Improved formulation for topical non-invasive application in vivo

专利摘要:
Even if the average diameter of the pores is smaller than the average diameter of the penetrant, the adaptability of the penetrant allows the penetrant to carry the drug after the penetrant enters the void or to allow the drug to penetrate the pores. A formulation consisting of a molecular sequence that can pass through, wherein the viscosity of the formulation is increased from above the viscosity of the non-enriched formulation to a maximum of 5 Nm / s so that at least one viscosity modifier and an oxidation index can be expanded and maintained. At least one antioxidant in an amount capable of reducing the increase to less than 100% per 6 months and the number of bacteria per total mass (g) of the total formulation after 4 days, from 1 million to less than 100 for aerobic bacteria, Contains bactericides that can be reduced to less than 10 for bacteria and less than 1 for Pseudomonas aeruginosa or Staphylococcus aureus Formulation which comprises.
公开号:KR20010107991A
申请号:KR1020017006708
申请日:1998-12-23
公开日:2001-12-07
发明作者:케에베그레고르
申请人:케에베 그레고르；이데아 악티엔게젤샤프트；
IPC主号:

专利说明:

Improved formulations for local non-invasive use in vivo {IMPROVED FORMULATION FOR TOPICAL NON-INVASIVE APPLICATION IN VIVO}
[2] The effect of drug action is due to the action of a number of variables, such as the inherent efficacy, cumulative amount, the rate of drug removal is important. Variables of drug-specific efficacy are determined entirely by the chemical composition of the drug, while variables such as cumulative amount and drug removal rate of the drug are sensitive to the herbal properties of the agent and also depend on the location and speed of drug administration.
[3] Therefore, in medicine as well as medicine, choosing the right method and type of drug use is just as important as finding the right drug. For example, if a drug treated on the skin does not penetrate and / or pass through the skin, even if the drug has a great effect, it has no practical meaning at all. Also, even if the drug passes easily through the skin, it will also be of no use if it is removed too soon before the desired biological action is fully achieved. In both cases, it is necessary to optimize the drug formulation. Studying the improvement of herbal medicines is much faster and less expensive than the invention of new chemicals.
[4] It is within the art known in the art to improve the adaptability of the membrane to the pores of the porous barrier wall by adding a surfactant to the membrane formed from the amphiphilic material. In addition, an amphiphilic molecule or an amphiphilic carrier material is surrounded by a corresponding layer of one or more layers and binds and / or associates the agent with the microdroplets suspended in a suitable liquid medium such that the agent penetrates and / or the skin. It is also already proposed that this fact can be used to transport through. These formulations are based on self-optimization of pharmaceutical carriers that can penetrate porous barriers such as skin due to their very high adaptability to voids. This is described in more detail in the prior application EP 475,160B1, PCT / EP96 / 04526, PCT / EP98 / 5539, which are part of the present application as prior art documents.
[5] While the above cited document discloses formulations consisting of highly adaptable topically administered pharmaceutical carriers suitable for transporting pharmaceuticals through and / or through barriers such as human skin, these formulations include storage and There is still a need to optimize certain biopharmaceutical properties in order to improve the practicality of use. This is particularly desirable for certain biopharmaceutical properties such as the viscosity of the formulation, chemical resistance to oxidative degradation and / or microbiological stability of the formulation.
[6] For example, the viscosity of the formulation should be adjusted appropriately to avoid repeated treatment and to obtain high local drug concentrations in view of the possible adverse effects, which may be achieved by enlarging the dosage area and / or layer thickness of the administered formulation. Can be achieved. Thus, changing the viscosity is an appropriate means to enable the avoidance of multiple successive treatments and the achievement of high drug concentrations.
[7] Problems related to storage are mostly caused by the lack of chemical resistance of the formulation to oxidative degradation of the formulation components. This is a problem not only when the formulation is stored in a container prior to administration but also when the formulation is exposed to atmospheric oxygen during administration of the medication at the administration site. All oxidation processes for the formulation components not only degrade the carrier and drug molecules to continually destroy their properties, but also lead to free radicalization, resulting in chemical attack on the carrier and drug molecules, thus accelerating the degradation of the formulation ingredients. . Therefore, proper storage and use of the formulation is always associated with protecting these components from oxidative degradation.
[8] Another problem associated with storage is the protection of the formulation from the effects of microorganisms such as bacteria and fungi. These microorganisms can lead to degradation of the carrier component and the agents associated with it. The microbiological effects not only reduce or eliminate the penetration of the carrier and the activity of the drug, but also increase the side effects of drug administration. Therefore, the formulation must be protected from the effects of microorganisms, as well as after storage before use, as well as after removal from the container for drug administration.
[9] The problems described above relating to the delivery of medicaments through and / or through the skin and their biopharmaceutical properties are very common for many corticosteroid based dermatological drugs. Approximately one-third of the dermatological drugs currently on sale include mineral corticosteroids and glucosteroids (hereafter referred to as the more general term corticosteroids). Corticosteroids are not only commonly used for the transdermal treatment of local inflammation, for example, but are also widely used for systemic medications, especially allergic syndromes.
[10] The amount to be administered is about several micrograms per cubic centimeter for the most potent corticosteroid drug, and up to 1 mg per cubic centimeter for drugs that are less potent. Lower doses reduce the effectiveness of the drug in concentrations that penetrate the skin, and in excess of these doses lead to excessive local or systemic side effects, which are not readily treatable in normal cases.
[11] For example, by increasing the concentration of the dermatological agent, it is possible to increase the speed of movement of the drug delivered into the skin and make a reservoir of the local drug to prevent the drug from being removed too soon. However, the use of high concentrations of the drug on the skin may pose a risk of the drug depositing on the skin, increasing the likelihood of undesirable side effects. For example, many reservoir formulations have very high skin irritation, which is a serious obstacle in the treatment with such drugs. One of the important reasons for this is that commonly used skin ointments or creams usually contain at least 0.1%, sometimes up to 5%, of active ingredients, and also contain relatively high skin penetration enhancers to fluidize. This skin penetration enhancer works to soften the skin, but it is very harmful to the skin. This is particularly the case when the drug must be used at a concentration very high enough to cause repetitive and / or serious side effects such as skin atrophy and the treatment must be discontinued. Traditional herbal preparations lack the overall efficacy and duration of biological function if they wish to avoid the undesirable and serious side effects caused by repeated treatments to obtain sufficient drug concentrations.
[12] In view of the above problems, in the form of traditional lotion or cream, not only can the biological function required longer than that of the same drug, but also eliminate or reduce the serious side effects caused by repeated use, and also more effective It is preferable to use formulations based on drug carriers with high adaptability.
[13] It is also desirable to make formulations based on highly adaptable pharmaceutical carriers that can carry a dosage area and / or a passing corticosteroid preparation to avoid repeated use in therapy. It would also be more desirable that the formulation can be protected from oxidative degradation and microbiological effects upon storage and use.
[1] The present invention relates to a formulation consisting of a molecular arrangement capable of penetrating the pores of the barrier wall even when the mean diameter of the pores is smaller than the mean diameter of the penetrant due to the adaptability of the penetrant. The penetrant may carry the medicament after entering the pore or allow the medicament to penetrate the pore. The present invention relates in particular to the addition of additives such as viscosity builders, antioxidants or bactericides to the formulations. The invention also relates to the preparation and use of the preparations when the medicament is selected from corticosteroids. Finally, the present invention relates to the preparation of all the above formulations.
[14] Therefore, the present invention aims to solve the above-mentioned problem. In particular, the present invention aims to solve the problems associated with the storage and use of optimized and highly adaptable pharmaceutical carriers.
[15] Another object of the present invention is to overcome the problems of the prior art for the delivery of corticosteroid preparations in controlling the movement of corticosteroid-based drugs through and / or infiltrate the skin. In addition, corticosteroid preparations must be viscosity controlled and protected from oxidative degradation and the effects of microorganisms.
[16] It is yet another object of the present invention to provide a process for the preparation of said formulation for non-invasive use.
[17] Means for solving these problems according to the invention are defined by the independent claims in the claims.
[18] Solutions to specific needs are provided by the dependent claims.
[19] The preparation and use of formulations based on a highly compatible pharmaceutical carrier as described above is described in the literature included as part of the present invention. The addition of viscosity modifiers and antioxidants to such formulations is already known (for example, PCT / EP96 / 04526; see section 18). However, this document only discloses general principles, not substantive content, and lacks detailed descriptions in use. This is especially the case when for example a viscosity modifier is added which allows the use of the drug in the formulation to be adjusted as intended. Such additions are inherently unaffected by simple trial and error or by skilled technicians because the final drug action is important. It is also very important to choose appropriately because the type and amount of antioxidants or fungicides added affect the storage and use of the formulation.
[20] The use of corticosteroids as a medicament combined with a highly adaptable medicament carrier is a known technique (see PCT / EP96 / 04526, 15, PCT / EP91 / 0196 Examples 173-175). However, for these additives, these documents only describe the general content of the degree of adding the drug to the carrier, and the description of the details considered to be very important in the use of the drug is omitted. Thus, the prior art merely discloses the use of corticosteroids as test agents for the improvement of feed penetration rates, and in the manufacture of easy-to-use dermatological products based on highly adaptable pharmaceutical carriers comprising corticosteroids. It is not disclosed. This can be seen by the total amount of hydrocortisone bound in the highly adaptable carrier. (PCT / EP91 / 01596 Example 173-® 10 μg per 100 mg dry weight of drug carrier) of hydrocortisone relative to the total dry weight of the formulation. The relative amount is very low, about 0.1, which is far from the drug concentration useful for treatment and also the concentration of corticosteroids used for this purpose.
[21] The prior art also does not disclose how certain uses of corticosteroids are affected to achieve improved systemic or local drug action. Therefore, it is necessary to deal with the systemic and local drug action of corticosteroid dermatitis used on the basis of a drug carrier having a very high adaptability as in the present application.
[22] In general, for both local and non-systemic and systemic administration of corticosteroid dermatitis, drugs with weaker effects, such as hydrocortisone, have short duration and weak efficacy, whereas more recently developed drugs such as prodrica Bart or triamcinolone-based derivatives are more powerful and long-lasting, but when used in high concentrations and / or repeated use may cause serious side effects, there is a problem that is harmful to the human body.
[23] In contrast, delivery of local corticosteroids using drug carriers with very high adaptability can be altered to significantly reduce or avoid serious side effects. Depending on the exact application conditions and the carrier composition, 100% to 5% of the locally administered drug may be deposited on the outermost part of the skin. Low dosage per unit area is desirable to keep the drug in the skin, and when a large amount of drug is used, the drug can be systemically circulated. When the corticosteroid is administered once over the skin by the carrier, the drug concentration in the blood can be up to a significant degree in treatment, while the concentration in the blood can be maintained at several percent or less.
[24] When the drug carrier having the high adaptability is used together with a drug selected from corticosteroids, a biologically effective material can be made even when the amount per area is unprecedentedly small. All corticosteroids tested as described below have excellent results in drug efficacy (2-10 times) and duration of action (5-10 times) when administered to intact skin by highly adaptable drug carriers. It was. In contrast to the prior art ointments and creams comprising corticosteroids showed excellent biological drug action with only a small amount of corticosteroids in a highly adaptable pharmaceutical carrier.
[25] In general, for conventional creams or lotions, physical friction shortens the therapeutic effect. It is another advantage of the present invention that such a problem is not observed in the present invention using a formulation based on a highly adaptable pharmaceutical carrier, and thus exhibits a long-term biological action as compared to conventional medicine. This is because the highly adaptable drug carrier creates a drug reservoir in the skin region rather than the skin surface.
[26] A characteristic configuration of the present invention is that, even when the average diameter of the pores is smaller than the average diameter of the penetrant, the adaptability of the penetrant allows the agent to transport the medicament through the pores or allow the medicament to penetrate the pores after they enter the pores. At least one viscosity modifier that has a molecular structure capable of penetrating the pores of the barrier wall, wherein the viscosity of the formulation is increased from not more than the viscosity of the unconcentrated formulation up to 5 Nm / s to increase and maintain the application area. And at least one antioxidant in an amount capable of reducing the increase in oxidation index to less than 100% per 6 months, and the number of bacteria per gross mass of the total formulation after 4 days from 1 million for aerobic bacteria. Less than 100, less than 10 for enteric bacteria, less than 1 for pseudomonas aeruginosa or staphylococci It relates to formulations comprising the fungicide comprises a keel that.
[27] Thus, the shelf life and shelf life of the formulation can be prolonged and the practicality of the formulation can be increased.
[28] The at least one viscosity modifier is preferably added in an amount capable of increasing the viscosity of the formulation to 1 Nm / s, more preferably to 0.2 Nm / s.
[29] In addition, the at least one antioxidant is preferably added in an amount that can reduce the increase in the oxidation index to less than 100% per 12 months, more preferably less than 50%.
[30] For formulations comprising soy phosphatidylcholine as the major degradation species, the oxidation index is reduced to less than 0.45 units per 12 months, more preferably less than 0.22 units, even more preferably less than 0.1 units.
[31] In a preferred embodiment of the present invention, the at least one fungicide has a bacteria count per gross mass of the total formulation, from 1 million to less than 100 for aerobic bacteria, less than 10 for enteric bacterium, and against Pseudomonas aeruginosa or Staphylococcus aureus. It is preferably added in an amount that can be reduced to less than one.
[32] When antioxidant is selected from synthetic phenolic antioxidants, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), di-t-butylphenol (LY178002, LY256548, HWA-131, BF-389, CI -9986, PD-127443, E-5119, BI-L-238XX etc.), t-butylhydroquinone (TBHQ), propyl gallate (PG), 1-0-hexyl-2,3,5-trimethylhydroquinone (HTHQ), aromatic amines (diphenylamine, p-alkylthio-0-anisidine, ethylenediamine derivatives, carbazole, tetrahydroindenoindole); Phenols and phenolic acids (wire alcohols, hydroquinones, vanillin, gallic acid and esters thereof, protocatechinic acid, quinic acid, siriginic acid, elacic acid, salicylic acid, norhydroguaylic acid (NDGA), eugenol); Tocopheryl-acylates (e.g. -acetate, -laurylate, -myristate, -palmitate, -oleate, -linoleate, etc. or other suitable tocopheryl-lipoates), tocopheryl-POE-succinate Tocopherols (including tocopherol alpha, beta, gamma, delta) and derivatives thereof such as nate, trolox and its amides, and thiocarboxamide analogs; Ascorbic acid and salts thereof, isoascorbate, (2 or 3 or 6) o-alkyl ascorbic acid, ascorbyl esters (for example 6-o-lauroyl, myristoyl, palmitoyl, oleoyl or linoleo Mono-L-ascorbic acid or the like). It is also desirable to use various drugs that interfere with oxidation. Non-limiting examples of such antioxidants include, but are not limited to, nonsteroidal anti-inflammatory agents (indometacin, diclofenac, mephenamic acid, flufenamic acid, phenylbutazone, oxylphenbutazone acetylsalicylic acid, naproxen, diflunisal, ibuprofen, ketopro NSAIDs such as pen, pyroxycam, phenylsilamine, phenylsilamine disulfide, pramaquine, quinacrine, chloroquine, hydroxychloroquine, azathioprine, phenobarbital and acetaminaphene; Aminosalicylic acid and its derivatives; Methotrexite, probucol, antiarrhythmic agents (amiodarone, apridine, asokinol), ambroxol, tamoxifen, b-hydroxytamoxifen; Calcium antagonists (nifedipine, nisoldipine, nimodipine, nicardipine, nilvadipine), beta-receptor blockers (antenolol, propranolol, nebivolol) and also sodium bisulfite, sodium bisulfite, thiourea Compounds which are selectively oxidized, such as these, and chelating agents such as EDTA, GDTA and desferal; Various endogenous defense systems such as transferrin, lactoferrin, ferritin, ceruloplasmin, heptoclobion, hemopexin, albumin, glucose and ubiquinol-10; Antioxidants including metal complexes having the same activity as dismutase peroxides, enzymatic antioxidants such as catalases, glutathione peroxidants, and less complex molecules such as beta carotene, bilirubin, uric acid, and the like; Flavonoids (flavones, flavonols, flavonones, parabonal, chacon, anthocyanins), N-acetylcysteine, mesna, glutathione, thiohistidine derivatives, triazoles, tannins, cinnamic acid, hydroxycinnamic acid and esters thereof (coumaric acid and its Esters, caffeic acid and esters thereof, peruric acid, (iso) chlorogenic acid, cinafinic acid); Spice extracts (eg clove, cinnamon, sage, rosemary, mace, oregano, alspice, nutmeg); Carnosine acid, carnosol, carsolic acid; Rosemarine acid, rosemarydiphenol, genticin acid, ferulic acid; Oat flour extracts such as avenantamide 1 and 2; Thioethers, dithioethers, sulfoxides, tetraalkylthiuram disulfides; Phytic acid, steroid derivatives (eg U74006F); It is useful to use tryptophan metabolites (eg 3-hydroxykynurenine, 3-hydroxyanthrannic acid) and organochalcogens.
[33] In particular, the concentration of preferred BHA or BHT is 0.001 to 2w%, more preferably 0.0025 to 2w%, most preferably 0.005 to 0.02w%. In addition, the concentration of preferred TBHQ and PG is 0.001 ~ 2w%, more preferably 0.005 ~ 0.2w%, most preferably 0.01 ~ 0.02w%. Preferable tocopherol concentration is 0.005 to 5w%, more preferably 0.01 to 0.5w%, most preferably 0.05 to 0.75w%. In addition, the concentration of the preferred ascorbic acid ester is 0.001 to 5w%, more preferably 0.005 to 0.5w%, most preferably 0.01 to 0.15w%. In addition, the preferred concentration of ascorbic acid is 0.001 to 5w%, more preferably 0.005 to 0.5w%, most preferably 0.01 to 0.1w%. In addition, the preferred concentration of sodium bisulfite or sodium metasulfite is 0.001 to 5w%, more preferably 0.005 to 0.5w%, most preferably 0.01 to 0.15w%, preferred concentration of thiourea is 0.0001 to 2w%, more preferred It is 0.0005 ~ 0.2w%, the most preferable is 0.001 ~ 0.01w%, and the most typical concentration is 0.005w%. In addition, the preferred concentration of cysteine is 0.01-5w%, more preferably 0.05-2w%, most preferred 0.1-1.0w%, most typical concentration 0.5w%, preferred concentration of monothioglycerol is 0.01-5w% , More preferably 0.05 to 2w%, most preferably 0.1 to 1.0w%, and the most typical concentration is 0.5w%. In addition, the preferred concentration of NDGA is 0.0005 to 2w%, more preferably 0.01 to 0.2w%, most preferably 0.005 to 0.02w%, and the most typical concentration is 0.01w%. In addition, the preferred concentration of glutathione is 0.005 to 5w%, more preferably 0.01 to 0.5w%, most preferably 0.05 to 0.2w%, most typical concentration is 0.1w%, preferred concentration of EDTA is 0.001 to 5w%, Preferred is 0.005 to 0.5, most preferred is 0.010 to 0.2w%, and the most typical concentration is 0.05 to 0.975w%. Further, the preferred concentration of citric acid is 0.001 to 5 w%, more preferably 0.005 to 3 w%, most preferably 0.01 to 0.2 w%, and the most typical concentration is 0.3 to 2 w%.
[34] In a preferred embodiment of the present invention, ethyl alcohol, isopropyl alcohol, chlorobutanol, benzyl alcohol, chlorobenzyl alcohol, dichlorobenzyl alcohol, short chain alcohols including hexachlorophene, cresol, 4-chloro-m-cresol, p- Chloro-m-xyleneol, dichlorophene, hexachlorophene, povidone-iodine, parabens, especially alkylparabens such as methyl-, ethyl-, propyl- or butyl-, benzylparabens; Acids such as sorbic acid, benzoic acid and salts thereof; Such as alkonium salts such as bromide, benzalkonium salts such as chloride or bromide, cetrimonium salts such as bromide, phenoalkesinium salts such as phenodedecenium bromide, cetylpyridinium chloride and other salts Quaternary ammonium compounds; A fungicide selected from mercury compounds such as phenyl mercury acetate, borate, nitrate, thiomersal, hexyl chloride and its gluconate or compounds with antibiotics of biological origin or suitable mixtures thereof is used.
[35] In a particularly preferred embodiment, the preferred bulk concentration of the short chain alcohols for ethyl, propyl, butyl or benzyl alcohols is 10 w% or less, more preferably 5 w% or less, most preferably 0.5 to 3 w% and preferred chlorobutanol The bulk concentration is 0.3-0.6w%, the bulk concentration of parabens is preferably 0.05-0.2w% for methyl parabens, 0.002-0.02w% for propiparabens. In addition, preferred bulk concentration of sorbic acid is 0.05-0.2w%, 0.1-0.5w% for benzoic acid, 0.1-0.3w% for bulk phenol and triclosan is preferable, and bulk concentration of hexidine chloride is 0.01-0.5 w% is preferred.
[36] Also partially esterified cellulose derivatives consisting of carboxymethyl-, hydroxymethyl, hydroxypropyl-, hydroxypropylmethyl-, methyl-cellulose; Polyacrylates, polymethacrylates, poly (hydroxyethyl)-, poly (hydroxypropyl)-, poly (hydroxypropylmethyl) methacrylates, polyacrylonitrile, metharyl-sulfonate, polyethylene, poly Oxyethylene, polyethylene glycol, polyethylene glycol-lactide, polyethylene glycol-diacrylate, polyvinylpyrrolidone, polyvinyl alcohol, poly (propylmethacrylamide), poly (propylene fumarate-co-ethylene glycol), polox Fully synthetic hydrophilic polymers such as summer, polyaspartamide, (hydrazine crosslinked) hyaluronic acid and silicone; Natural gums such as alginate, carrageenan, guar gum, gelatin, tragagant, (amidated) pectin, xanthan, chitosan collagen and agarose; It is preferred to include a viscosity modifier selected from derivatives of other pharmaceutical copolymers or pharmaceutically acceptable hydrophilic polymers selected from at least biologically acceptable polymers. In particular, the weight fraction of the preferred polymer is 0.05-10%, more preferably 0.1-5%, still more preferably 0.25-3.5%, most preferably 0.5-2%.
[37] The viscosity can be adjusted most appropriately when an amount of viscosity modifier is added that can be increased from above the viscosity of the formulation that does not thicken the formulation to preferably at least 1 Nm / s, more preferably at 0.2 Nm / s. Was found.
[38] According to another aspect of the present invention, the medicament can be combined with a penetrant such as a glucocorticoid or a mineralocorticosteroid (corticosteroid) to move the medicament through the pores after the penetrant enters the pores, or can penetrate the medicament. Therefore, even if the average diameter of the pores is smaller than the average diameter of the infiltrate, the formulations having a molecular structure capable of penetrating the pores of the barrier wall due to the adaptability of the penetration have a relative content of corticosteroid of 0.1 w% based on the total total dry weight of the formulation. It is characterized by the above. It is also preferred to add at least one viscosity modifier and / or at least one antioxidant and / or at least one bactericide to the formulation as detailed below.
[39] The corticosteroids are alkronetasone dipropionate, alkronetasone amcinonate, beclomethasone dipropionate, clobetasol, betamethasone 17-valerate, betamethasone 17, 21-divalerate, betamethasone 21 Acetate, betamethasone 21-butylate, betamethasone 21-propionate, betamethasone 21-valerate, betamethasone benzoate, betamethasone dipropionate, betamethasone valerate, budesonide, clobetasol 17-acetate, clobetasol Butylate, Cortexolone, Corticosterone, Cortisone, Cortisone 17-acetate, 21-dioxybetamethasone, 21-dioxybetamethasone 17-propionate, deoxycorticosterone, desonide, desoxymethasone, dexamethasone Diflorason pivalate, fluorosinone acetonide, fluorosinide, flucortin butyl, flu Cortoron, 9-alpha-fluorocortisone, 9-alpha- pullohydrohydrocortisone, 9-alpha-fluoronisolone, flupridinidine acetate, flulandrenolo, halcinolone, hydrocortisone, hydrocortisone 17 Acetate, hydrocortisone 17-butylate, hydrocortisone 17-propionate, hydrocortisone 17-valerate, hydrocortisone 21-acetate, hydrocortisone 21-butylate, hydrocortisone 21-propionate, hydrocortisone 21- Preferred is selected from valerate, 17-alpha-hydroxy progesterone, methylprednisolone acetate, mometasone floate, prednisolone, prednisone, prednisone 17-acetate, prednisone 17-valerate, progesterone, triamcinolone, triamcinolone acetonide .
[40] In certain embodiments of the invention, the penetrant is suspended or dispersed in a polar liquid in the form of a fluid droplet surrounded by a coating in the form of a membrane coated with one or several layers, said coating having at least two types or forms having a cohesive tendency. Wherein the at least two kinds of substances are homogeneous when the solubility in the liquid differs by about 10 or is more soluble, and in the case of a combination of the two substances. When in the form of the material has a preferred diameter which is smaller than the diameter of the homogenous population containing only low solubility material. The presence of more soluble materials also lowers the average elastic energy of the coating in the form of a film at thermal energy.
[41] Higher solubility material can dissolve microdroplets, and the amount of the material is preferably 99 mol% or less of the dissolved concentration or 99 mol% or less of the saturated concentration in the undissolved droplets. The content of the more soluble material is preferably less than 50%, in particular less than 40% and most preferably less than 30% relative to the relative dissolution concentration of the material. In addition, the content of the more soluble substance is preferably less than 80% of the saturation concentration of the substance in the droplets, more preferably less than 65%, most preferably less than 50%.
[42] In a particularly preferred embodiment of the present invention, the low solubility in the flocculating material is a lipid or lipid-like material, in particular a polar lipid, while the high solubility in suspension and an increase in the adaptability of droplets is similar to the surfactant type or surfactant. Has characteristics. Certain embodiments of the present invention are prepared from lipids or lipid analogs (lipids or fats derived from biological origin, or synthetic lipids or variants thereof), wherein the lipids are preferably It is preferred to belong to the corresponding class of pure phospholipids.
[43]
[44] Wherein R ₁ , R ₂ are aliphatic chains, typically C _10-20 -acyl or alkyl or partially unsaturated fatty acid residues, in particular oleoyl, -palmitoeroyl, -elidoyl-, -linoleyl ,-Linolenyl,-linolenoyl,-arachidyl,-vacinyl, lauroyl-, myristoyl-, palmitoyl-, stearoyl chain and the like, R ₃ is hydrogen, 2-trimethylamino- 1-ethyl, 2-amino-1-ethyl, C _1-4 alkyl, carboxy substituted C _1-5 alkyl, hydroxy substituted C _2-5 alkyl, carboxy and hydroxy substituted C _2-5 alkyl, carboxy and amino substituted C _2-5 alkyl, inositol, sphingosine or a salt of said substance, said lipid forming a lipid or two other layers comprising glycerides, isoprenoid lipids, steroids, sterins or sterols, sulfur or hydrocarbons It consists of lipids, especially protonated fluid fatty acids. Preferably, the lipid is phosphatidylcholine, phosphatidylethanolamine, phosphatidyl glycerol, phosphatidyl inositol, phosphatidic acid, phosphatidylserine, sphingomyelin and other sphingophospholipids, glycosphingolipids (cerebrosides, ceramide polyceramides) Hexosides, sulfides, including sphingoplastmarogen), gangliosides and other glycolipids or synthetic lipids, in particular from sphingosine derivatives or other glycolipids or synthetic lipids, in particular sphingosine derivatives or It is preferably selected from the outer glycolipids, wherein the ester group is bonded to the main chain of the same or two different chains (as diacyl and diallkenoyl compounds) or by the main chain and ether bonds as dialkyl lipids.
[45] The surfactant or surfactant analog is preferably a nonionic, zwitterionic, anionic or cationic surfactant, in particular one of fatty acids or alcohols, alkyl-tri / di / methyl-ammonium salts, alkylsulfate salts, cholates. Salts deoxycholate, glycocholate, glycodeoxycholate, taurodeoxycholate, taurocholate and the like are preferred, or acyl- or alkanoyl-dimethyl-aminooxide, especially dodecyl-dimethyl-aminooxide , Alkyl or alkanoyl-N-methylglucamide, N-alkyl-N, N-dimethylglycine, 3- (acyldimethylammonio) -alkanesulfonide, N-acyl-sulfobetaine, polyethylene-glycol-octyl Phenyl ethers, in particular nonaethylene-glycol-octylphenyl ethers, polyethylene-acyl ethers, nonaethylene-dodecyl ethers, polyethylene-glycol-ioacyl ethers, in particular octaethylene-glycol-isotridecyl Ethers, polyethylene-acyl ethers, in particular polyethylene-glycols, such as octaethylene-dodecyl ether, polyethylene glycol-20-monolauric acid (Tween 20), polyethylene glycol-20-sorbitan-monolioleate (Tween20) Non-acyl ether, polyhydroxyethylene-acyl ether, polyhydroxyethylene-4, 6, 8, 10 or 10, polyhydroxyerylene-lauryl,-myristoyl, cetylstearyl-, oleoyl ether Lauryl ether (as Brij series) or the corresponding ethers, such as polyhydroxy ethylene-8-stearate (Myrij 45), laurate or -urearate or polyepoxylate castor oil 40, and the like. Sorbitan monoalkylates (in Arlacel or Span), in particular sorbitan-monolaurate, acyl- or alkanoyl-N-methylglucamide, especially decanoyl- or dodecanoyl-N-methylglucamide, alkyl Sulphates (salts), for example lauryl- or oleoyl-sulfate, sodium deoxycholate, sodium glycodeoxycholate, sodium oleate, sodium taurate, sodium acrylate, sodium laurate and the like, n- Lysophospholipids such as octadecylene (oleoyl) -glycerophosphatidic acid, -phosphorylglycerol, -phosphorylserine, lauryl or oleyl-glycero-phosphatidic acid, -phosphorylglycerol or phosphophil Lysophospholipids such as serine, n-tetradecyl-glycero-phosphatidic acid, -phosphorylglycerol, -phosphorylserine, palmitooleyl-, elliodoyl-, basenyl-lysophospholipid or the like It is preferred to consist of a corresponding short chain phosphoropyrup or surface active polypeptide.
[46] When the average diameter of the penetrant is between 30 and 500 nm, the penetration rate of the pharmaceutical carrier can be maximized, more preferably 40 to 250 nm, still more preferably 50 to 200 nm, most preferably 60 to 150 nm.
[47] The pore permeation rate of the pharmaceutical carrier can be optimized according to the relative ratio of the size of the permeate and the pore size, and it is preferable that the average diameter of the permeant is 2 to 25 times larger than the average diameter of the pore of the blocking wall, more preferably 2.25. 15 times, more preferably 2.5 to 8 times, most preferably 3 to 6 times.
[48] Certain embodiments of the present invention provide that the dry weight of all carrier droplets of the formulations used for human or animal skin is 0.01-40 w%, in particular 0.1-30 w%, more preferably 0.5-20 w%, most preferred, relative to the total formulation weight. Preferably it is characterized in that the range of 1 ~ 10w%.
[49] When the formulation is applied to mucous membranes of humans or animals, the dry weight of all carrier droplets in the formulation is preferably selected in the range of 0.0001-30 w% of the total formulation mass.
[50] Since the stability of the formulation in the preparation of the formulation is determined by the pH of the carrier suspension, the pH of the carrier suspension is preferably from 4 to 10, preferably from 5 to 9 and sometimes from 8.5 to maximize this.
[51] The method for the preparation of a non-invasive preparation in vivo according to the present invention comprises at least one positive affinity material, at least one hydrophilic fluid, at least one edge active or surfactant, and the total dry weight of the preparation. At least one corticosteroid added in an amount greater than or equal to 0.1 w% and other conventional ingredients that make up the formulation.
[52] At least one edge active material or surfactant, at least one affinity material, at least one hydrophilic fluid and medicament are preferably dissolved to form a solution and, if necessary, separated and mixed to form a mixture or a convenient drive pressure. It is preferable to form a mixture or solution by applying mechanical energy such as shaking, stirring, vibration, homogenization, ultrasonic vibration, shear deformation, cooling, and thawing filtration to form a permeate combined with and / or mixed with a drug. Do.
[53] The affinity material may be used as is, dissolved in a physiologically compatible polar fluid (the polar fluid may be water or miscible), or a polar solution is used with a solvating modifier.
[54] The affinity substance is preferably dissolved in a highly volatile alcohol, in particular ethanol, or pharmaceutically acceptable, preferably dissolved in an organic solvent that can be removed by evaporation or the like prior to final preparation.
[55] It is also preferred that the polar solution contains at least one edge active material or surfactant.
[56] In the preparation of the preparations according to the invention, the formation of such penetrants is induced by adding the required substances into the fluid phase and evaporating from the reverse phase by injection or dialysis or the like. At this time, use a convenient, especially low (1 MPa) or medium (10 MPa) drive, shake, whisk, especially at high speeds, vibration, homogenization, ultrasonic vibration, shear deformation, freezing and thawing filtration, etc. Also good.
[57] When the penetrant is formed by filtration, the filtration material preferably has a pore size of 0.01 ~ 0.8㎛, more preferably 0.02 ~ 0.3㎛, more preferably 0.05 ~ 0.15㎛, several filters are sequentially or It can also be used in parallel.
[58] In addition, the drug and the penetrant may be dissolved in a pharmaceutically acceptable fluid such as ethanol, 1, 2-propanol, benzyl alcohol, propylene glycol polyethylene glycol (molecular weight 200-400D) or glycerol after the composition of the penetrant. It is preferably made by injecting at least partially into the suspension medium. The penetrant is prepared prior to or concurrently with drug infusion using other suitable methods of preparation. It is also possible to use cosolvents of the drug or at least some kinds of penetrant components.
[59] Penetrants bound to and / or mixed with drug molecules are preferably prepared just prior to use of the agent, and suitable thickening or lyophilic agents may be used.
[60] The content of the corticosteroid is preferably in the range of 0.1 to 20 rw% (relative weight) relative to the total weight of the penetrant, more preferably 0.25 to 10 rw%, and still more preferably 0.5 to 5 rw%.
[61] In addition, when the corticosteroid is a triamcinolone such as acetonide or the like or a derivative thereof, the relative amount thereof is preferably less than 2w% of the dry weight of the carrier on which the whole drug is loaded, more preferably less than 1w%, most typically 0.5w% Is less than.
[62] In addition, when the corticosteroid is hydrocortisone or a derivative thereof, the relative amount thereof is preferably less than 20w% of the dry weight of the carrier loaded with the entire drug, more preferably less than 12.5w%, most typically less than 5w%.
[63] In addition, when the corticosteroid is one of the dexamethasol or derivatives thereof, the relative amount thereof is preferably less than 15w% of the dry weight of the entire drug carrier, more preferably less than 10w%, most typically less than 5w% to be.
[64] In addition, when the corticosteroid is clobetasol or a derivative thereof, the relative amount thereof is preferably less than 15w% of the dry weight of the entire drug loading carrier, more preferably less than 10w%, most typically less than 5w%.
[65] According to a preferred feature of the invention, it is necessary that the content of the corticosteroid is less than the maximum saturation amount. The saturation maximum is defined as the point at which corticosteroids begin to crystallize inside or outside the carrier, and the maximum amount is determined by the interaction between the affinity molecule consisting of the carrier molecule and the drug molecule. In addition, the maximum saturation amount often reflects the membrane / or oil / water separation coefficient between the main carrier component and the corticosteroid, or low affinity associated with improper binding of the molecular size between the carrier and the corticosteroid molecule. Drugs that have typically have low saturation values.
[66] In order to improve the rate of drug action, it is preferable to add a penetration enhancer, and the penetration enhancer may be 1-acyl-acylcycloheptan-2-one (azone), 1-acyl-glucoside, 1-acyl-polyoxyethylene, 1-acyl-saccharide, 2-n-acyl-cyclohexanone, 2-n-acyl-1, 3-dioxolane (SEPA), 1, 2, 3-triacyl-glycerol, 1-alkanol, 1-alkanoic acid, 1-alkyl-acetate, 1-alkyl-amine, 1-alkyl-N-alkyl-polyoxyethylene, 1-alkyl-alkylate, n-alkyl-beta-D-thioclocoside, 1-alkyl-glyceride, 1-alkyl-propylene glycol, 1-alkyl-polyoxyethylene, (1-alkyl-) 2-pyrrolidone, alkyl-acetoacetate, alkylene-glycol, alkyl-methyl-sulfoxide (Alkyl-DMSO), alkyl-propionate, alkyl-sulfate, thiacyl-succinate, diacyl-N, N-dimethylaminoacetate (DDAA), diacyl-N, N-dimethylaminoisopropionate ( DDAIP), Phenyl-alkyl-amine It is selected from the preferred.
[67] The addition of the penetration enhancer is not similar to the addition of penetration enhancers such as ointments or lotions that are already used in conventional herbal preparation in the prior art. The penetration enhancer of the present invention serves to increase the drug action rate, which increases the rate of distribution between the drug carrier and its surroundings. The role of the penetration enhancer is not limited to emulsifying the skin to increase the feed penetration rate of the carrier medicament and thus is essentially different from conventional penetration enhancers in this respect.
[68] The preferred bulk concentration range of the reinforcing agent used is preferably 5% or less for 1-capryl-propylene glycol, with 1- [2- (decylthio) ethyl] azaylcropentane-2-one (= HPE-101) 6-10% for less than 10% for 1-dodecanol, less than 10% for 1-dodecyl-azacycloheptan-2-one (= azone), 2-n-nonyl-1,3-di About 10% for oxolane (SEPA), less than 10% for 2-N-octylcyclohexanone, preferably less than 20% for DMSO, 5-40% for ethanol, 10% or more for ethylene glycol, Less than 30% for ethyl acetate, 5 to 50% for glycerol, less than 75% for isopropanol, 1 to 20% for isopropyl myristate, 20% for oleic acid and oleyl alcohol, oleyl-polyoxyethylene -About 1% for ether and at least 10% for propylene glycol.
[69] The meaning of these ranges is that the relative and absolute efficacy of various skin penetration enhancers is different, which makes absolute comparison difficult. In principle, it is the concentration of the strengthening agent in the skin that determines the strengthening effect. However, what is typically considered or cited in the literature is the nominal enhancer concentration on the skin. These two values of varying digits in size are very sensitive to the combination of the drug and the reinforcing agent and may also vary depending on the conditions of use. If the reservoir of reinforcement on the skin surface is too small, for example, it may be depleted if the reinforcement diffuses or evaporates too quickly through the skin. This also changes the properties of the final system.
[70] According to a preferred feature of the invention, the corticosteroid is added so that the formulation can be used in an amount corresponding to the amount used per area, that is, expressed by the total dry mass of the penetrant used per unit area, 0.1 ~ 10mg / Cm 2, particularly preferred is 0.75-5 mg / cm 2, most preferably 1-2.5 mg / cm 2, wherein the corticosteroid is substantially subcutaneous subcutaneous, including, for example, a muscle or joint, tissue or distant tissue that includes the entire body. It is desirable to exert a therapeutic effect.
[71] In the non-invasive use of corticosteroids by the penetrant according to the invention, mainly local, i.e. expressed in terms of the total dry mass of the penetrant applied per unit area in order for the drug to have an effect on the surface rather than on the whole body. The dosage per area is preferably selected in the range of 1 to 250 µg / cm 2, and more preferably in the range of 2.5 to 100 mg / cm 2, more preferably 5 to 50 mg / cm 2, and most preferably 7.5 to 20 mg / cm 2.
[72] When the corticosteroid combined with the encapsulated penetrant according to the present invention is used in a non-invasive manner, it is preferable that the corticosteroid is formed by a method such as powdering, rubbing, rolling, or wiping with sponges, and in particular, a nebulizer, a spreader, a sponge, or the like. It is preferable to use appropriately.
[73] The preparations according to the present invention are inflammatory diseases, cutaneous osteomas, renal or hepatic insufficiency, adrenal insufficiency, malabsorption syndrome, Behcet's syndrome, bite or puncture, cold erythrocyte agglutination, hemolytic anemia, hypereosinophilia, dysplastic anemia It is preferably used for the treatment of blood disorders such as macroglobulinemia, thrombocytophenin purpura, and also skeletal disorders, cerebral edema, cogan cydrome, congenital adrenal hyperplasia, thyroid, cardiac lupus erythematosus, multiple myalgia rheumatoid, multiple myositis , Connective tissue disorders such as dermatitis, epilepsy, cataracts, grave eye disease, hemangioma, herpes infection, neuropathy, retinal vasculitis, eye diseases such as scleritis, gastro-intestinal diseases such as inflammatory bowel disease, nausea and esophageal disease, calcium Treatment of excess, infections, such as eye infections (as infectious mononucleosis), and a variety of treatments such as Kawasaki disease, postoperative herpetic pain, etc. Respiratory diseases such as syndrome, polyneuropathy, pancreatitis and asthma, rheumatoid and skeleitis, rhinitis, sarcoidosis, alopecia, eczema, polymorphic erythema, thyroid, swelling, ductal swelling, psoriasis, necrotic pyoderma, urticaria, thyroid disease It is preferable to use for the treatment of vascular diseases.
[74] The results of in vitro and in vitro studies shown in the following examples and the accompanying drawings illustrate the invention without departing from the scope of the invention.
[75] Example 1-4
[76] Furtherance:
[77] 73.2mg, 64.5mg, 54.8mg, 37.7mg Soy Phosphatidylcholine (SPC)
[78] 26.8 mg, 35.5 mg, 45.2 mg, 62.3 mg polysorbate (tween 80)
[79] 1mg / g triamcinolone acetonide
[80] 899 mg phosphate buffer (10 mM, pH 6.5)
[81] Produce:
[82] Various SPCs and triamcinolone acetonides are dissolved in 50 mL chloroform and 50 mL methanol in defined amounts. The solvent kept warm (approximately 40 ° C.) is evaporated under a nitrogen stream and the balance is vacuum dried at room temperature. A fixed amount of Tween 80 and phosphate buffer are added to the lipid film, resulting in a coarse suspension, which is sonicated to produce smaller mixed lipid vesicles. The resulting suspension is milky white, slightly yellowish, sonicated for several minutes and stable for at least one day. Test samples are used 24 hours after manufacture.
[83] Biological and / or characterization:
[84] All of the above suspensions are tested as described below.
[85] Examples 4-5:
[86] Furtherance:
[87] 37.74mg soy phosphatidylcholine (SPC)
[88] 62.26mg Tween 80
[89] 0.4mg triamcinolone acetonide
[90] 0, 26.25mg benzyl alcohol
[91] 4.47g Phosphate buffer 50mM pH 6.5
[92] 0.3mg probucol
[93] 0.3mg desferral
[94] Produce:
[95] SPC, probucol and triamcinolone acetonide are dissolved in a mixture of chloroform / methane. The dry lipid mixture is prepared as described in Example 1. Add desperal, Tween80 and 894.23 mg of buffer to dry lipids. The resulting suspension is stirred overnight. If benzyl alcohol is selected, 26.25 mg benzyl alcohol in 3.58 g of buffer is added to the suspension, then the mixture is extruded through a 200 nm polycarbonate membrane and extracted again through a 50 nm membrane using sufficient pressure to be an acceptable flow rate. . The resulting particle diameter is less than 150 nm.
[96] Example 6:
[97] Furtherance:
[98] 37.74mg SPC
[99] 62.26mg Tween 80
[100] 35mg ethanol
[101] 0.4mg triamcinolone acetonide
[102] 26.25mg benzyl alcohol
[103] 4.47 g phosphate buffer (50 mM pH 6.5)
[104] 0.3mg probucol
[105] 0.3mg desferral
[106] Produce:
[107] SPC, probucol and triamcinolone acetonide are dissolved in ethanol. Desperal, Tween 80, 5.25 mg benzyl alcohol and 894.23 mg buffer are added. To the resulting suspension. The suspension is first compressed through the 200 nm pores of the polycarbonate membrane and then extruded through the 50 nm membrane. The resulting particle radius is approximately 60 nm.
[108] Stability analysis of the formulation by HPLS showed that probucol and desperal help the chemical stability of the suspension.
[109] Examples 7-14:
[110] Furtherance:
[111] 88.1g, 87.4g, 86.6g, 85.75g Soy Phosphatidylcholine (SPC)
[112] 11.9g, 12.6g, 13.4g, 14.25g Sodium Cholate (NaCho1)
[113] 80g ethanol
[114] 0.5 g triamcinolone acetonide
[115] ad 1000g phosphate buffer (pH 7.1)
[116] Produce:
[117] SPC and triamcinolone acetonide are dissolved in ethanol and NaCho1 (only partially dissolved) is added. After addition of the buffer, the resulting cloudy and whitish suspension is stirred overnight. The milky final suspension is obtained by extruding the suspension through a 200 nm membrane and again under pressure through a 100 nm membrane or by treatment with a high pressure homogenizer (eg operating in a low pressure range of 200 psi) to make the vesicles final.
[118] From the above-described preparation method, two different formulations can be prepared in which the total lipid concentration is 5w% and 2w%, respectively, by diluting the suspension in a buffer (containing 0.5V% benzyl alcohol).
[119] Examples 15-49:
[120] Furtherance:
[121] 377.4 mg soy phosphatidylcholine (SPC)
[122] 622.6mg Tween 80
[123] 50mg benzene alcohol
[124] 9000mg phosphate buffer 50mM pH 6.5
[125] a) 12.5 mg, 25 mg, 50 mg betamethasone
[126] b) 12.5 mg, 25 mg, 50 mg betamethasone dipropionate
[127] c) 12.5 mg, 25 mg, 50 mg betamethasone 17 valerate
[128] d) 12.5 mg, 25 mg, 50 mg clobetasol-17-propionate
[129] e) 12.5 mg, 25 mg, 50 mg dexamethasone or
[130] f) 25 mg, 50 mg, 75 mg hydrocortisone
[131] g) 12.5 mg, 25 mg, 50 mg prednicabate
[132] h) 12.5 mg, 25 mg, 50 mg triamcinolone
[133] Produce:
[134] Selected SPC and corticosteroids are dissolved in ethanol. After addition of a buffer comprising Tween 80 and benzyl alcohol, the resulting very whitish suspension is thoroughly mixed for at least 24 hours, more preferably for several days. The suspension is extruded through a 200 nm film and repeated several times if necessary. The vesicles of the resulting suspension are still relatively large in size and tend to settle over time, but can be easily homogenized again by shaking or other light mixing methods. It is useful to perform the final extrusion through the 100 nm membrane to stabilize the suspension by obtaining smaller final sized vesicles (vesicles with the highest drug concentration may contain some drug in the suspension, which is coated with drug crystals Can be in the form of parcels.)
[135] Example 50:
[136] Furtherance:
[137] 347 mg soybean phosphatidylcholine (SPC)
[138] 623mg Tween 80
[139] 30mg Sodium Dodecyl Sulfate (SDS)
[140] 50mg benzyl alcohol
[141] 9000mg phosphate buffer 50mM pH 6.5
[142] 25mg clovestasol-17-propionate
[143] Produce:
[144] The corticosteroid suspension was prepared in the same manner as in the above-described examples except that the SDS dissolved in the roundworm solution was added. The SDS functions as a promoter of the distribution of drugs in the target tissue.
[145] Formulations containing SDS showed superior rates in human skin bleaching assays compared to those without SDS.
[146] Hereinafter very highly adaptable agent carriers, i.e. highly adaptable is high and also flexible several kinds of lipid vesicles of corticosteroids: hydro-based (Transfersome ^TM see above citation) - clinician vivo in vitro and of the formulation lotion form Describe your previous experience. The novel carrier based formulations can be seen to increase the drug concentration in the skin to the desired level even after only one use of the agent in Transfersome.
[147] The new corticosteroid delivery concept may lower the risk of side effects of topical therapy with the drug. This is possible due to the reduction in the amount of use and the new drug delivery mechanism. Corticosteroids in transfersomes cannot penetrate blood vessels directly because of their large carrier size. Thus, the effect of the drug is limited to intercellular spaces that can exhibit the expected biological action. (Only when administered in ampoules, it can be distributed throughout the body via lymphatic and blood circulation.)
[148] Data measured in animals and humans indicate that several widely used corticosteroids can hardly reach blood when applied on the skin in suspensions of Transfersomes. It may be argued that this phenomenon depends on the extreme deformability of the Transfersome membrane, which allows the drug carrier to cross the skin permeable barrier. This high level of control of infiltration and the elimination of vascular foreign body invasion has made it possible to limit the biological effects of Transfersome-corticosteroids on the skin at the site of treatment. Separate vasoconstriction induced by the cream / lotion form or the corticosteroid of Transfersome indirectly supports this conclusion. The use of deformable carriers to a significant extent increases the efficacy of corticosteroids by one order of magnitude compared to conventional commercial formulations. Final drug stability is also improved. (The site of administration required for successful treatment of Transfersome-adjusted dexamethasone or triamcinolone acetonide at the surface of the skin to be treated should be 1.5 m 2 before the total drug used reaches the intrinsic hydrocortisone amount in the blood).
[149] In Vitro Penetration Studies
[150] Differences in the ability of different drugs and drug carriers to penetrate the artificial transport barrier clearly indicate the relative benefits of Transfersome, which is highly deformable compared to standard liposomes, for example. Liposomes rarely cross the artificial skin barrier, whereas Transfersomes pass through the micropores with little or no obstruction to the barrier. The following table illustrates this behavior.
[151] Penetration capacity for pores 3-4 times smaller than penetrant size of transfersomes, liposomes and micelles loaded with corticosteroids under the influence of water pressure (to water) FormulationLow pressure (0.2 MPa)High pressure (0.9 MPa) Michelle1.1 ± 0.11.1 ± 0.1 Liposomes≤0.0001≤0.001 Transfersome≤0.0011 ± 0.1 Hydrocortisone and Liposomes≤0.0001≤0.001 Hydrocortisone and Transfersome≤0.0011 ± 0.1 Dexamethasone and Transfersome≤0.0011 ± 0.1 Triamcinolone-Acetonide and Transfersomes≤0.0011 ± 0.1
[152] An artificial barrier made of a polycarbonate film also forms pores of 100 nm. Liposomes and Transfersomes are about the same size. The carrying capacity corresponds to the ratio of aggregate / water transport rates measured under the same conditions (HPLC and gravimetric conditions).
[153] When used on intact skin surfaces, phospholipid suspensions are not harmful to the skin. On the other hand, some types of phospholipid preparations have been reported to enhance hydration of aging skin (and therefore only marginally in appearance). Phospholipid suspensions also do not irritate the skin until they are degraded at least 30%.
[154] The amount of corticosteroid based transfersomes is about the same as the amount of lipid (100 mg per day) as parenteral (≦ 75 mg / injection) or oral (≦ 150 mg / day) administration.
[155] Preferred daily doses of Transfersome corticosteroids for human use are significantly lower (≦ 25 mg) except for hydrocortisone, which requires slightly higher doses for systemic treatment.
[156] The total amount of phospholipid used in the skin in the form of corticosteroid preparations using transfersomes is always less than 0.5 g / day. It is also less than 10%, the naturally variable range of phosphatidylcholine concentrations in the plasma of the average healthy person. It can be concluded that corticosteroid dermatitis using Transferomes as a carrier based on these data given below is a very safe product.
[157] From a pharmaceutical standpoint, the maximum amount of corticosteroid (1 mg / day for dexamethasone or triamcinolone-acetonide, 20 mg for hydrocortisone) similar to the amount produced in the human body (12-30 mg per day for hydrocortisone) Used locally. The amount of leakage per area is usually about 0.1 µg / cm 2 and about 1 µg / cm 2, respectively, with high potency and weak potency. As can be seen in the table below only a very small portion of the drug to be administered on the skin is circulated.
[158] Concentration ratio of corticosteroids in blood and endothelium of rat (measured value) and human (calculated value) Usage amount (㎍ / ㎠)Hydrocortisone (rat)Hydrocortisone (rat)Dexamethasone (rat)Dexamethasone (rat)Triamcinolone-Acetonide (Rat)Triamcinolone-Acetonide (Rat) 0.50000 1.30.020.00007 4.90.0120.0000040.10.00003 13.20.040.00011 20.60.030.0001 49.50.0150.0000050.250.00009
[159] Thus, corticosteroids using Transfersome can be expected to produce fewer side effects than currently available formulations. This is due to the bio-distribution of the drug from the preferred Transfersome concentrated in the tissue at the treatment site. The proportion of drug taken from the carrier by strong proliferative cells, one of the main goals of corticosteroid treatment, is quite high. Very low doses of corticosteroids used can completely eliminate the problem of skin dysfunction after such repeated treatment).
[160] The assessment of the practical value of Transfersome-based corticosteroids can be made clear from the results of the animal tests described below.
[161] Preclinical Studies
[162] All materials used in this study have pharmaceutical properties. Soy phosphatidylcholine (SPC) was purchased from Lipoid KG (Rodwigshafen, Germany) or Nattermann Phospholipid-Rhone-Poulence Rorer (Cologne, Germany) and is at least 95% pure. The remaining ingredients described in detail in the European patent cited above are available from Henkel (Düsseldorf, Germany) or CPC (Hamburg, Germany). Active ingredients (dexamethasone, hydrocortisone, triamcinolone acetonide) were purchased from Synopharm (Hamburg, Germany). Fungicides, chelating agents and antioxidants were purchased from Ciba-Geigy (Switzerland, Basel) or Synopharm. Distilled water twice with injectable quality was purchased from a local pharmacy. Commercial pharmacologics from local pharmacies were used for comparison; , Munchen) and Delphocort-Cream (Ledrele, Wolfratshausen).
[163] Drugs in suspension of Transfersomes. The formulations used in the biodistribution studies are represented by the triyoic corticosteroids purchased from Amersham or ICN. Preparations for animals are made by dissolving an appropriate amount of lipoid in methanol / chloroform (1/1 v / v) and preparing a dry mixed lipid membrane under vacuum (≦ 10 Pa; ≧ 12 h). The use of potentially harmful organic solvents has been completely avoided in the manufacture of medicines for human use.
[164] The formulation contains 0.01 to 0.5 w% of the specific corticosteroid per mL of single suspension. The latter consists mainly of phosphatidylcholine (SPC) at a final concentration of 0.5w% to 5w%. The lipids are mixed with the buffer and homogenized (for animal experiments: sonication with titanium microtips, Heat System W 380, USA, 30 minutes at 4 ° C., other mechanical means for human treatment). At least one carrier component is characterized by the basic theory of transfersomes construction and membrane solubility as required by the applicant's cited patent application. Substances affecting the membrane are always associated with the carrier at Sub-lytic Concentration. Since the high efficiency of the drug carrier for transporting through the dermis is required, this ensures a high possibility of deformation of the carrier without compromising the unity of the Transfersome vesicles. The final particle size is determined by photon correlation spectroscopy (PQCS) (90 °, ALV-5000 ALV-Laser Vertriebgesellschaft Langen, Germany), typically between 100 nm and 200 nm. For experimentation, the lipid suspension is appropriately diluted. A more detailed description of the characteristic data is discussed below.
[165] In vivo experiments Using 8-12 weeks of NMRI mice maintained under standard experimental conditions (3-5 per cage; Standard chew and optional water; 12h light / dark regime). Stress and pain manipulations were always performed after general anesthetic injection. .
[166] One day before the biodistribution experiment, the hair of the selected skin area was shaved less than 2 mm with a pair of scissors. Mark the correct application site on the upper back and apply the appropriate amount of drug formulation (0.5 μl to 25 μl) with a micropipette over the skin. Allow the application area to dry evenly with the same pipette tip.
[167] A blood sample is taken from the tail with a glass capillary (20 μl). After 8 hours, the animals are cardiac injected and killed, and the treated skin area is carefully excised. The outermost layer of the stratum corneum is collected by five tape strippings. The remaining skin tissue and other organ samples are then prepared to remove dirt and used for radio counting.
[168] For experiments on pig skin, the entire tracheal thickness of 20 × 30 cm 2 is excised and fixed on a wet fabric. Several 1 cm 2 test sites are marked and treated as in vivo.
[169] Biological activity in rats is often tested as a measure of the degree of inhibition of chemically induced edema by locally administered corticosteroids. For this purpose, the experimental animal first contained a mixture containing 6 ml of 0.9% NaCl, 1 ml of Ketavet 100 (Parke-Davis, Berlin, FRG) and 0.25 ml Rompun (Bayer, Leverkusen, Germany) per 1 g of body weight. Anesthetize by injection in μL intraperitoneal. Apply the appropriate amount of drug formulation to the inner side of one ear and dry. Then, the surface preparation is wiped off with a cotton swab. For a given time, the experimental rats are anesthetized, and arachidonic acid (1/2 V / V, 10 / muL) mixed with ethanol is applied to the same ear part. By measuring the thickness of the ear with a micro caliper (our method) or by weighing the dead rat (original procedure), the change in ear edema is judged (as compared to when stimulated but not treated). Get the same result. All values are the average of at least three independent measurements and represent the average standard deviation.
[170] Human research
[171] According to scientific literature, it is common to use so-called "skin staining" assays when testing the biological efficacy of different corticosteroids in humans. The test is not as suitable for the study of corticosteroids bound to the carrier as for the corresponding drug solutions for the following reasons.
[172] Nevertheless, local vasoconstriction tests are used to compare the rate of action of corticosteroids on rodent and human skin.
[173] In experiments with three volunteers, the test formulation was applied in parallel rows with different dosages for one target. An area of 1 cm 2 was covered using high precision micropipettes, respectively. Vasoconstriction for each of the skin regions was determined by visual inspection (at least once by different observers not aware of the drug application pattern). And the number of squares or corners is indicated by the skin staining score.
[174] Human skin showed a response similar to the local administration of corticosteroids in Transfersome compared to that of rats: at about 1 μg / cm 2 of drug dose, vasoconstriction (skin staining) effect was maximized after about 7 hours. 50% of was reached and saturated after t ≧ 8 hours. High biological activity was observed for at least 32 hours, with a final reduction of 50% between 36 and 48 hours (FIG. 4).
[175] Similar development of skin staining is observed even after local treatment of triamcinolone-acetonide in conventional creams, but only when the amount of the drug is used exceeds 10 µg / cm 2.
[176] Skin paleness in the initial stages after cream use (8 ≦ t / h ≦ 16) is more severe (whiter) and faster for vasoconstricted cortico-Trnasfersomes. In our opinion, this may be due to the limited ability of Trnasfersome-bound drugs to enter peripheral blood vessels. This phenomenon is not only seen with commercially available formulations, but spreads through or through the skin in a single molecule (or at least separated) form. This explains the rapid onset of edema suppression (desired) and the delay in vasoconstriction (less preferred), indicating that the drug has penetrated into the vascular circulation. This is also due to the very low reactivity of either: it responded very slowly to the drug in the Transfersome, not at all to the low doses of commercial creams, and did not show any effect after the average drug time had elapsed. )
[177] result
[178] The results of representative experiments are shown in the accompanying drawings.
[179] The upper panel of FIG. 1 shows the biological edema inhibition action of hydrocortisone in the commercial cream (○ symbol) and Transfersome, a highly adaptable lipid particle (symbol). Data are given as mean values measured from 3 to 4 animals, with error ranges representing the corresponding standard deviations.
[180] The lower panel of FIG. 1 shows the relationship between dose versus action tested as a local edema inhibitory action after 16 hours of hydrocortisone of commercial cream (○) and Transfersome suspension (•). The value depends on the function of action speed and usage (see FIG. 2)).
[181] It can be seen from FIG. 1 that the biological effect of the hydrocortisone of the formulations using Transfersome far exceeds the effects of conventional formulations in the form of creams containing the same drug. That is, the amount of drug to be administered per area can be reduced, and the therapeutic effect can be enhanced. These data indicate that excellent hydrocortisone formulations in the form of (hydro) lotion containing only 0.1% of drug can be manufactured and sold for commercial use. Such unexpected low drug content can also reduce the risk of side effects.
[182] The upper panel of Figure 2 shows the inhibitory effect of arachidonic acid-induced edema by dexamethasone of commercial cream (marked with ○) and Transfersome (marked with) on the skin of intact rats as a function of time after drug administration. will be. In both cases, excess drug was flushed from the application site 8 hours after administration.
[183] The bottom panel shows the effect of varying doses per area on the inhibition of dexamethasone-induced skin edema in the rat ear model (different symbols are given for different trials, see FIG. 1 for details).
[184] From the results of FIG. 2, it can be seen that dexamethasone exhibits a stronger biological effect than hydrocortisone when tested locally on the skin due to its strong intrinsic efficacy. By combining dexamethasone with a highly deformable carrier, Transfersome can further enhance the therapeutic effect. The effect of using transfersomes is more pronounced when excess drug is removed from the treated skin area. Appropriate skin treatments can be performed with formulations containing only 0.02% dexamethasone (strong) or about 0.005% metason (weak).
[185] The upper panel of Figure 3 shows the biological edema inhibitory activity of the triamcinolone acetonide contained in the commercial lotion (○ symbol) or Transfersome (● symbol) in the ear model of the rat, the lower panel is used for the skin of the intact rat The dosage and action curves for the triamcinolone acetonide contained in the transfersome (symbol symbol, two different manufacturing methods and experiments), commercial cream and commercial lotion (symbol symbol ○) are shown.
[186] The biological efficacy of the commercially available triamcinolone acetonide is 10 times lower than the drugs in the Transfersome suspension. The latter also has a long duration of therapeutic effect to the same extent. Compared to dexamethasone using transfersome, the effect of triamcinolone acetonide in a highly deformable pharmaceutical carrier is somewhat strong, but its biological sustainability is slightly less. The concentration of the drug for commercial preparations using Transfersome is 0.005 to 0.02.
[187] FIG. 4 shows, as a function of time, the vasoconstriction assay in the skin of intact humans following gastric administration of chloramcinolone acetonide contained in Transfersome (top panel) or commercial cream (bottom panel).
[188] It can be seen that the efficacy of the corticosteroids contained in the transfersome shows a more potent therapeutic effect on human skin than the conventional triamcinolone acetonide cream. Single topical drug administration by transfersomes can sustain superior biological function for more than one day at a dose of 1 μg / cm 2. Commercial creams cause short-term "deep blanching", whereas formulations using Transfersome allow for more gradual, long-lasting surface vasoconstriction. This indicates that the penetration of the drug from the formulation with the carrier into the purifying system is reduced (see also the following figure).
[189] 5 shows the penetration profile of different drugs in the skin of mammals. The data is taken from the body (left) and pig skin (right) of the rat in vitro.
[190] White symbols indicate measurement results for commercial creams and black symbols indicate dexamethasone suspension loaded on Transfersome.
[191] Using Transfersome to transport corticosteroids in the skin evens out the drug's penetration profile. Relative drug concentrations increase in the deep skin region as compared to the results obtained with commercially available formulations of the same drug.
[192] Fig. 6 shows corticosteroids accumulated (held) in the skin after treatment with Transfersome on the intact surface (i and Δ represent inner and outer skin, and ◇ represent their sum).
[193] As a result, it can be seen that the ratio of drug administered to skin is relatively high in Transfersome.
[194] Figure 7 shows the case where Transfersome is used for delivery of transdermal corticosteroids systemically circulated.
[195] Systemic delivery is possible by selecting a suitably optimized drug carrier (excellent transfersome) and an appropriate amount per area used. Reducing the amount per area can increase the relative drug concentration at the carrier administration site on the skin.
[196] FIG. 8 shows the relative efficacy of various triamcinolone acetonide formulations tested by mouse edema test. The latter two data are not satisfactory when these drugs are loaded into two types of transfersomes (top) and the biological activity of commercial creams (bottom) and conventional liposomes (bottom). Level.
[197] In order to maximize the effect of drug delivery in the skin and to obtain excellent effects, it is necessary to use a particularly optimized and proprietary pharmaceutical carrier, namely Transfersome. By replacing only the transfersome having such excellent deformability, the conventional liposomes can obtain an effect superior to that obtained by commercial creams (or lotions).

权利要求:
Claims (50)
[1" claim-type="Currently amended] Even if the average diameter of the pores is smaller than the average diameter of the penetrant, the adaptability of the penetrant allows the penetrant to carry the drug after the penetrant enters the void or to allow the drug to penetrate the pores. As a formulation consisting of a molecular array that can pass through,
The viscosity of the formulation can be increased from above the viscosity of the non-concentrated formulation up to 5 Nm / s to reduce the increase in the application area to at least one viscosity modifier and the increase in oxidation index to less than 100% per 6 months. Amount of at least one antioxidant and bacteria per total mass (g) of total preparation after 4 days from 1 million to less than 100 for aerobic bacteria, less than 10 for enteric bacteria, Pseudomonas aeruginosa or Staphylococcus aureus In the case of the formulation characterized in that it comprises a fungicide which can be reduced to less than one.
[2" claim-type="Currently amended] 2. The formulation of claim 1, wherein the viscosity modifier is added in an amount capable of increasing the viscosity of the formulation to 1 Nm / s, more preferably to 0.2 Nm / s.
[3" claim-type="Currently amended] The method according to claim 1 or 2,
Wherein said at least one antioxidant is added in an amount capable of reducing the increase in oxidation index per 12 months to less than 100%, more preferably less than 50%.
[4" claim-type="Currently amended] The method according to any one of claims 1 to 3,
Said at least one fungicide has a bacterial count per gross mass (g) of the total formulation after 3 days, more preferably 1 day, from 1 million to less than 100 for aerobic bacteria, less than 10 for enteric bacteria, In the case of Pseudomonas aeruginosa or Staphylococcus, the agent is added in an amount that can be reduced to less than one.
[5" claim-type="Currently amended] The method according to any one of claims 1 to 4,
The viscosity modifiers include, but are not limited to, partially esterified cellulose derivatives consisting of carboxymethyl-, hydroxymethyl, hydroxypropyl-, hydroxypropylmethyl-, methyl-cellulose; Polyacrylates, polymethacrylates, poly (hydroxyethyl)-, poly (hydroxypropyl)-, poly (hydroxypropylmethyl) methacrylates, polyacrylonitrile, metharyl-sulfonate, polyethylene, poly Oxyethylene, polyethylene glycol, polyethylene glycol-lactide, polyethylene glycol-diacrylate, polyvinylpyrrolidone, polyvinyl alcohol, poly (propylmethacrylamide), poly (propylene fumarate-co-ethylene glycol), polox Fully synthetic hydrophilic polymers such as summer, polyaspartamide, (hydrazine crosslinked) hyaluronic acid and silicone; Natural gums such as alginate, carrageenan, guar gum, gelatin, tragagant, (amidated) pectin, xanthan, chitosan collagen and agarose; A formulation, characterized in that it is selected from pharmaceutically acceptable hydrophilic polymers selected from derivatives of other pharmaceutical copolymers or at least biologically acceptable polymers.
[6" claim-type="Currently amended] The method of claim 5,
The weight fraction of the polymer is in the range of 0.05 to 10%, more preferably 0.1 to 5%, more preferably 0.25 to 3.5%, most preferably 0.5 to 2%.
[7" claim-type="Currently amended] The method according to any one of claims 1 to 6,
The antioxidants are butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), di-t-butylphenol (LY178002, LY256548, HWA-131, BF-389, CI-9986, PD-127443, E-5119, BI-L-238XX, etc.), t-butylhydroquinone (TBHQ), propyl gallate (PG), 1-0-hexyl-2,3,5-trimethylhydroquinone (HTHQ) Phenolic antioxidants; Aromatic amines (diphenylamine, p-alkylthio-0-anisidine, ethylenediamine derivatives, carbazole, tetrahydroindenoindole); Phenols and phenolic acids (wire alcohols, hydroquinones, vanillin, gallic acid and esters thereof, protocatechinic acid, quinic acid, siriginic acid, elacic acid, salicylic acid, norhydroguaylic acid (NDGA), eugenol); Tocopheryl-acylates (e.g. -acetate, -laurylate, -myristate, -palmitate, -oleate, -linoleate, etc. or other suitable tocopheryl-lipoates), tocopheryl-POE-succinate Tocopherols (including tocopherol alpha, beta, gamma, delta) and derivatives thereof, such as nate, trolox and its amides, and thiocarboxamide analogs; Ascorbic acid and salts thereof, isoascorbate, (2 or 3 or 6) o-alkyl ascorbic acid, ascorbyl esters (for example 6-o-lauroyl, myristoyl, palmitoyl, oleoyl or linoleo Yl-L-ascorbic acid, etc.); nonsteroidal anti-inflammatory agents (indometacin, diclofenac, mefenamic acid, flufenamic acid, phenylbutazone, oxylphenbutazone acetylsalicylic acid, naproxen, diflunisal, ibuprofen, ketoprofen, NSAIDs such as pyoxycamp, phenylsilamine, phenylsilamine disulfide, pramaquine, quinacrine, chloroquine, hydroxychloroquine, azathioprine, phenobarbital, acetaminaphene); Aminosalicylic acid and its derivatives; Methotrexite, probucol, antiarrhythmic agents (amiodarone, apridine, asokinol), ambroxol, tamoxifen, b-hydroxytamoxifen; Calcium antagonists (nifedipine, nisoldipine, nimodipine, nicardipine, nilvadipine), beta-receptor blockers (antenolol, propranolol, nebivolol) and also sodium bisulfite, sodium bisulfite, thiourea Compounds which are selectively oxidized, such as these, and chelating agents such as EDTA, GDTA and desferal; Various endogenous defense systems such as transferrin, lactoferrin, ferritin, cearuloplasmin, heptoclobion, hemopexin, albumin, glucose and ubiquinol-10; Antioxidants including metal complexes having the same activity as dismutase peroxides, enzymatic antioxidants such as catalases, glutathione peroxidants, and less complex molecules such as beta carotene, bilirubin, uric acid, and the like; Flavonoids (flavones, flavonols, flavonones, parabonal, chacon, anthocyanins), N-acetylcysteine, mesna, glutathione, thiohistidine derivatives, triazoles, tannins, cinnamic acid, hydroxycinnamic acid and esters thereof (coumaric acid and its Esters, caffeic acid and esters thereof, peruric acid, (iso) chlorogenic acid, cinafinic acid); Spice extracts (eg clove, cinnamon, sage, rosemary, mace, oregano, alspice, nutmeg); Carnosine acid, carnosol, carsolic acid; Rosemarine acid, rosemarydiphenol, genticin acid, ferulic acid; Oat flour extracts such as avenantamide 1 and 2; Thioethers, dithioethers, sulfoxides, tetraalkylthiuram disulfides; Phytic acid, steroid derivatives (eg U74006F); An agent characterized in that it is selected from tryptophan metabolites (eg 3-hydroxykynurenine, 3-hydroxyanthrannic acid) and organochalcogen.
[8" claim-type="Currently amended] The method of claim 7, wherein
Preferred concentrations of BHA or BHT are 0.001 to 2w%, more preferably 0.0025 to 2w%, most preferably 0.005 to 0.02w%, preferred concentrations of TBHQ and PG are 0.001 to 2w%, more preferably 0.005 to 0.2w %, Most preferably 0.01 to 0.02w%, preferred tocopherol concentration is 0.005 to 5w%, more preferably 0.01 to 0.5w%, most preferably 0.05 to 0.75w%, and the preferred concentration of ascorbic acid ester is 0.001 to 5w%, more preferably 0.005 to 0.5w%, most preferably 0.01 to 0.15w%, and the preferred concentration of ascorbic acid is 0.001 to 5w%, more preferably 0.005 to 0.5w%, most preferably 0.01 It is -0.1w%, and the preferable concentration of sodium bisulfite or sodium metasulfite is 0.001-5w%, more preferably 0.005-0.5w%, most preferably 0.01-0.15w%, and preferred concentration of thiourea is 0.0001 ˜2w%, more preferably 0. 0005 ~ 0.2w%, most preferred is 0.001 ~ 0.01w%, most typical concentration is 0.005w%, preferred cysteine concentration is 0.01 ~ 5w%, more preferred concentration is 0.05 ~ 2w%, most preferred 0.1 ~ 1.0 w%, the most typical concentration is 0.5w%, the preferred concentration of monothioglycerol is 0.01-5w%, more preferably 0.05-2w%, most preferred 0.1-1.0w%, most typical concentration is 0.5w% In addition, the preferred concentration of NDGA is 0.0005 to 2w%, more preferably 0.01 to 0.2w%, most preferably 0.005 to 0.02w%, most typical concentration is 0.01w%, and preferred concentration of glutathione is 0.005 to 5w% , More preferably 0.01 to 0.5w%, most preferred 0.05 to 0.2w%, most typical concentration is 0.1w%, preferred EDTA concentration is 0.001 to 5w%, more preferably 0.005 to 0.5, most preferred 0.010 -0.2w%, the most typical concentration is 0.05-0.975w% In addition, the preferred concentration of citric acid is 0.001 ~ 5w%, more preferably 0.005 ~ 3w%, most preferably 0.01 ~ 0.2w%, the formulation is characterized in that the most typical concentration is 0.3 ~ 2w%.
[9" claim-type="Currently amended] The method according to any one of claims 1 to 8,
The fungicides are ethyl alcohol, isopropyl alcohol, chlorobutanol, benzyl alcohol, chlorobenzyl alcohol, dichlorobenzyl alcohol, short chain alcohols including hexachlorophene, cresol, 4-chloro-m-cresol, p-chloro-m- Xylenol, dichlorophene, hexachlorophene, povidone-iodine, parabens, especially alkyl parabens such as methyl-, ethyl-, propyl- or butyl-, benzylparabens; Acids such as sorbic acid, benzoic acid and salts thereof; 4 such as alkonium salts such as bromide, benzalkonium salts such as chloride or bromide, cetrimonium salts such as bromide, phenoalkesinium salts such as phenodedecenium bromide, cetylpyridinium chloride and other salts Ammonium compound; A phenyl mercury compound such as mercury acetate, borate, nitrate, thiomersal, hexyl chloride and its gluconate, or an antibiotic having a biological origin or a suitable mixture thereof.
[10" claim-type="Currently amended] The method of claim 9,
In the case of ethyl, propyl, butyl or benzyl alcohol, the bulk concentration of the short chain alcohol is 10 w% or less, more preferably 5 w% or less, most preferably 0.5 to 3 w%, and the bulk concentration of chlorobutanol is 0.3 to 0.6 w %, The bulk concentration of parabens is 0.05-0.2w% for methylparaben, 0.002-0.02w% for propiparaben, the bulk concentration of sorbic acid is 0.05-0.2w%, 0.1-0.5w% for benzoic acid, The bulk concentration of phenol and triclosan is 0.1-0.3w%, and the bulk concentration of hexidine chloride is 0.01-0.5w%.
[11" claim-type="Currently amended] Even if the average diameter of the pores is smaller than the average diameter of the penetrant, the adaptability of the penetrant allows the penetrant to carry the drug after the penetrant enters the void or to allow the drug to penetrate the pores. It consists of a molecular arrangement that can pass through, the drug is a formulation consisting of a glucocorticoid or a mineralocorticosteroid (corticosteroid) penetrating agent,
The relative content of the corticosteroid is a formulation, characterized in that more than 0.1w% relative to the total dry mass of the formulation.
[12" claim-type="Currently amended] The method of claim 11,
A formulation characterized in that at least one viscosity modifier and / or at least one antioxidant and / or at least one bactericide according to any one of claims 1 to 10 is added.
[13" claim-type="Currently amended] The method of claim 11 or 12,
The corticosteroids are alkronetasone dipropionate, alkronetasone amcinonate, beclomethasone dipropionate, clobetasol, betamethasone 17-valerate, betamethasone 17, 21-divalate, betamethasone 21-acetate, betamethasone 21-butylate, betamethasone 21-propionate, betamethasone 21-valerate, betamethasone benzoate, betamethasone dipropionate, betamethasone valerate, budesonide, clobetasol 17-acetate, clobeta Sol butyrate, cortexsolone, corticosterone, cortisone, cortisone 17-acetate, 21-dioxybetamethasone, 21-dioxybetamethasone 17-propionate, deoxycorticosterone, desonide, desoxymethasone, Dexamethasone Diacetate Diphosphason Pivalate, Flocinolone Acetonide, Florinoid, Flucortin Butyl, Flu Cortoron, 9-alpha-fluorocortisone, 9-alpha- pullohydrohydrocortisone, 9-alpha-fluoronisolone, flupridinidine acetate, flulandrenolo, halcinolone, hydrocortisone, hydrocortisone 17 Acetate, hydrocortisone 17-butylate, hydrocortisone 17-propionate, hydrocortisone 17-valerate, hydrocortisone 21-acetate, hydrocortisone 21-butylate, hydrocortisone 21-propionate, hydrocortisone 21- Valerate, 17-alpha-hydroxy progesterone, methylprednisolone acetate, mometasone floate, prednisolone, prednisone, prednisone 17-acetate, prednisone 17-valerate, progesterone, triamcinolone, triamcinolone acetonide Formulation.
[14" claim-type="Currently amended] The method according to any one of claims 1 to 13,
The penetrant is suspended or dispersed in a polar liquid in the form of a fluid droplet surrounded by a coating in the form of a membrane coated with one or several layers, the coating comprising at least two kinds or types of amphiphilic materials having a cohesive tendency and When the at least two kinds of substances are in the form of homogeneous when the solubility in the liquid is different or about 10 or more soluble, and when the combination of the two substances is in the form of heterogeneous, A formulation having a preferred diameter smaller than the diameter of a homogeneous aggregate containing only low solubility material and lowering the average elastic energy of the coating in the form of a film in the vicinity of thermal energy due to the presence of a higher solubility material.
[15" claim-type="Currently amended] The method of claim 14,
The higher solubility material may dissolve microdroplets, and the amount of the material may be 99 mol% or less of the dissolution concentration, or 99 mol% or less of the saturation concentration in the undissolved droplets.
[16" claim-type="Currently amended] The method of claim 15,
The content of the more soluble material is less than 50%, in particular less than 40%, most preferably less than 30% relative to the relative dissolution concentration of the material.
[17" claim-type="Currently amended] The method of claim 15,
The content of the more soluble material is less than 80%, more preferably less than 65%, most preferably less than 50% of the saturation concentration of the material in the droplets.
[18" claim-type="Currently amended] The method according to any one of claims 14 to 17,
The low solubility in the flocculating material is a lipid or a lipid-like material, in particular, a polar lipid, whereas a material having high solubility in the suspension and increasing the adaptability of droplets is characterized by having a surfactant type or a surfactant-like property. Formulation.
[19" claim-type="Currently amended] The method of claim 18,
The agent is a lipid or a lipid-like substance or a lipid or fat derived from a biological origin, or a synthetic lipid or a variant thereof, and the lipid preferably belongs to the class of pure phospholipids corresponding to the following formula. Formulation.

Wherein R, R are aliphatic chains, typically C _10-20 -acyl or alkyl or partially unsaturated fatty acid residues, in particular oleoyl, -palmitoeroyl, -elidoyl-, -linoleyl,- Linolelenyl, -linolenoyl, -arachidoyl, -basinyl, lauroyl-, myristoyl-, palmitoyl-, stearoyl chain and the like, R ₃ is hydrogen, 2-trimethylamino-1- Ethyl, 2-amino-1-ethyl, C _1-4 alkyl, carboxy substituted C _1-5 alkyl, hydroxy substituted C _2-5 alkyl, carboxy and hydroxy substituted C _2-5 alkyl, carboxy and amino substituted C _{2 -5} alkyl, inositol, sphingosine or a salt of said substance, said lipid being a glyceride, an isoprenoid lipid, a steroid, a sterin or a sterol, a lipid comprising sulfur or a hydrocarbon or a lipid forming two other layers Consisting of protonated fluid fatty acids, in particular Silver phosphatidylcholine, phosphatidylethanolamine, phosphatidyl glycerol, phosphatidyl inositol, phosphatidic acid, phosphatidylserine, sphingomyelin and other sphingophospholipids, glycosphingolipids (cerebrosides, ceramide polyhexoxides, sulfides , Including sphingoplasmagen), gangliosides and other glycolipids or synthetic lipids, in particular from sphingosine derivatives or other glycolipids or synthetic lipids, in particular from sphingosine derivatives or other glycolipides Preferably, the ester group is bonded (as diacyl and dialkenoyl compound) to the backbone of two chains, identical or different, or by the backbone and ether linkages as dialkyl lipids.
[20" claim-type="Currently amended] The method of claim 18,
Such surfactants or surfactant analogs are nonionic, zwitterionic, anionic or cationic surfactants, in particular fatty acids or monovalent salts of alcohols, alkyl-tri / di / methyl-ammonium salts, alkylsulfate salts, cholates Deoxycholate, glycocholate, glycodeoxycholate, taurodeoxycholate, taurocholate, or acyl- or alkanoyl-dimethyl-aminooxide, especially dodecyl-dimethyl-aminooxide, alkyl or alkanoyl -N-methylglucamide, N-alkyl-N, N-dimethylglycine, 3- (acyldimethylammonio) -alkanesulfonide, N-acyl-sulfobetaine, polyethylene-glycol-octylphenyl ether, in particular nona Ethylene-glycol-octylphenyl ether, polyethylene-acyl ether, nonaethylene-dodecyl ether, polyethylene-glycol-ioacyl ether, especially octaethylene-glycol-isotridecyl ether, polyethylene-ac Seal ethers, in particular polyethylene-glycol-sorbitan-acyl ethers, such as octaethylene-dodecyl ether, polyethylene glycol-20-monolauric acid (Tween 20), polyethylene glycol-20-sorbitan-monolioleate (Tween20) Lauryl as polyhydroxyethylene-acyl ether, polyhydroxyethylene-4, 6, 8, 10 or 10, polyhydroxyerylene-lauryl, -myristoyl, cetylstearyl-, oleoyl ether and the like. Ethers (as Brij series) or equivalent ethers, for example polyhydroxy ethylene-8-stearate (Myrij 45), laurate or-orarate type or polyepoxylate castor oil 40, sorbitan monoal Chelates (in Arlacel or Span), in particular sorbitan-monolaurate, acyl- or alkanoyl-N-methylglucamide, especially decanoyl- or dodecanoyl-N-methylglucamide, alkylsulfate (salts) , For example Fatty acid salts such as cotton lauryl- or oleoyl-sulfate, sodium deoxycholate, sodium glycodeoxycholate, sodium oleate, sodium taurate, sodium oleate, sodium laurate, n-octadecylene (oleoyl) Lysophospholipids such as -glycerophosphatidic acid, -phosphorylglycerol, -phosphorylserine, lauryl or oleyl-glycero-phosphatidic acid, -phosphorylglycerol or phosphophylserine, n-tetradecyl- Lysophospholipids, such as glycero-phosphatidic acid, -phosphorylglycerol, -phosphorylserine, palmitooleyl-, elliodoyl-, basenyl-lysophospholipids or the corresponding short chain phosphodils Formulations selected from leaf or surface active polypeptides.
[21" claim-type="Currently amended] The method according to any one of claims 14 to 20,
Formulation, characterized in that the average diameter of the penetrant is 30-500nm, more preferably 40-250nm, more preferably 50-200nm, most preferably 60-150nm.
[22" claim-type="Currently amended] The method according to any one of claims 14 to 20,
The average diameter of the penetrant is 2 to 25 times, more preferably 2.25 to 15 times, more preferably 2.5 to 8 times, and most preferably 3 to 6 times the average diameter of the pores of the barrier wall. Formulation.
[23" claim-type="Currently amended] The method according to any one of claims 14 to 22,
The dry weight of all carrier droplets in the formulation is in the range of 0.01-40 w%, in particular 0.1-30 w%, more preferably 0.5-20 w%, most preferably 1-10 w%, relative to the total formulation weight. Formulation.
[24" claim-type="Currently amended] The method according to any one of claims 14 to 22,
When the formulation is applied to mucous membranes of humans or animals, the dry weight of all carrier droplets in the formulation is in the range of 0.0001-30% by weight of the total formulation mass.
[25" claim-type="Currently amended] The method according to any one of claims 1 to 24,
The pH of the carrier suspension necessary for maximizing the stability of the formulation is 4 to 10, preferably 5 to 9, sometimes 8.5 or less.
[26" claim-type="Currently amended] A method for preparing a formulation for non-invasive use in vivo according to any one of claims 1 to 25,
At least one amphoteric material, at least one hydrophilic fluid, at least one edge active material or surfactant, at least one corticosteroid added in an amount of at least 0.1 w% based on the total dry weight of the formulation, The manufacturing method of the formulation characterized by using the other conventional component which comprises.
[27" claim-type="Currently amended] The method of claim 26,
The at least one edge active material or surfactant, at least one affinity material, at least one hydrophilic fluid and the medicament are dissolved to form a solution, and, if necessary, separated and mixed to form a mixture or using a convenient driving pressure. Mechanical energy such as shaking, stirring, vibration, homogenization, ultrasonic vibration, shear deformation, cooling, and thawing filtration to act as a (partial) mixture or solution, in which the permeate is combined and / or mixed with a medicament. Method of Preparation of the Formulation.
[28" claim-type="Currently amended] The method of claim 26 or 27,
The affinity material may be used as it is, dissolved in a physiologically compatible polar fluid (the polar fluid may be water or miscible), or a polar solution is used together with a solvating modifier. Method of Preparation of the Formulation.
[29" claim-type="Currently amended] The method of claim 26 or 27,
The positive affinity material is dissolved in an alcohol having a high volatility, in particular ethanol, or a pharmaceutical preparation, characterized in that dissolved in an organic solvent which can be removed by evaporation or the like before final production.
[30" claim-type="Currently amended] The method of claim 28 or 29,
Wherein said polar solution comprises at least one edge active substance or surfactant.
[31" claim-type="Currently amended] The method according to any one of claims 26 to 30,
The formation of the penetrant is induced by adding the required material into the fluid phase and evaporating from the reverse phase by injection or dialysis or the like, and, if necessary, shaking with a convenient, especially low (1 MPa) or medium (10 MPa) drive pressure, Stirring, in particular using a high speed stirring, vibration, homogenization, ultrasonic vibration, shear deformation, freezing and thawing filtration method.
[32" claim-type="Currently amended] The method of claim 31, wherein
The penetrating agent is formed by filtration, and the pore size of the filtration material is 0.01 to 0.8 µm, more preferably 0.02 to 0.3 µm, still more preferably 0.05 to 0.15 µm, and several filters are used sequentially or in parallel. Method for producing a formulation, characterized in that.
[33" claim-type="Currently amended] 33. The method according to any one of claims 26 to 32,
The drug and the penetrating agent may be a drug solution dissolved in a pharmaceutically acceptable fluid such as ethanol, 1, 2-propanol, benzyl alcohol, propylene glycol polyethylene glycol (molecular weight 200-400D) or glycerol after the composition of the penetrant. Made by incorporating at least partly after injecting into the suspending medium, the penetrating agent being prepared prior to or simultaneously with injecting the drug using other suitable methods of preparation and also using co-solvents of the drug or using at least some kind of penetrant components. Method for producing a preparation, characterized in that.
[34" claim-type="Currently amended] The method according to any one of claims 26 to 33,
The penetrant, bound to and / or mixed with the drug molecule, is prepared immediately prior to use of the agent and is prepared for the preparation of a preparation comprising a suitable thickening or lyophilic agent for convenience.
[35" claim-type="Currently amended] The method according to any one of claims 11 to 25,
The content of the corticosteroid is 0.1-20w% with respect to the total weight of the total penetrant, more preferably 0.25-10w%, and more preferably 0.5-5w%.
[36" claim-type="Currently amended] The method of claim 35, wherein
When the corticosteroid is a triamcinolone such as acetonide or the like or a derivative thereof, the relative amount thereof is less than 2w%, more preferably less than 1w%, most preferably less than 0.5w% of the dry weight of the carrier on which the drug is loaded. Formulation.
[37" claim-type="Currently amended] The method of claim 35, wherein
When the corticosteroid is hydrocortisone or a derivative thereof, the relative amount thereof is less than 20w%, more preferably less than 12.5w%, most preferably less than 5w% of the dry weight of the carrier loaded with the entire drug. Formulation.
[38" claim-type="Currently amended] 36. The method of claim 35 wherein
If the corticosteroid is one of dexamethasol or a derivative thereof, the relative amount is less than 15w%, more preferably less than 10w%, most preferably less than 5w% of the dry weight of the entire drug loading carrier. Formulation.
[39" claim-type="Currently amended] The method of claim 35, wherein
When the corticosteroid is clobetasol or a derivative thereof, the relative amount thereof is less than 15w%, more preferably less than 10w%, most preferably less than 5w% of the dry weight of the entire drug loading carrier.
[40" claim-type="Currently amended] The method according to any one of claims 35 to 39,
The content of the corticosteroid is a formulation, characterized in that less than the saturation maximum defined by the point that the corticosteroid begins to crystallize inside or outside the carrier.
[41" claim-type="Currently amended] The method according to any one of claims 1 to 25 and 35 to 38,
Formulations characterized in that penetration enhancers are added to improve the rate of drug action.
[42" claim-type="Currently amended] 42. The method of claim 41 wherein
The penetration enhancers include 1-acyl-acylcycloheptan-2-one (azone), 1-acyl-glucoside, 1-acyl-polyoxyethylene, 1-acyl-saccharide, 2-n-acyl-cyclohexanone , 2-n-acyl-1, 3-dioxolane (SEPA), 1, 2, 3-triacyl-glycerol, 1-alkanol, 1-alkanoic acid, 1-alkyl-acetate, 1-alkyl- Amine, 1-alkyl-N-alkyl-polyoxyethylene, 1-alkyl-alkylate, n-alkyl-beta-D-thioclocoside, 1-alkyl-glyceride, 1-alkyl-propyleneglycol, 1- Alkyl-polyoxyethylene, (1-alkyl-) 2-pyrrolidone, alkyl-acetoacetate, alkylene-glycol, alkyl-methyl-sulfoxide (alkyl-DMSO), alkyl-propionate, alkyl-sulfate, Formulations selected from thiacyl-succinate, diacyl-N, N-dimethylaminoacetate (DDAA), diacyl-N, N-dimethylaminoisopropionate (DDAIP), phenyl-alkyl-amine .
[43" claim-type="Currently amended] The method of claim 42,
The bulk concentration range of the penetration enhancer is 5% or less for 1-capryl-propylene glycol, 6- for 1- [2- (decylthio) ethyl] azacyclopentane-2-one (= HPE-101). 10%, <10% for 1-dodecanol, <10% for 1-dodecyl-azacycloheptan-2-one (= azone), 2-n-nonyl-1,3-dioxolane (SEPA ), Less than 10% for 2-N-octylcyclohexanone, preferably less than 20% for DMSO, 5-40% for ethanol, 10% or more for ethylene glycol, ethyl acetate Less than 30%, 5-50% for glycerol, 75% or less for isopropanol, 1-20% for isopropyl myristate, 20% for oleic acid and oleyl alcohol, 20% for oleyl-polyoxyethylene-ether About 1%, in the case of propylene glycol, at least 10%.
[44" claim-type="Currently amended] The method according to any one of claims 11 to 25, 35 to 43,
When the corticosteroid exerts a substantial therapeutic effect, for example, in subcutaneous subcutaneous tissue including muscles, joints, tissues, or distant tissue that includes the entire body, the corticosteroid may be used in an amount corresponding to the amount of the preparation per area, ie per unit area. It is added so that it can be used in an amount expressed by the total dry mass of the penetrant used, and is 0.1-15 mg / cm 2, preferably 0.5-10 mg / cm 2, more preferably 0.75-5 mg / cm 2, most preferably 1- Formulations are added in the range of 2.5 mg / cm 2.
[45" claim-type="Currently amended] The method according to any one of claims 11 to 25, 35 to 43,
If the corticosteroid is primarily local, i.e. the drug is intended to have an effect on the surface rather than on the whole body, then the dosage per area of the corticosteroid expressed as the total dry mass of the penetrant applied per unit area is 1 A formulation selected from the range of ˜250 μg / cm 2, more preferably from 2.5 to 100 mg / cm 2, more preferably from 5 to 50 mg / cm 2, most preferably from 7.5 to 20 mg / cm 2. .
[46" claim-type="Currently amended] The method according to any one of claims 11 to 25, 35 to 45,
The viscosity, or other properties of the formulation, is appropriately selected to enable the formulation to be applied by spraying, rubbing, rolling, or wiping with sponges on the application.
[47" claim-type="Currently amended] As a method of use for non-invasive use of corticosteroids by the agent according to any one of claims 1 to 25 and 35 to 46,
When the corticosteroid exerts a substantial therapeutic effect, for example, in deep subcutaneous tissue including muscles, joints, tissues or distant tissue including the entire body, the amount per area expressed as the total dry weight of the penetrant used per area is 0.1 to 15 mg / cm 2, preferably 0.5 to 10 mg / cm 2, particularly preferably 0.75 to 5 mg / cm 2, most preferably 1 to 2.5 mg / cm 2.
[48" claim-type="Currently amended] As a method of use for non-invasive use of corticosteroids by the agent according to any one of claims 1 to 25 and 35 to 46,
If the corticosteroid is mainly local, i.e. the drug is intended to have an effect on the surface rather than on the whole body, then the dose per area of the corticosteroid expressed as the total dry mass of the penetrant applied per unit area is 1 Selected from the range of ˜250 μg / cm 2, more preferably from 2.5 to 100 mg / cm 2, more preferably from 5 to 50 mg / cm 2, most preferably from 7.5 to 20 mg / cm 2. .
[49" claim-type="Currently amended] A method of using a non-invasive use of a corticosteroid, encapsulated by or in combination with the penetrant by the agent according to any one of claims 1 to 25, 35 to 46,
The preparation is a method of using, characterized in that applied by spraying, rubbing, rolling, or wiping with a sponge to the application site by a sprayer, a spreader, a roller or a sponge.
[50" claim-type="Currently amended] Use of a formulation according to any one of claims 1 to 25 and 35 to 46,
Inflammatory diseases, cutaneous osteomas, kidney or liver failure, adrenal insufficiency, adrenal insufficiency syndrome, Behcet's syndrome, bites or punctures, cold and cold erythrocytes, hemolytic anemia, hypereosinophilia, dysplastic anemia, macroglobulinemia, thrombus It is preferable to be used for the treatment of blood disorders such as Bosaitophenin purpura, and also skeletal disorders, cerebral edema, cogan cydrome, congenital adrenal hyperplasia, thyroid, cardiac lupus erythematosus, multiple myalgia rheumatoid, multiple myositis, dermatitis, epilepsy, etc. Connective tissue disorders, cataracts, grave eye diseases, hemangiomas, herpes infections, neuropathies, eye diseases such as retinitis vasculitis, scleritis, gastro-intestinal diseases such as inflammatory bowel disease, nausea and esophageal diseases, hypercalcium, infections, for example For example, treatment of eye infections (as infectious mononucleosis), various pain syndromes such as Kawasaki disease, Myasthenia Gravis Pain, and multiple nerves. Treatment of respiratory diseases such as pancreatitis and asthma, rheumatism and skeletalitis, rhinitis, sarcoidosis, alopecia, eczema, polymorphic erythema, tachycardia, pemphigus, dermoid swelling, psoriasis, necrotizing pyoderma, urticaria, vascular diseases of thyroid disease Use for being used for.

类似技术:

---

公开号 | 公开日 | 专利标题

---

AU2018206812B2|2020-02-20|Topical pharmaceutical composition based on semifluorinated alkanes

---

US9968680B2|2018-05-15|Topical bioadhesive formulations

---

JP5709826B2|2015-04-30|Therapeutic composition

---

Heilmann et al.2013|A thermosensitive morphine-containing hydrogel for the treatment of large-scale skin wounds

---

Jadon et al.2009|Enhanced oral bioavailability of griseofulvin via niosomes

---

Kumar et al.2011|Nonionic surfactant vesicular systems for effective drug delivery—an overview

---

Charrois et al.2004|Drug release rate influences the pharmacokinetics, biodistribution, therapeutic activity, and toxicity of pegylated liposomal doxorubicin formulations in murine breast cancer

---

Shuwaili et al.2016|Optimization of elastic transfersomes formulations for transdermal delivery of pentoxifylline

---

El-Laithy et al.2011|Novel sugar esters proniosomes for transdermal delivery of vinpocetine: preclinical and clinical studies

---

Ahad et al.2012|Formulation and optimization of nanotransfersomes using experimental design technique for accentuated transdermal delivery of valsartan

---

Tabbakhian et al.2006|Enhancement of follicular delivery of finasteride by liposomes and niosomes: 1. In vitro permeation and in vivo deposition studies using hamster flank and ear models

---

CA2594710C|2011-01-25|Topical bioadhesive formulations

---

RU2331423C2|2008-08-20|Delivery system with controlled release for intranasal applying

---

Manconi et al.2011|Penetration enhancer containing vesicles as carriers for dermal delivery of tretinoin

---

Caddeo et al.2014|Topical anti-inflammatory potential of quercetin in lipid-based nanosystems: in vivo and in vitro evaluation

---

ES2249891T3|2006-04-01|Gelificable pharmaceutical compositions.

---

Maghraby et al.2006|Can drug‐bearing liposomes penetrate intact skin?

---

EP1888033B1|2014-02-19|Method and composition for treating inflammatory disorders

---

Elsayed et al.2006|Deformable liposomes and ethosomes: mechanism of enhanced skin delivery

---

Benson2005|Transdermal drug delivery: penetration enhancement techniques

---

US7728042B2|2010-06-01|Transdermal pharmaceutical composition

---

US4944948A|1990-07-31|EGF/Liposome gel composition and method

---

US5422361A|1995-06-06|Stable cream and lotion bases for lipophilic drug compositions

---

Agarwal et al.2001|Preparation and in vitro evaluation of liposomal/niosomal delivery systems for antipsoriatic drug dithranol

---

US6258377B1|2001-07-10|Hydrophobic preparations containing medium chain monoglycerides

同族专利:

---

公开号 | 公开日

---

CZ20012038A3|2001-09-12|

---

HK1040629A1|2005-01-28|

---

US20070184114A1|2007-08-09|

---

NO20013164D0|2001-06-22|

---

AT272391T|2004-08-15|

---

BR9816113A|2001-10-23|

---

EP1140021B1|2004-08-04|

---

US20020064524A1|2002-05-30|

---

DE69825495T2|2005-07-28|

---

EP1140021A1|2001-10-10|

---

CA2356080A1|2000-07-06|

---

RU2207844C2|2003-07-10|

---

JP2002533379A|2002-10-08|

---

CN1320880C|2007-06-13|

---

HRP20010309A2|2002-06-30|

---

HRP20010309B1|2005-06-30|

---

TR200101790T2|2001-10-22|

---

ES2226203T3|2005-03-16|

---

DE69825495D1|2004-09-09|

---

CA2356080C|2009-05-12|

---

AU770803B2|2004-03-04|

---

MXPA01006424A|2002-06-04|

---

HU0104424A2|2002-03-28|

---

NO20013164L|2001-08-22|

---

CN1327382A|2001-12-19|

---

PL349467A1|2002-07-29|

---

AU2513799A|2000-07-31|

---

US7175850B2|2007-02-13|

---

PL193824B1|2007-03-30|

---

HU0104424A3|2002-12-28|

---

EE200100342A|2002-10-15|

---

KR100638150B1|2006-10-26|

---

WO2000038653A1|2000-07-06|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

法律状态:
1998-12-23|Application filed by 케에베 그레고르, 이데아 악티엔게젤샤프트

---

1998-12-23|Priority to PCT/EP1998/008421

---

2001-12-07|Publication of KR20010107991A

---

2005-02-28|First worldwide family litigation filed

---

2006-10-26|Application granted

---

2006-10-26|Publication of KR100638150B1

优先权:

---

申请号 | 申请日 | 专利标题

---

PCT/EP1998/008421|WO2000038653A1|1998-12-23|1998-12-23|Improved formulation for topical non-invasive application in vivo|