatitis.
[798] As a subject patient, it applied to the following patients.
[799] Subject patient b: Male 40 years old with atopic dermatitis
[800] Way:
[801] The external cream of Example 11 was applied twice a day for 4 consecutive weeks to the left arm suffering from atopic dermatitis of subject patient b, and the state of inflammation was observed.
[802] Moreover, the external cream prepared in Example 24 was applied twice a day over 4 consecutive weeks to the right arm which atopic dermatitis inflammation of the same subject patient b was affected, and the state of the inflammation was observed.
[803] The treatment effect was evaluated by rating the symptoms of dermatitis such as redness and eczema at the start of treatment, and the timely healing situation thereafter after 3 days, 1 week, 2 weeks, 3 weeks, and 4 weeks. In addition, the presence or absence of pruritus on the surface of the skin after 4 weeks was evaluated.
[804] Moreover, the grade of evaluation is the same as that of the test example 5.
[805] The results are summarized in Table 9 below.
[806] In Table 9, S1 represents the grade of the state of the skin, and S2 represents the grade of the pruritus.
[807] TABLE 9
[808] 3 weeks after start, 1 week after 2 weeks, 3 weeks after 4 weeks
[809] Target S1: S2 S1: S2 S1: S2 S1: S2 S1: S2 S1: S2 S1: S2
[810] Right arm 5: 3 5: 1 4: 1 2: 1 2: 1 2: 1 1: 1
[811] Left arm 5: 3 5: 3 4: 2 4: 2 3: 1 3: 1 3: 1
[812] As described above, the skin condition of the left and right arms was improved after 4 weeks in the same symptoms of the patient b who was the same person. The right arm to which the external cream agent of Example 24 which was a composite agent was applied earlier than the left arm to which the external agent of Example 11 which is the external agent of tinidazole alone disappeared, and the improvement of skin was also quick.
[813] (Test Example 9)
[814] The external preparations prepared in Examples were applied to patients suffering from actual eczema / inflammatory and seborrheic dermatitis, and the therapeutic effects were examined.
[815] As a subject patient, it applied to the following patients.
[816] Subject Patients c: Women 60 years of age with cosmetic inflammation.
[817] Subject Patient d: Male 34 years of age with seborrheic dermatitis.
[818] Subject Patient e: A 45 year old male suffering from hyperphilia (mite).
[819] Subject Patient f: Male, age 57, with ringworm.
[820] Subject patient g: Female 30 years of age with acne.
[821] Patient h: A 28 year old male suffering from purulent dermatitis in the head.
[822] Patient i: A 25 year old male with herpes dermatitis (blister) on the neck.
[823] Subject Patient j: Female, age 45, suffering from candidiasis between fingers.
[824] Target patient k: Male 63 years old with dry eczema on back.
[825] Subject l: Male, age 28, with purulent dermatitis in the head.
[826] Subject m: Male 63 years of age with swelling and eczema in the neck.
[827] Target patient n: Male of age 33 years old with herpes at the forehead.
[828] Subject Patients o: Women aged 23 years with dry eczema in the lower extremities.
[829] Way:
[830] The subjects c and d were applied with the external cream prepared in Example 22 twice a day for four consecutive weeks, and the effect was observed.
[831] For the subject patient e, the external ointment prepared in Example 33 was applied twice a day until symptoms improved, and the effect was observed.
[832] For the subject patient f, the external cream prepared in Example 31 was applied twice a day for 4 consecutive weeks, and the effect was observed.
[833] For the target patient g, the external cream prepared in Example 30 was applied twice a day until symptoms improved, and the effect was observed.
[834] For the subject patient h, the gel preparation prepared in Example 39 was applied 2 to 3 times a day until symptoms improved, and the effect was observed.
[835] For the subject patient i, the external cream prepared in Example 32 was applied two to three times a day until symptoms improved, and the effect was observed.
[836] For the subject patient j, the external ointment prepared in Example 35 was applied twice a day until symptoms improved, and the effect was observed.
[837] About the target patient k, the external lotion agent manufactured in Example 36 was apply | coated 2-3 times a day for 4 weeks continuously, and the effect was observed.
[838] About the target patient 1, the patch prepared in Example 37 was applied 2-3 times a day for 3 consecutive weeks, and the effect was observed.
[839] About the target patient m, the plaster agent manufactured in Example 38 was sent 2-3 times a day for 3 consecutive weeks, and the effect was observed.
[840] For the subject patient n, the cream agent prepared in Example 21 was applied until symptoms improved 2 to 4 times a day, and the effect was observed.
[841] For the subject patient o, the external ointment prepared in Example 34 was applied two to three times a day until symptoms improved, and the effect was observed.
[842] The treatment effect was evaluated by rating the symptoms of dermatitis such as redness and eczema at the start of treatment, and the timely healing situation thereafter after 3 days, 1 week, 2 weeks, 3 weeks, and 4 weeks. In addition, the presence or absence of pruritus on the surface of the skin after 4 weeks was evaluated.
[843] In addition, the evaluation grade was added to the same thing as Test Example 5, and the following substance was used about pain.
[844] State of Pain:
[845] 3: severe pain.
[846] 2: Pain not to be worried about if I do not touch it.
[847] 1: No pain at all.
[848] The results are summarized in Table 10 below.
[849] In Table 10, S1 represents the grade of the state of the skin, S2 represents the grade of pruritus, and S3 represents the grade of pain.
[850] TABLE 10
[851] 3 weeks after launch 1 week after 2 weeks 3 weeks after 4 weeks
[852] Patient evaluation
[853] c S1: S2 5: 3 5: 2 4: 1 3: 1 2: 1 2: 1 2: 1
[854] d S1: S2 4: 3 3: 2 2: 1 2: 1 1: 1 1: 1 1: 1
[855] e S1: S2 3: 3 2: 1 1: 1-:--:--:-1: 1
[856] f S1: S2 5: 3 4: 2 3: 2 3: 1 2: 2 2: 1 2: 2
[857] g S1: S2 4: 3 3: 1 2: 1 2: 1 1: 1 1: 1 1: 1
[858] h S1: S3 4: 3 2: 1 2: 1 1: 1-:--:-1: 1
[859] i S1: S2 4: 3 2: 1 1: 1 1: 1-:--:-1: 1
[860] j S1: S3 3: 3 2: 1 1: 1-:--:--:-1: 1
[861] k S1: S3 4: 2 3: 2 1: 1 1: 1 1: 1-:-1: 1
[862] l S1: S2 4: 3 4: 3 3: 1 2: 1 2: 1-:-2: 1
[863] m S1: S3 3: 3 3: 3 2: 2 2: 1 2: 1-:-2: 1
[864] n S1: S2 3: 3 1: 1-:--:--:--:-1: 1
[865] o S1: S2 4: 3 3: 1 2: 1 1: 1 1: 1-:-1: 1
[866] As described above, the external preparations of the present invention showed improvement of symptoms 3 to 7 days after the start of treatment in the treatment of various skin diseases, and remained intact with normal skin after 3 to 4 weeks. Patient c has been using steroids for about six months, so the side effect is that the skin is keloid-like, but dermatitis has subsided. Patient f was not cured after 4 weeks because the disease in ringworm was about 40 years, but the improvement in skin condition was remarkable. Moreover, also in application | coating, there was no irritation by the formulation. Moreover, even after discontinuation of administration, no rebounds such as side effects that appear in the steroid-based external preparations were confirmed.
[867] (Test Example 10)
[868] The external preparations prepared in Examples were applied to patients suffering from actual eczema / rash and seborrheic dermatitis, and the therapeutic effects were examined.
[869] It applied to the following patients as a subject patient.
[870] Patient P: A 10 year old male with palpable psoriasis on the instep.
[871] Subject Patients q: 10 years old male with vulgar psoriasis affected by the lower extremity.
[872] Subject Patient r: A 45-year-old male suffering from acute dermatitis caused by insect bites.
[873] Patient s: A 50-year-old woman with facial scleroderma.
[874] Subject patient t: Female 20 years of age with acne.
[875] Patient u: A 23-year-old woman with eczema on her upper arm.
[876] Patient v: A 50 year old female with atopic dermatitis in the head.
[877] Patient w: A 63 year old female with ringworm on her toes.
[878] Target patient x: Male, age 65, with a tumor (smell, pain) in the neck.
[879] Way:
[880] About the target patients p and q, the external creams prepared in Example 44 were applied twice a day for 4 consecutive weeks, and the effect was observed.
[881] For the subject patient r, the external ointment prepared in Example 46 was applied twice a day until symptoms improved, and the effect was observed.
[882] To the subject patient s, the external cream prepared in Example 41 was applied twice a day for 4 consecutive weeks, and the effect was observed.
[883] For the target patient t, the external cream prepared in Example 40 was applied twice a day until symptoms improved, and the effect was observed.
[884] For the subject patient u, the external cream prepared in Example 42 was applied two to three times a day until symptoms improved, and the effect was observed.
[885] For the subject patient v, the gel prepared in Example 25 was applied two to three times a day until symptoms improved, and the effect was observed.
[886] For the target patient w, the lotion agent prepared in Example 47 was applied two to three times a day until symptoms improved, and the effect was observed.
[887] For the subject patient x, the external cream prepared in Example 50 was applied 2-3 times a day for 4 weeks in succession, and the effect was observed.
[888] The treatment effect was evaluated by rating the symptoms of dermatitis such as redness and eczema at the start of treatment, and the timely healing situation thereafter after 3 days, 1 week, 2 weeks, 3 weeks, and 4 weeks. In addition, the presence or absence of pruritus on the surface of the skin after 4 weeks was evaluated.
[889] In addition, the same grade as Test Example 10 was used for the evaluation.
[890] The results are summarized in Table 11 below.
[891] In Table 11, S1 represents the grade of the state of the skin, S2 represents the grade of pruritus, and S3 represents the grade of pain.
[892] TABLE 11
[893] 3 weeks after start, 1 week after 2 weeks, 3 weeks after 4 weeks
[894] Patient evaluation
[895] p S1: S2 4: 3 3: 2 2: 1 2: 1 1: 1 1: 1 1: 1
[896] q S1: S2 4: 3 2: 1 2: 1 2: 1 1: 1 1: 1 1: 1
[897] r S1: S3 4: 3 2: 1 2: 1 1: 1 1: 1-:-1: 1
[898] s S1: S2 5: 2 4: 1 3: 1 2: 1 2: 1 2: 1 2: 1
[899] t S1: S2 3: 3 1: 1 1: 1-:--:--:-1: 1
[900] u S1: S2 4: 3 2: 1 2: 1 1: 1-:--:-1: 1
[901] v S1: S2 4: 3 3: 1 3: 1 2: 1 2: 1 1: 1 1: 1
[902] w S1: S2 4: 3 2: 1 2: 1 2: 1 1: 1 1: 1 1: 1
[903] x S1: S3 4: 3 4: 3 3: 2 3: 2 2: 1 2: 1 2: 1
[904] As described above, the external cream agent of the present invention showed improvement in the symptoms of dermatitis three to seven days after the start of application when treating various dermatitis, and remained intact with normal skin after three to four weeks. In addition, the head of patient v had partially lost hair, but hair had sprouted slightly from around 3 weeks.
[905] Moreover, also in application | coating, there was no irritation by the formulation. Moreover, even after discontinuation of administration, no rebound or the like such as side effects appearing in the external preparation of the steroid system was confirmed.
[906] (Test Example 11)
[907] The treatment effect was examined by applying the external preparation of the present invention to patients suffering from actual skin inflammation and odor.
[908] It applied to the following patients as a subject patient.
[909] Subject y (right): Right arm side of male 33 years old affected by liquid odor
[910] Subject y (the left): The left arm side of 33-year-old man affected by liquid odor
[911] Way:
[912] Subject y (right): External cream agent of Example 52
[913] Subject y (left): External cream agent of Example 53
[914] The said external cream agent was apply | coated twice a day to the site | parts affected by the liquid odor, respectively, and the progress was observed.
[915] The treatment effect was evaluated by evaluating symptoms such as odor at the start of treatment and the subsequent healing situation after 3 days, 1 week, 2 weeks, and 3 weeks later.
[916] Moreover, the grade of evaluation is as follows.
[917] Contamination of the skin
[918] 4: dirty
[919] 3: a little dirty
[920] 2: generally clean
[921] 1: clean
[922] smell
[923] 4: it smells terrible
[924] 3: smells a little
[925] 2: almost no smell
[926] 1: does not smell
[927] The results are summarized in Table 12 below.
[928] In Table 12, S4 represents a grade of skin contamination, and S5 represents a grade of smell.
[929] TABLE 12
[930] 3 weeks after start 1 week after 2 weeks after 3 weeks
[931] Target S4: S5 S4: S5 S4: S5 S4: S5 S4: S5
[932] Right arm 4: 4 4: 4 3: 3 3: 1 1: 1
[933] Left arm 4: 4 4: 4 3: 3 3: 1 1: 1
[934] As described above, all liquid odors of the subject y were alleviated after 7 to 14 days in the right and left sides, and were cured after 14 to 21 days.
[935] Moreover, also in application | coating, there was no irritation and abnormality in the skin of the subject y.
[936] Test Example 12 Treatment of Liquid Odor
[937] The treatment effect was examined by applying the external preparation of the present invention to patients suffering from actual skin inflammation and odor.
[938] It applied to the following patients as a subject patient.
[939] Subject z: Male 33 years old affected by liquid odor
[940] Subject Aa: Male 33 years of age affected by liquid odor
[941] Way:
[942] Subject z: External cream of Example 22
[943] Subject Aa: External cream of Example 24
[944] The said external cream agent was apply | coated twice a day to the site | parts affected by the liquid odor, respectively, and the progress was observed.
[945] The treatment effect was evaluated by evaluating symptoms such as odor at the start of treatment and the subsequent healing situation after 3 days, 1 week, 2 weeks, and 3 weeks later.
[946] In addition, the same grade as Test Example 10 and Test Example 12 was used for evaluation.
[947] The results are summarized in Table 13 below.
[948] In Table 13, S1 represents the grade of the skin condition, and S5 represents the grade of the smell.
[949] TABLE 13
[950] 3 weeks after launch 1 week after 2 weeks 3 weeks after 4 weeks
[951] Patient evaluation
[952] z S1: S5 4: 3 2: 1 1: 1 1: 1-:--:-1: 1
[953] Aa S1: S5 3: 3 2: 1 1: 1-:--:--:-1: 1
[954] As described above, the external preparation of the present invention improved the skin condition and odor of the liquid odor in a short time.
[955] Test Example 13 Treatment of Liquid Odor
[956] The treatment effect was examined by applying the external preparation of the present invention to patients suffering from actual skin inflammation and odor.
[957] Target person Ab: Right arm side of male 27 years old affected by liquid odor
[958] Target person Ac: The left arm side of male 27 years old affected by odor
[959] Eligible Ad: Right arm of a 44 year old male suffering from liquid odor
[960] Subject Ae: Left arm side of male 44 years old affected by odor
[961] Target person Af: The right arm side of woman 23 years old affected by liquid odor
[962] Target person Ag: The left arm side of woman 23 years old affected by odor
[963] Way:
[964] Subject Ab: External cream of Example 54
[965] Subject Ac: external cream of Example 55
[966] Subject Ad: External cream of Example 56
[967] Subject Ae: External cream of Example 57
[968] Subject Af: External cream of Example 58
[969] Subject Ag: External cream of Example 59
[970] The said external cream agent was apply | coated twice a day to the site | parts affected by the liquid odor, respectively, and the progress was observed.
[971] The treatment effect was evaluated by scoring the symptoms such as smell at the start of treatment and the subsequent healing situation over time.
[972] The evaluation used the same rating as that in Test Example 11.
[973] The results are summarized in Table 14 below.
[974] In Table 14, S4 represents the grade of contamination of the skin and S5 represents the grade of the smell.
[975] TABLE 14
[976] 3 days after starting 5 days after 7 days after 10 days
[977] Patient evaluation
[978] Ab S4: S5 4: 4 4: 4 3: 2 2: 1 2: 1 1: 1
[979] Ac S4: S5 4: 4 4: 3 3: 2 3: 1 2: 1 1: 1
[980] Ad S4: S5 4: 4 4: 3 3: 2 3: 1 2: 1 1: 1
[981] Ae S4: S5 4: 3 4: 3 3: 1 3: 1 1: 1 1: 1
[982] Af S4: S5 4: 4 3: 3 2: 3 2: 1 2: 1 1: 1
[983] Ag S4: S5 4: 4 4: 3 3: 3 3: 1 2: 1 2: 1
[984] As mentioned above, all the subjects reduced the smell in the liquid odor after 3 to 5 days, and the liquid odor and the condition of the skin also improved after 7 to 10 days.
[985] Moreover, also in application | coating, all the subjects showed no irritation and abnormality in skin.
[986] The external smell of Example 25 and 60-64 also improved odor about 3 to 5 days similarly to the above, and after 7 to 10 days, both odor and skin condition improved. In addition, it was a lotion agent and a gel agent which were easy to use.
[987] In addition, since the case where the liquid odor was reduced by the effect of the base alone was also considered, it was applied twice a day for about two weeks in a placebo, but there was no effect.
[988] Test Example 14 Treatment of Odor
[989] Indeed, the external odor of the present invention was applied to a foot malodorous patient to examine its therapeutic effect.
[990] It applied to the following patients as a subject patient.
[991] Subject Ah: Right foot (often foot-smelling) of a 24 year old male with a bad smell below the ankle
[992] Subject Ai: The left foot of a 24-year-old man with a bad smell below his ankle
[993] Way:
[994] Subject Ah: The external lotion agent of Example 63
[995] Subject Ai: A lotion placebo placebo without the active ingredient of Example 63
[996] When the external lotion containing the active ingredient was applied to the right foot, the smell of the foot disappeared in about 4 to 5 hours. However, when the placebo was applied to the left foot, the foot odor did not disappear even after about 4 to 5 hours.
[997] (Test Example 15)
[998] The treatment effect was examined by applying the external preparation of the present invention to patients suffering from actual skin inflammation and psoriasis.
[999] As a subject patient, it applied to the following patients.
[1000] Subject Aj: Right foot of a 43 year old male suffering from psoriasis
[1001] Target person Ak: Left foot of man 43 years old affected by psoriasis
[1002] Subject Al: Right foot of 40-year-old male with psoriasis
[1003] Subject Am: The left foot of the man 40 years old suffering from psoriasis
[1004] Subject An: Right foot of woman age 38 with psoriasis
[1005] Subject Ao: Left foot of woman aged 38 with psoriasis
[1006] Subject Ap: Right foot of woman age 49 with psoriasis
[1007] Subject Aq: Left foot of woman age 49 with psoriasis
[1008] Way:
[1009] Subject Aj: External cream of Example 52
[1010] Subject Ak: The external cream agent of Example 53
[1011] Subject Al: External cream of Example 65
[1012] Subject Am: External cream of Example 66
[1013] Subject An: The external cream agent of Example 130
[1014] Subject Ao: External cream of Example 131
[1015] Subject Ap: External cream of Example 67
[1016] Subject Aq: External cream of Example 68
[1017] Said external cream agent was apply | coated three times a day to the site affected by psoriasis, and the progress was observed.
[1018] Moreover, the grade of evaluation is as follows.
[1019] evaluation:
[1020] 5: worse than initiation
[1021] 4: initiation and immutability
[1022] 3: a little improvement
[1023] 2: significant improvement
[1024] 1: not different from normal skin
[1025] The results are summarized in Table 15 below.
[1026] TABLE 15
[1027] After 3 days After 7 days After 21 days After 1 month After 2 months After 3 months
[1028] Target person
[1029] Aj 4 3 3 2 2 1
[1030] Ak 4 3 3 2 2 1
[1031] Al 4 2 2 2 1 (1)
[1032] Am 4 2 2 2 1 (1)
[1033] An 4 2 2 2 1 1
[1034] Ao 4 2 2 1 1 1
[1035] Ap 4 2 2 1 1 (1)
[1036] Aq 4 2 2 1 1 (1)
[1037] As described above, all of the subjects changed their symptoms after 7 to 21 days of psoriasis and was cured after 1 to 2 months. The application of Al, Am, Ap, and Aq was stopped after 2 months, but there was no recurrence after 1 month. In addition, no side effects were observed.
[1038] Test Example 16 Treatment of Psoriasis
[1039] Subject Ar: Right foot of a 38 year old male with psoriasis
[1040] Subject As: Left foot of male age 38 with psoriasis
[1041] Way:
[1042] Subject Ar: External cream of Example 65
[1043] Subject As: commercial alpha ointment [Tenjin] (component: Takacitol 0.0002%)
[1044] The external cream agent was applied twice a day to the site affected by psoriasis, and the progress of each treatment was observed.
[1045] In addition, the same grade as Test Example 15 was used for the evaluation score.
[1046] The results are summarized in Table 16 below.
[1047] TABLE 16
[1048] After 3 days After 7 days After 21 days After 1 month After 2 months After 3 months
[1049] Target person
[1050] Ar 4 2 2 1--
[1051] As 4 4 3 2--
[1052] As described above, the subject As, that is, the metronidazole external preparation, apparently improved the skin condition. In both cases, side effects of the preparation were not seen.
[1053] (Test Example 17)
[1054] Subject At: 33-year-old male tofu affected by psoriasis
[1055] Subject Au: Right elbow of male age 38 with psoriasis
[1056] Target person Av: Left elbow of man 38 years old affected by psoriasis
[1057] Way:
[1058] Subject At: Lotion Agent of Example 72
[1059] Subject Au: External preparation of Example 73
[1060] Subject Av: external cream of Example 65
[1061] The external cream agent was applied twice a day to the site affected by psoriasis, and the progress of each treatment effect was observed.
[1062] In addition, the same thing as Test Example 15 was used for the evaluation grade.
[1063] The results are summarized in Table 17 below.
[1064] TABLE 17
[1065] After 3 days After 7 days After 21 days After 1 month After 2 months After 3 months
[1066] Target person
[1067] At 4 2 1 1--
[1068] Au 4 2 2 1 1-
[1069] Av 4 3 2 2 1-
[1070] As mentioned above, remarkable improvement was seen after 7 to 21 days. In the case of comparing the subjects Au and Av, a combination of metronidazole (2%) was applied to the right leg and a metronidazole monosaccharide (2%) on the left foot, and the combination had a better effect. Moreover, each side effect was not seen.
[1071] Test Example 18 Treatment of Psoriasis
[1072] As in Test Example 15, subjects Aw, Ax, Ay, Az, Ba, and Bb were tested.
[1073] Way:
[1074] Subject Aw and Ax: External Ointment of Example 69
[1075] Subject Ay and Az: external ointment of Example 70
[1076] Subject Ba: lotion agent of Example 72
[1077] Subject Bb: Combination of Example 74
[1078] For all the subjects, the external preparation of the present invention showed a remarkable effect, four of the subjects were cured within one month, and the other two were also cured within one to three months.
[1079] Test Example 19 Treatment of Psoriasis
[1080] Subject Bc: Right foot at age 70 with psoriasis
[1081] Subject Bd: Left foot at age 70 with psoriasis
[1082] Way:
[1083] Subject Bc: External cream of Example 73
[1084] Subject Bd: External cream agent without the metronidazole adjusted in the same manner as in Example 73 (Tranilast mono)
[1085] The external cream agent was applied twice a day to the site affected by psoriasis, and the progress of each treatment was observed.
[1086] In addition, the same thing as Test Example 15 was used for the evaluation grade.
[1087] The results are summarized in Table 18 below.
[1088] TABLE 18
[1089] After 3 days After 7 days After 21 days After 1 month After 2 months After 3 months
[1090] Target person
[1091] Bc 4 2 2 2 1 1
[1092] Bd 4 4 4 4 3 4
[1093] As described above, no effect was observed at 0.1% of tranilast.
[1094] Test Example 20 Use for Scars and Spots
[1095] Audience:
[1096] Subject Be: Right arm of a 40 year old man with a scar
[1097] Subject Bf: Right arm of a scared male 40 years old
[1098] Subject Bg: Facial of woman with age 38 with blemish
[1099] Subject Bh: Facial of a 60-year-old man with blemish
[1100] Subject Bi: Right foot of scar age 27 years old
[1101] Subject Bj: Left foot of scar age 27 years old
[1102] Way:
[1103] Be: external preparation of Example 75
[1104] Bf: External preparation of Example 76
[1105] Bg: External preparation of Example 78
[1106] Bh: External preparation of Example 77
[1107] Bi: External preparation of Example 77
[1108] Bj: External preparation adjusted as in Example 75 without addition of metronidazole
[1109] Said external preparation was apply | coated three times a day (twice a day with respect to subject Bi and Bj), and the progress was observed.
[1110] Moreover, the grade of evaluation is as follows.
[1111] evaluation:
[1112] 3: no condition or change before administration
[1113] 2: improved compared to the past
[1114] 1: clearly improved compared to assessment 2
[1115] The results are summarized in Table 19 below.
[1116] TABLE 19
[1117] 2 weeks after start 3 weeks after 1 month after 2 months
[1118] Target person
[1119] Be 3 3 3 2 2
[1120] Bf 3 3 2 2 1
[1121] Bg 3 3 2 1 1
[1122] Bh 3 3 2 2 1
[1123] Bi 3 3 2 1 1
[1124] Bj 3 3 3 3 3
[1125] As a result, the condition of the skin was improved. In particular, there were no side effects. Moreover, the state of the skin became shiny and smooth skin compared with before application. The only subject Bj did not change.
[1126] (Test Example 21)
[1127] Audience:
[1128] Subject Bk: Right hand of 34-year-old man whose skin is damaged by burn
[1129] Subject Bl: Right finger of age 33 years old man with cut wound
[1130] Subject Bm: Right hand of 34-year-old man whose skin after cutting the wart is damaged
[1131] Subject Bn: Right foot of 12 year old boy with abrasions
[1132] Subject Bo: Left foot of 12 year old boy with abrasions
[1133] Subject Bp: Facial of 5 years old child whose skin is damaged by Harquin wound
[1134] Subject Bq: Right arm of 5 years old child whose skin is damaged by Harlequin wound
[1135] Subject Br: Left arm of a child of age 5 years old whose skin is damaged by a Harlequin wound
[1136] Way:
[1137] Bk: External preparation of Example 79
[1138] Bl: External preparation of Example 81
[1139] Bm: External preparation of Example 82
[1140] Bn: External preparation of Example 79
[1141] Bo: External preparation of Example 81
[1142] Bp: External preparation of Example 80
[1143] Bq: External preparation of Example 82
[1144] Br: External preparation adjusted as in Example 79 without adding metronidazole
[1145] Each of the external preparations was applied three times a day (twice a day for the subjects Bq and Br), and the progress thereof was observed.
[1146] Moreover, the grade of evaluation is as follows.
[1147] evaluation:
[1148] 3: no condition or change before administration
[1149] 2: improved compared to the past
[1150] 1: clearly improved compared to assessment 2
[1151] The results are summarized in Table 20 below.
[1152] In Table 20, S6 represents a skin condition, S7 represents pain, and S8 represents irritation.
[1153] TABLE 20
[1154] 1 day after start 3 days after 1 week after 2 weeks
[1155] Subject Evaluation
[1156] Bk S6: S7 3: 3 3: 2 1: 1 1: 1-:-
[1157] Bl S6: S7 3: 3 3: 2 1: 1 1: 1-:-
[1158] Bm S6: S7 3: 3 3: 2 2: 2 1: 2 1: 1
[1159] Bn S6: S7 3: 3 3: 3 2: 1 1: 1-:-
[1160] Bo S6: S7 3: 3 3: 2 2: 1 1: 1-:-
[1161] Bp S6: S8 3: 3 3: 2 1: 1 1: 1 1: 1
[1162] Bq S6: S8 3: 3 2: 2 2: 1 1: 1 1: 1
[1163] Br S6: S8 3: 3 3: 3 3: 3 3: 3-:-
[1164] As a result, the condition of the skin was improved. There was no expression of side effects. Especially good is that the pain improves or disappears fairly quickly. In addition, the state of the skin became glossy and smooth skin as compared with before application. Since the subject Br only had no change in particular, the application of only the base was stopped after a week, and the cured agent of Example 82 was roughly cured for about one to two weeks because of the desire of the person and the parents.
[1165] (Test Example 22)
[1166] Audience:
[1167] Subject Bs: Right foot of woman 22 years of age affected by skin disease by contact of pool
[1168] Subject Bt: Right hand of woman 22 years of age affected by skin disease by contact of pool
[1169] Target person Bu: Two places of face of male 27 years old affected by insect bite
[1170] Subject Bv: Right hand of a 27 year old male with insect bites
[1171] Subject Bw: Right hand of a woman aged 24 years with contact dermatitis
[1172] Subject Bx: Right foot of a 47 year old male with contact dermatitis
[1173] Target person By: Woman who is 28 years old affected by dermatitis by rash such as detergent
[1174] Way:
[1175] Bs: external preparation of Example 83
[1176] Bt: External preparation of Example 85
[1177] Bu: External preparation of Example 84
[1178] Bv: External preparation of Example 86
[1179] Bw: External preparation of Example 86
[1180] Bx: External preparation of Example 86
[1181] By: External Agent of Example 85
[1182] The external preparations were applied two or three times a day (two times a day for the subjects Bu and Bv, and the hands were washed for the subjects Bw and By), and the progress thereof was observed.
[1183] Moreover, the grade of evaluation is as follows.
[1184] evaluation:
[1185] 3: no condition or change before administration
[1186] 2: improved compared to the past
[1187] 1: clearly improved compared to assessment 2
[1188] The results are summarized in Table 21 and Table 22 below.
[1189] TABLE 21
[1190] 1 hour after start 3 hours after 6 hours after 1 day after 3 days
[1191] Target person
[1192] Bs 3 3 2 1 1-
[1193] Bt 3 3 2 1 1-
[1194] Bu 3 3 2 2 1 1
[1195] Bv 3 3 2 1 1 1
[1196] Table 22
[1197] 3 days after launch 7 days after 2 weeks after 1 month after 3 months
[1198] Target person
[1199] Bw 3 3 2 2 1 1
[1200] Bx 3 3 3 2 2 1
[1201] By 3 2 1 1--
[1202] As a result, the condition of the skin was improved. There was no expression of side effects. In particular, itching, discomfort, pain, etc. have been found to be lost by time. Subjects Bu and Bv had traces of insect bites, but disappeared for about a week from the start of application. Similarly, subjects Bw and Bx took time to improve, but itching and the like improved or disappeared about 3 to 7 days after application.
[1203] (Test Example 23)
[1204] Audience:
[1205] Subject Bz: Back of 78-year-old man suffering from dry pruritus
[1206] Target person Ca: Back of age 71 years old affected by eczema considered to be side effect by drug (hypertensive agent)
[1207] Subject Cb: Back of 83 year old male suffering from eczema
[1208] Subject Cc: The arms of a 83 year old male with eczema
[1209] Subject Cd: Back of 68-year-old woman suffering from dry pruritus
[1210] Subject Ce: Facial of a woman of 30 years of age affected by eczema due to cosmetic side effects
[1211] Subject Cf: Facial of a 40-year-old woman affected by eczema due to cosmetic side effects
[1212] Way:
[1213] The subjects Bz, Ca, Cb, Cc and Ce were applied twice a day using the external preparation of Example 87, and the subjects Cd and Cf using the external preparation of Example 88, respectively, and the progress thereof was observed.
[1214] Moreover, the grade of evaluation is as follows.
[1215] evaluation:
[1216] 3: no condition or change before administration
[1217] 2: improved compared to the past
[1218] 1: clearly improved compared to assessment 2
[1219] The results are summarized in Table 23 below.
[1220] TABLE 23
[1221] 3 weeks after start 1 week after 2 weeks after 1 month
[1222] Target person
[1223] Bz 3 1 1 1-
[1224] Ca 3 2 2 1 1
[1225] Cb 3 2 1 1-
[1226] Cc 3 2 1 1-
[1227] Cd 3 1 1 1 1
[1228] Ce 3 3 2 2 1
[1229] Cf 3 3 2 2 1
[1230] As a result, the condition of the skin was improved. There was no expression of side effects. Itching stopped in a few days, and the condition of the skin improved over time. Subjects Ce and Cf had a severe makeup rash and the skin condition took about 1 month to cure, but itching disappeared after 3 days.
[1231] (Test Example 24)
[1232] Audience:
[1233] Subject Cg: Right hand of a 26 year old male suffering from skin splitting
[1234] Subject Ch: Left hand of a 26 year old male suffering from skin splitting
[1235] Subject Ci: Right foot of 26 year old male with frostbite
[1236] Subject Cj: Left foot of 26 year old male with frostbite
[1237] Way:
[1238] Cg: External preparation of Example 89
[1239] Ch: external preparation prepared in the same manner as in Example 89 without using metronidazole
[1240] Ci: External preparation of Example 90
[1241] Cj: external preparation prepared in the same manner as in Example 89 without using metronidazole
[1242] For the subjects Cg and Ch, external preparations were used to wash hands, and the subjects Ci and Cj were applied twice a day to observe their progress.
[1243] Moreover, the grade of evaluation is as follows.
[1244] evaluation:
[1245] 3: no condition or change before administration
[1246] 2: improved compared to the past
[1247] 1: clearly improved compared to assessment 2
[1248] The results are summarized in Table 24 below.
[1249] TABLE 24
[1250] 3 weeks after start 1 week after 2 weeks after 1 month
[1251] Target person
[1252] Cg 3 3 2 2 2
[1253] Ch 3 3 3 3 3
[1254] Ci 3 2 2 2 1
[1255] Cj 3 3 3 3 3
[1256] As a result, the condition of the skin was improved. There was no expression of side effects. Formulations containing no active ingredient have not been improved, while prescriptions containing the active ingredient have obviously improved. In particular, itching and discomfort improved in about a week.
[1257] (Test Example 25)
[1258] Audience:
[1259] Subject Ck: Back of 74-year-old man suffering from dry scleroderma
[1260] Subject Cl: arm of a 74 year old male with dry scleroderma
[1261] Subject Cm: Back of 80-year-old man suffering from purulent psoriasis pneumonia
[1262] Way:
[1263] For the subjects Ck and Cm, the external preparation of Example 91 was applied, and for the subject Cl, the external preparation of Example 92 was applied twice a day, and the progress thereof was observed.
[1264] Moreover, the grade of evaluation is as follows.
[1265] evaluation:
[1266] 5: worsening of symptoms than before administration
[1267] 4: no condition or change before administration
[1268] 3: slightly better than before
[1269] 2: improved status compared to assessment 3
[1270] 1: clearly improved compared to assessment 2
[1271] The results are summarized in Table 25 below.
[1272] TABLE 25
[1273] 3 days after start 1 week after 2 weeks after 1 month after 2 months
[1274] Target person
[1275] Ck 4 4 3 3 2 2
[1276] Cl 4 4 3 3 2 2
[1277] Cm 4 4 3 3 2 2
[1278] As a result, the condition of the skin was improved. There was no expression of side effects. Itching has improved to about a week. It took time because of skin disease that is relatively hard to cure.
[1279] (Test Example 26)
[1280] Audience:
[1281] Subject Cn: Right foot of 55 year old male with ringworm
[1282] Target person Co: Left foot of man 55 years of age affected by ringworm
[1283] Subject Cp: Right hand of woman 46 years old with ringworm ringworm
[1284] Subject Cq: Right hand of woman age 38 with ringworm ringworm
[1285] Way:
[1286] For the subject Cn, the external preparation of Example 93 was twice a day, for the subject Co, the external preparation of Example 94 was twice a day, for the subject Cp, the external preparation of Example 94 was three times a day, and for the subject Cq, The external preparation was apply | coated three times a day, and the progress was observed.
[1287] Moreover, the grade of evaluation is as follows.
[1288] evaluation:
[1289] 5: worsening of symptoms than before administration
[1290] 4: no condition or change before administration
[1291] 3: slightly better than before
[1292] 2: improved status compared to assessment 3
[1293] 1: clearly improved compared to assessment 2
[1294] The results are summarized in Table 26 below.
[1295] TABLE 26
[1296] 1 week after start 2 weeks after 3 weeks after 1 month after 2 months
[1297] Target person
[1298] Cn 4 4 3 3 2 2
[1299] Co 4 3 3 2 2 2
[1300] Cp 4 3 2 2 1 1
[1301] Cq 4 3 2 2 2 2
[1302] As a result, the condition of ringworm skin was improved. There was no expression of side effects.
[1303] (Test Example 27)
[1304] Audience:
[1305] Subject's Cr: Left foot of 49 year old male with purulent skin disease
[1306] Subject Cs: Mouth of a 61-year-old male suffering from herpes
[1307] Subject Ct: Forehead of a 33 year old male suffering from herpes
[1308] Subject Cu: The left arm of a 64 year old woman suffering from purulent skin disease
[1309] Subject Cv: Right hand, age 56, suffering from Candida
[1310] Subject Cw: Both hands of a 38 year old woman suffering from biliary tract
[1311] Subject Cx: the back of a 33 year old male with skin pruritus
[1312] Way:
[1313] For the subject Cr, the external preparation of Example 96 was applied three times a day, for the subject Cs, the external preparation of Example 95 was used three times a day, for the subject Ct, the external preparation of Example 95 was twice a day, and for the subject Cu, The external preparation was washed three times a day, the subject Cv was treated with the external preparation of Example 96 three to four times a day, the subject Cw was washed with the external preparation of Example 96, and the subject Cx was treated with the external preparation of Example 95 2 Apply each time and observe the progress.
[1314] Moreover, the grade of evaluation is as follows.
[1315] evaluation:
[1316] 4: no condition or change before administration
[1317] 3: slightly better than before
[1318] 2: obviously improved condition
[1319] 1: not different from normal skin
[1320] The results are summarized in Tables 27 and 28 below.
[1321] TABLE 27
[1322] 1 day after start 3 days after 1 week after 2 weeks after 1 month
[1323] Target person
[1324] Cs 4 2 1 1--
[1325] Ct 4 1 1 1--
[1326] Cx 4 2 1 1--
[1327] TABLE 28
[1328] 1 week after start 2 weeks after 3 weeks after 1 month after 2 months
[1329] Target person
[1330] Cr 4 3 3 2 2 2
[1331] Cu 4 3 3 3 2 2
[1332] Cv 4 3 3 3 2 2
[1333] Cw 4 3 3 2 2 1
[1334] As a result, the condition of the skin was improved. There was no expression of side effects. All subjects lost pruritus, pain, and discomfort before the skin condition improved.
[1335] (Test Example 28)
[1336] Audience:
[1337] Subject Cx: Facial of a 62 year old female with signs of normal skin.
[1338] Subject Cy: Facial of a 38 year old male with scars from the side effects of steroids.
[1339] Subject Cz: Foot of 5 years old boy with scar by side effect of steroid
[1340] Method: The subject applied the external cream of Example 97 twice a day.
[1341] Moreover, the grade of evaluation is as follows.
[1342] evaluation:
[1343] 5: A condition that can clearly distinguish blemishes and scars from other skins.
[1344] 4: Spots and scars can be clearly distinguished from other skins, but not about 5.
[1345] 3: A condition that can distinguish spots, scars, etc. from other skins.
[1346] 2: A slight blemish, scar, etc. can be seen, but not roughly different from other skin.
[1347] 1: No different from other skins.
[1348] The results are summarized in Table 29 below.
[1349] TABLE 29
[1350] 1 week after start 2 weeks after 3 weeks after 4 weeks after 2 months after 3 months
[1351] Target person
[1352] Cx 4 4 4 3 3 2 2
[1353] Cy 5 5 5 5 5 3 2
[1354] Cz 3 3 2 1 1--
[1355] As described above, it has been clarified that the topical preparations of the present invention are remarkably improved against scars caused by side effects of blemishes and steroids.
[1356] (Test Example 29)
[1357] Audience:
[1358] Subject Da: Facial of 63 year old female with normal skin black.
[1359] Subject Db: Facial of a 65 year old female with normal skin black.
[1360] Way:
[1361] For the subject Da, the external preparation of Example 98 was applied twice a day, and for the subject Db, the formulation of Example 99 was applied twice a day.
[1362] Moreover, the grade of evaluation is as follows.
[1363] evaluation:
[1364] 3: A face that is generally considered black in its present state.
[1365] 2: Not rated 3 but slightly blurred.
[1366] 1: A state that the color became clear white compared with evaluation 3.
[1367] The results are summarized in Table 30 below.
[1368] TABLE 30
[1369] 2 weeks after 2 months after 2 months after 3 months
[1370] Target person
[1371] Da 3 3 2 1 1
[1372] Db 3 3 2 1 1
[1373] As mentioned above, it has been found that the external preparation of the present invention significantly improves on the deposition of pigments.
[1374] (Test Example 30)
[1375] Audience:
[1376] Subject Dc: Right foot of a 54 year old male suffering from blisteritis
[1377] Subject Dd: The back of a 75-year-old man affected by a breakthrough
[1378] Subject de: Male 60 years old suffering from laceration due to bruise
[1379] Subject Df: Left hand of male 32 years of age with pain from scratch
[1380] Subject Dg: left shoulder of 44 year old male with purulent skin disease
[1381] Subject Dh: Male, age 38, whose eyebrows are peeling off as a side effect of steroid topical medication
[1382] Subject Di: Both arms of a 38-year-old man whose scars remain as a side effect of steroid external preparations
[1383] Way:
[1384] The subject Dc received the external preparation of Example 100 twice a day, the subject Dd received the external preparation of Example 101 twice a day, the subject De received the external preparation of Example 102 three times a day, and the subject Df received the external preparation of example 103 two times a day. To the subject Dg, the external preparation of Example 104 was applied twice a day, the subject Dh to the subject 105 was applied three to four times a day, and the subject Di was applied to the external preparation of Example 106 twice a day, and the progress was observed. .
[1385] Moreover, the grade of the evaluation about subject Dc-Dg and Di is as follows.
[1386] evaluation:
[1387] 5: The condition which the skin symptom is very worse.
[1388] 4: Symptoms on the skin are worse, but not about 5.
[1389] 3: The condition of the skin is moderate.
[1390] 2: A condition in which skin symptoms can hardly be confirmed.
[1391] 1: normal skin.
[1392] The results are summarized in Table 31 below.
[1393] Table 31
[1394] 3 weeks after start 1 week after 2 weeks after 3 weeks after 4 weeks
[1395] Target person
[1396] Dc 4 3 1 1--
[1397] Dd 3 1 1 1 1 1
[1398] De 3 2 1 1--
[1399] Df 3 1----
[1400] Dg 4 3 2 2--
[1401] Di 5 5 4 4 3 3
[1402] In addition, the grade of the evaluation about the subject Dh is as follows.
[1403] evaluation:
[1404] 5: No eyebrows and no bowels.
[1405] 4: without eyebrows. The state of sprouting comes out.
[1406] 3: The eyebrows are raised slightly.
[1407] 2: The eyebrows have sprouted, but there is a slight discomfort in appearance.
[1408] 1: Not different from normal people.
[1409] The results are summarized in Table 32 below.
[1410] Table 32
[1411] 3 weeks after start 1 week after 2 weeks after 3 weeks after 4 weeks
[1412] Target person
[1413] Dh 5 5 4 3 3 2
[1414] As is apparent from the above, the external preparation of the present invention showed an improvement effect on each subject.
[1415] In addition, the subject of Dd has been used for a long period of time due to hypertension and eczema and pruritus due to side effects caused by blood pressure lowering agents.
[1416] In addition, the targets of Dh and Di are the same person. The state of skin was evaluation 3 after 4 weeks, but was 1 after 1 month. The eyebrows are evaluated 2 after 3 months from the start, but are gradually increasing.
[1417] (Test Example 31) Effect of moist skin and smooth feeling
[1418] Audience:
[1419] Subject Dj: Right face of 62 year old female with normal skin.
[1420] Subject Dk: Left face of a 62 year old female with normal skin.
[1421] Subject Dl: Right face of 69 year old female with normal skin.
[1422] Subject Dm: Left face of 69 year old female with normal skin.
[1423] Subject Dn: Left arm of a 62 year old female with normal skin.
[1424] Subject Do: Right arm of a 62 year old female with normal skin.
[1425] Method: External preparation of Example 107 for subject Dj, metronidazole for subject Dk, external preparation prepared in Example 107, external preparation of Example 108 for subject Dl, and tinidazole for subject Dm. The external preparation prepared in Example 108 was applied twice a day, the external preparation prepared in Example 109 was applied to the subject Dn, and the external preparation prepared in Example 110 was applied to the subject Do three times a day. The course was observed for two consecutive months. Moreover, the progress after stopping application | coating two months after application | coating start was observed.
[1426] Moreover, the grade of evaluation is as follows.
[1427] Evaluation (evaluation of the skin's wet and smooth feeling during the next day of application):
[1428] 5: worse condition compared to before use.
[1429] 4: State before use or invariant state.
[1430] 3: slightly improved than before use.
[1431] 2: Clearly improved than before use.
[1432] 1: Very good condition.
[1433] The results are summarized in Table 33 and Table 34 below.
[1434] Table 33 (Elapsed Use)
[1435] After 3 days of use After 1 week After 2 weeks After 3 weeks After 4 weeks After 2 months
[1436] Target person
[1437] Dj 4 4 3 2 2 1 1
[1438] Dk 4 4 4 4 4 4 3
[1439] Dl 4 4 3 2 2 1 1
[1440] Dm 4 4 4 4 4 4 4
[1441] Dn 4 3 2 2 2 1 1
[1442] Do 4 3 2 2 1 1 1
[1443] Table 34 (Elapsed after Stopping Application)
[1444] 3 days after suspension 1 week after 2 weeks after 1 month
[1445] Target person
[1446] Dj 1 1 1 2 2
[1447] Dk 3 4 4 4 4
[1448] Dl 1 1 1 1 2
[1449] Dm 4 4 4 4 4
[1450] Dn 1 1 1 2 2
[1451] Do 1 1 1 1 2
[1452] As mentioned above, the favorable condition continued until 7 to 14 days after application | coating stop, and the formulation which does not contain an active ingredient was ineffective, but there is no side effect, and it is a formulation with high stability.
[1453] (Test Example 32)
[1454] Audience:
[1455] Subject Dp: The left foot of a 7 year old boy with a cutaneous wound with atopic dermatitis.
[1456] Subject Dq: The right foot of a 7 year old male with a cutaneous wound with atopic dermatitis.
[1457] Subject Dr: The left arm of a 39 year old male with a cutaneous wound with atopic dermatitis.
[1458] Subject Ds: Right arm of a 39 year old male with a cutaneous wound with atopic dermatitis.
[1459] Way:
[1460] Dp: Formulation of Example 112 twice a day.
[1461] Dq: Including the formulation of Example 113 twice a day.
[1462] Dr: Inclusion of the formulation of Example 114 three times a day.
[1463] Ds: containing the formulation of Example 115 three times a day.
[1464] Moreover, the grade of evaluation is as follows.
[1465] 5: Dermatitis symptoms such as redness and eczema are severe, severe pruritus, and unconsciously scratching the skin.
[1466] 4: Symptoms of dermatitis such as redness, eczema and severe pruritus.
[1467] 3: Dermatitis symptoms such as redness and eczema can be confirmed, and there is a feeling of pruritus.
[1468] 2: Dermatitis symptoms such as redness, eczema, etc. can be seen a little, but not so different from normal normal skin, but slightly soft, but can stop scratching the skin.
[1469] 1: No symptoms of dermatitis such as redness, eczema, and pruritus under normal skin conditions.
[1470] The results are summarized in Table 35 below.
[1471] Table 35
[1472] 3 days after launch 7 days after 2 weeks after 3 weeks after 1 month
[1473] Target person
[1474] Dp 4 4 3 2 1 1
[1475] Dq 4 4 3 2 2 2
[1476] Dr 5 5 4 3 3 2
[1477] Ds 5 5 4 3 3 2
[1478] Usually, ketoconazole and isoconazole nitrate cannot be administered to a wounded site. However, in the external preparation of the present invention, it was possible to use ketoconazole and wounded sites as a combination with a nitroimidazole derivative. Subjects Cp and Cq did not change skin condition after about 3 days, but the pruritus stopped almost, and after 5 days, they did not scratch even at bedtime.
[1479] Subjects Cr and Cs had a history of atopic dermatitis for about 20 years, and were in a state of great deterioration due to side effects caused by steroids. After about 5 days, it stopped roughing, and after about 7 days it did not scratch.
[1480] (Test Example 33)
[1481] Audience:
[1482] Subject Dt: The left back (from the shoulder to the waist) of the 72-year-old man suffering from skin pruritus
[1483] Subject Du: Left back (homologous) of a 69-year-old woman suffering from skin pruritus
[1484] Subject Dv: Right back (homologous) of a 72 year old male suffering from skin pruritus
[1485] Subject Dw: Right back (homologous) of 69-year-old woman suffering from skin pruritus
[1486] In addition, the evaluation grade is as follows.
[1487] Method: A topical preparation prepared in Example 29 without using metronidazole for subject Dt, and a subject preparation Dv without using metronidazole in subject Du, and prepared in Example 29 with an amount of crotamiton as 10 g. To the external preparation of Example 111, and the subject Dw, the external preparation of Example 29 was apply | coated twice a day, respectively.
[1488] evaluation:
[1489] 5: The pruritus is worse than when it started.
[1490] 4: Onset or severe pruritus.
[1491] 3: The feeling of pruritus is slightly reduced.
[1492] 2: I don't really care, but sometimes I have pruritus.
[1493] 1: a state of no pruritus at all
[1494] The results are summarized in Table 36 below.
[1495] TABLE 36
[1496] 3 weeks after start 1 week after 2 weeks after 3 weeks
[1497] Target person
[1498] Dt 4 4 3 2 2 1 Almost unchanged
[1499] Du 4 4 3 2 2 2 little improvement
[1500] Dv 5 5 4 3 3 2 After 3 to 1 week
[1501] Markedly improved
[1502] Dw 5 5 4 3 3 2 After 2-3 days
[1503] Markedly improved
[1504] As described above, the external preparation of the present invention significantly improves the skin pruritus compared to the preparation containing only crotamiton, but especially when it contains crotamiton, the effect is early.
[1505] Test Example 34 Stability Test
[1506] The external ointment prepared in Example 1, the external cream prepared in Example 4, the external ointment prepared in Example 11 and the external cream prepared in Example 14 were stored at room temperature and 40 ° C. Changes in pH, content and viscosity were observed after 6 months.
[1507] The results are shown in Table 37 below.
[1508] In Table 37, NC shows that there was no change before preservation.
[1509] TABLE 37
[1510] Appearance pH Content Viscosity
[1511] Example Room temperature 40 ° C Room temperature 40 ° C Room temperature 40 ° C Room temperature 40 ° C
[1512] 1 NC NC NC NC NC NC NC NC
[1513] 4 NC NC NC NC NC NC NC NC
[1514] 11 NC NC NC NC NC NC NC NC
[1515] 14 NC NC NC NC NC NC NC NC
[1516] The external preparation of the present invention did not change in appearance and pH, and no significant change was observed in content and viscosity.
[1517] Accordingly, it has been found that the external preparation provided by the present invention is pharmaceutically stable.
[1518] The external preparation for treating, preventing or improving skin diseases containing the nitroimidazole derivatives of the present invention has excellent therapeutic effects and is useful as a safe and effective therapeutic agent for skin diseases.

权利要求:
Claims (40)
[1" claim-type="Currently amended] Nitroimidazole derivatives
General formula (I)
(I)
(Wherein, R ¹ , R ³ and R ⁴ are the same or different independently from each other, and are the same or different selected from hydrogen atom, nitro group, lower alkyl group, <substituent group α> and <substituent group β>) Lower alkyl group, lower alkenyl group substituted with 1 or 2 or more substituents, or lower alkenyl group substituted with 1 or 2 or more substituents with the same or different substituents selected from <substituent group α> and <substituent group β>, and R ² is Lower alkyl group, lower alkenyl group, or <substituent group α> and <substituent group β> substituted at least 1 or 2 with the same or different substituents selected from a hydrogen atom, a lower alkyl group, <substituent group α> and <substituent group β> Lower alkenyl groups substituted with one or two or more of the same or different substituents selected from: provided that any one of R ¹ , R ³ and R ⁴ is a nitro group, a pharmacologically acceptable salt thereof, That Of the ester or other derivative thereof
Containing as an active ingredient,
The <substituent group α> is selected from a lower alkyloxy group, a lower alkyloxy group, a lower alkylcarbonyloxy group, and a <substituent group β> substituted with one or two or more of the same or different substituents selected from the lower alkyloxy group and the <substituent group β>. A lower alkylcarbonyloxy group substituted with one or two or more substituents with the same or different substituents, a lower alkylsulfonyl group, a lower alkylsulfonyl group substituted with one or two or more substituents with the same or different substituent selected from <substituent group β>, and a cycloalkyl group , A cycloalkyl group substituted by one or two or more with the same or different substituents selected from <substituent group β>, a heteroaryl group, a heteroaryl group substituted by one or two or more with the same or different substituents selected from <substituent group β>, An aryl group substituted with one or two or more of the same or different substituents selected from an aryl group and <substituent group β>,
The <substituent group β> is a hydroxyl group, mercapto group, halogen atom, amino group, lower alkylamino group, lower alkyloxy group, lower alkenyl group, cyano group, carboxyl group, carbamoyloxy group, carboxyamide group, thiocarboxyamide group and Morpholinogiin
External preparations for the treatment, prevention or amelioration of skin diseases.
[2" claim-type="Currently amended] The method of claim 1,
An external preparation wherein R ⁴ is a nitro group.
[3" claim-type="Currently amended] The method of claim 2,
A lower alkyl group, a lower alkenyl group, or a <substituent group, wherein R ¹ and R ² are the same or different and are substituted with one or two or more substituents same or different with a lower alkyl group, <substituent group α> and <substituent group β>; A topical agent which is a lower alkenyl group substituted with one or two or more of the same or different substituents selected from α> and <substituent group β>, and R ³ is a hydrogen atom.
[4" claim-type="Currently amended] The method of claim 3,
<Substituent group (alpha)> is a lower alkyloxy group, and <substituent group (beta) is a hydroxyl group, an amino group, a halogen atom, a cycloalkyl group, a heteroaryl group, or an aryl group.
[5" claim-type="Currently amended] The method of claim 4, wherein
The external preparation whose <substituent group (beta)> is a hydroxyl group, an amino group, a halogen atom, or a heteroaryl group.
[6" claim-type="Currently amended] The method of claim 5,
An external preparation wherein R ¹ is a lower alkyl group.
[7" claim-type="Currently amended] The method according to claim 5 or 6,
The external preparation wherein R ² is a lower alkyl group substituted with a hydroxy group.
[8" claim-type="Currently amended] The method of claim 4, wherein
An external preparation containing 2- (2-methyl-5-nitroimidazol-1-yl) ethanol (common name: metronidazole), a pharmacologically acceptable salt thereof, an ester thereof or other derivative as an active ingredient.
[9" claim-type="Currently amended] The method of claim 3,
<Substituent group α> is a lower alkylsulfonyl group substituted with the same or another substituent selected from lower alkylsulfonyl group or <substituent group β>, and <substituent group β> is a hydroxy group, a halogen atom, an amino group, a lower alkylamino group And an external agent which is a lower alkyloxy group, a lower alkenyl group, a cyano group, a carboxyl group, a cycloalkyl group, and an aryl group.
[10" claim-type="Currently amended] The method of claim 9,
The external preparation wherein R ¹ is a lower alkyl group or a lower alkyl group substituted with the same or different substituent selected from <substituent group β> or the same or different substituent selected from <substituent group β>.
[11" claim-type="Currently amended] The method of claim 9 or 10,
The external preparation wherein R ² is a lower alkylsulfonyl group or a lower alkyl group substituted with a lower alkylsulfonyl group substituted with the same or another substituent selected from <substituent group β>.
[12" claim-type="Currently amended] The method of claim 9,
An external preparation containing 1- (2-ethylsulfonylethyl) -2-methyl-5-nitroimidazole (common name: tinidazole) or a pharmacologically acceptable salt thereof as an active ingredient.
[13" claim-type="Currently amended] At least one compound of the nitroimidazole derivatives according to any one of claims 1 to 12, an antifungal agent, an antibacterial agent, a sulfa agent, an immunosuppressive agent, an anti-inflammatory agent, an antibiotic, an antiviral agent, a metabolic antagonist, an antihistamine drug, and tissue repair An external preparation for administering at least one of the promoters, vitamins, anti-allergic drugs, local anesthetics, hair preparations or steroids simultaneously or separately.
[14" claim-type="Currently amended] The method of claim 13,
Antifungal, antibacterial, sulfa, immunosuppressive, anti-inflammatory, antibiotic, antiviral, metabolic antagonists, antihistamines, tissue repair promoters, vitamins, antiallergic drugs, local anesthetics, hair preparations or steroids may External preparation which is a concentration not shown.
[15" claim-type="Currently amended] The method according to any one of claims 1 to 14,
An external preparation containing crotamiton.
[16" claim-type="Currently amended] The method according to any one of claims 1 to 15,
An external preparation wherein the skin disease is atopic dermatitis.
[17" claim-type="Currently amended] The method of claim 16,
The external preparation wherein the skin disease is facial atopic dermatitis.
[18" claim-type="Currently amended] The method according to claim 16 or 17,
The external preparation wherein the skin disease is atopic dermatitis in children.
[19" claim-type="Currently amended] The method according to any one of claims 1 to 15,
An external preparation wherein the skin disease is a blemish, pigmentation or scar on the skin.
[20" claim-type="Currently amended] The method according to any one of claims 1 to 15,
The external preparation for which the skin disease is psoriasis.
[21" claim-type="Currently amended] The method according to any one of claims 1 to 15,
An external preparation wherein the skin disease is odor, body odor or odor.
[22" claim-type="Currently amended] The method according to any one of claims 1 to 15,
An external preparation wherein the skin disease is contact dermatitis, plant dermatitis or hyperemia.
[23" claim-type="Currently amended] The method according to any one of claims 1 to 15,
An external preparation wherein the skin disease is skin pruritus or weakness.
[24" claim-type="Currently amended] The method according to any one of claims 1 to 15.
The external preparation for which the skin disease is alumni.
[25" claim-type="Currently amended] The method according to any one of claims 1 to 15,
The external preparation for which the skin disease is erythematosis.
[26" claim-type="Currently amended] The method according to any one of claims 1 to 15,
The external preparation for which the skin disease is ringworm.
[27" claim-type="Currently amended] The method according to any one of claims 1 to 15,
The external preparation wherein the skin disease is a purulent skin disease.
[28" claim-type="Currently amended] The method according to any one of claims 1 to 15,
An external preparation wherein the skin disease is pressure sores.
[29" claim-type="Currently amended] The method according to any one of claims 1 to 15,
An external preparation wherein the skin disease is a trauma.
[30" claim-type="Currently amended] The method according to any one of claims 1 to 15,
The skin diseases include enteric erythematosis, squamous swelling, gloss swelling, pore red nasal gin, Gibber rosaceous nasal gin, erythematosis (polymorphic exudative erythema, nodular erythema, centrifugal annular erythema on the legs), chronic disc erythematous lupus erythematosus Poisoning, alopecia areata, lacerations (including scars and keloids), pemphigus, chelating herpes dermatitis (including rheumatic swelling), seborrheic dermatitis, cutaneous stomatitis, candidiasis (landic erosion, interrogation / skin candidiasis, infant parasites) Erythema, prostheticitis, vulvar candidiasis) or stroke.
[31" claim-type="Currently amended] The method according to any one of claims 1 to 30,
A topical preparation wherein the formulation is a cream, lotion, shampoo, gel, rinse, lotion, emulsion, pasta, shaving cream, foundation, colon, pack, ointment, patch, semisolid, solid or liquid.
[32" claim-type="Currently amended] The method of any one of claims 1 to 31,
An external preparation having a concentration of nitroimidazole derivatives of 1.5 to 10% by weight based on the weight of the preparation.
[33" claim-type="Currently amended] Use of the nitroimidazole derivative according to any one of claims 1 to 12 for producing an external preparation for treating or preventing atopic dermatitis.
[34" claim-type="Currently amended] Use of the nitroimidazole derivative according to any one of claims 1 to 12 for producing an external preparation for use in improving the appearance of blemishes, pigmentation, or scars on the skin.
[35" claim-type="Currently amended] Use of the nitroimidazole derivative according to any one of claims 1 to 12 for producing an external preparation for treating or preventing psoriasis.
[36" claim-type="Currently amended] Use of the nitroimidazole derivative according to any one of claims 1 to 12 for the preparation of external preparations for the treatment or prevention of odor, body odor or odor.
[37" claim-type="Currently amended] The treatment or prevention of atopic dermatitis using the external preparation as described in any one of Claims 1-15.
[38" claim-type="Currently amended] The improvement of the stain, pigmentation, or scar of skin using the external preparation as described in any one of Claims 1-15.
[39" claim-type="Currently amended] The treatment or prevention of psoriasis using the external preparation as described in any one of Claims 1-15.
[40" claim-type="Currently amended] The treatment or prevention of liquid odor, body odor or odor, using the external preparation as described in any one of Claims 1-15.

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同族专利:

---

公开号 | 公开日

---

CA2379270C|2007-04-10|

---

EP1206937A1|2002-05-22|

---

HK1046639B|2007-10-05|

---

HK1046639A1|2007-10-05|

---

AU6016100A|2001-02-05|

---

CN1304001C|2007-03-14|

---

US20030092754A1|2003-05-15|

---

CN1361688A|2002-07-31|

---

CA2379270A1|2001-01-25|

---

AT384524T|2008-02-15|

---

DE60037892T2|2009-01-15|

---

KR100671879B1|2007-01-19|

---

EP1206937A4|2005-01-19|

---

AU773881B2|2004-06-10|

---

WO2001005400A1|2001-01-25|

---

EP1206937B1|2008-01-23|

---

DE60037892D1|2008-03-13|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1999-07-16|Priority to JPJP-P-1999-00234496

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1999-07-16|Priority to JP23449699

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1999-07-21|Priority to JP20650899

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1999-07-21|Priority to JPJP-P-1999-00206508

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1999-09-24|Priority to JPJP-P-1999-00271077

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1999-09-24|Priority to JP27107799

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1999-09-28|Priority to JP31284099

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1999-09-28|Priority to JPJP-P-1999-00312840

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2000-01-14|Priority to JP2000042012

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2000-01-14|Priority to JPJP-P-2000-00042012

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2000-02-04|Priority to JP2000067746

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2000-02-04|Priority to JPJP-P-2000-00067746

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2000-07-14|Application filed by 가부시키가이샤 쇼에이

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2002-03-15|Publication of KR20020020780A

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2007-01-19|Application granted

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2007-01-19|Publication of KR100671879B1

优先权:

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申请号 | 申请日 | 专利标题

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JPJP-P-1999-00234496|1999-07-16|

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JP23449699|1999-07-16|

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JP20650899|1999-07-21|

---

JPJP-P-1999-00206508|1999-07-21|

---

JPJP-P-1999-00271077|1999-09-24|

---

JP27107799|1999-09-24|

---

JP31284099|1999-09-28|

---

JPJP-P-1999-00312840|1999-09-28|

---

JP2000042012|2000-01-14|

---

JPJP-P-2000-00042012|2000-01-14|

---

JP2000067746|2000-02-04|

---

JPJP-P-2000-00067746|2000-02-04|