Hydroxide-releasing agents as skin permeation enhancers

专利摘要:
Provided are methods for increasing the permeability of skin or mucosal tissues of a pharmacological or cosmetic active agent administered locally or transdermally. The method involves using an optimal amount, a specific amount of hydroxide-releasing agent, which increases the influx of active agent through the skin surface while minimizing such as skin damage, irritation or sensitization. Also provided are drug delivery devices using a hydroxide-releasing agent as penetration enhancers and locally applied formulations.
公开号:KR20020082468A
申请号:KR1020027007719
申请日:2000-12-15
公开日:2002-10-31
发明作者:씨. 류오에릭；씨. 제이콥슨에릭；휴충민；메이시러셀
申请人:더마트랜드 인코포레이티드；
IPC主号:

专利说明:

Hydroxide-releasing agents as skin permeation enhancers
[2] Delivery of drugs through the skin offers many advantages. Firstly, such delivery means is a comfortable, convenient and non-invasive way of drug administration. Uneven rates of absorption and metabolism encountered in oral treatment can be avoided and other inherent discomforts such as discomfort such as gastrointestinal irritation can also be eliminated. Transdermal drug delivery also makes it possible to adjust the blood concentration of any particular drug to a high degree.
[3] The skin is structurally complex and relatively thick membrane. Molecules that migrate from or through intact skin from a particular environment must first penetrate the stratum corneum and any material present on its surface. The molecules then penetrate the viable epidermis, papillary dermis and capillary walls to enter the blood vessels or lymph nodes. To be so absorbed, molecules must overcome different penetration resistance in each type of tissue. Therefore, transport through the skin membrane is a complex phenomenon. However, it is the cells of the stratum corneum that provide a first barrier to uptake of the topical composition or transdermal drug. The stratum corneum is a thin layer of dense, highly keratinized cells having a thickness of approximately 10-15 microns in most human bodies. High density keratinization in these cells as well as their dense packing is believed to form a substantially impermeable barrier to drug penetration in most cases. For many drugs, the penetration rate through the skin is very low without the use of some means to improve skin permeability.
[4] Various approaches have been tried to increase the rate of drug penetration through the skin, one of which involves the use of chemical or physical penetration enhancers. Physical strengthening of skin penetration includes electrophoretic techniques such as, for example, iontophoresis. The use of ultrasound (or “phonophoresis”) as a physical penetration enhancer has also been studied. Chemical enhancers are compounds that are administered with a drug to increase the permeability of the stratum corneum (or in some cases the skin may be pretreated with a chemical enhancer), thereby providing improved penetration of the drug through the skin. Ideally, such chemical penetration enhancers (or the compounds herein referred to as “permeation enhancers”) are harmless and simply serve to promote the diffusion of the drug through the stratum corneum. .
[5] Various compounds for enhancing the permeability of the skin are known in the art and described in related literature or books. Compounds that have been used to improve skin permeability include sulfoxides such as dimethylsulfoxide (DMSO) and decylmethylsulfoxide (C ₁₀ MSO); Diethylene glycol monoethyl ether ⁽ trans kyutol (Transcutol), commercially available in a) and diethylene glycol monomethyl ether and like ethers; Sodium laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide, benzalkonium chloride, poloxamers (231, 182, 184), tween (20, 40, 60) , 80) and surfactants such as lecithin (US Pat. No. 4,783,450); 1-substituted azacycloheptan-2-one, specifically 1-n-dodecylcyclazahephep-2--2-one (1-n-dodecylcyclazacycloheptan-2-one) Nelson Research & Development Co., Irvine, is available as Azone TM from ^{Calif; .,} see U.S. Patent No. 3,989,816, 1 - No. 4,316,893, No. 4,405,616 and No. 4,557,934 Lake); Alcohols such as ethanol, propanol, octanol, benzyl alcohol and the like; Fatty acids such as lauric acid, oleic acid and valeric acid; Fatty acid esters such as isopropyl myristate, isopropyl palmitate, methylpropionate and ethyl oleate; Polyols and esters thereof such as propylene glycol, ethylene glycol, glycerol, butanediol, polyethylene glycol and polyethylene glycol monolaurate (PEGML; see US Pat. No. 4,568,343); Amides and other nitrogenous compounds such as urea, dimethylracetamide (DMA), dimethylformamide (DMF), 2-pyrrolidone, 1-methyl-2-pyrrolidone, ethanolamine, diethanolamine and triethanolamine; Terpenes; Alkanones; And organic acids, specifically salicylic acid and salicylate, citric acid and succinic acid.
[6] Percutaneous Penetration Enhancers, eds. Smith et al. (CRC Press, 1995) provides a good overview of the field and more background on numerous chemical and physical enhancers. Although many chemical penetration enhancers are known, they are very effective in increasing the proportion of drugs that penetrate the skin, do not cause skin damage, irritation, sensitization, and even for transdermal delivery of polymeric drugs such as peptides, proteins and nucleic acids. There is a continuing need for reinforcing agents that can be effectively used. It has now been found that hydroxide-releasing agents are very effective penetration enhancers even when used without co-enhancers and provide all the aforementioned advantages over known penetration enhancers. Furthermore, in contrast to conventional enhancers, transdermal administration of the hydroxide-releasing agent as a penetration enhancer with the drug to a moderate degree does not cause systemic toxicity.
[1] The present invention relates to topical and transdermal administration of pharmacologically active agents, and more particularly to methods and compositions for enhancing the permeability of topically applied pharmacologically active agents in skin or mucosal tissues.
[153] 1 is a graph illustrating the accumulation of estradiol from a matrix patch as described in Example 1. FIG.
[154] FIG. 2 is a graph illustrating the accumulation amount of ketoprofen from the matrix patch as described in Example 2. FIG.
[155] 3 is a graph illustrating the accumulation of phenylpropanolamine from the matrix patch as described in Example 3. FIG.
[156] 4 is a graph illustrating the accumulation amount of ibpropene from the gel described in Example 5. FIG.
[157] FIG. 5 is a graph illustrating the accumulation of phenylpropanolamine from the matrix patch as described in Example 6. FIG.
[158] FIG. 6 is a graph illustrating the accumulation of phenylpropanolamine from the matrix patch as described in Example 7. FIG.
[159] FIG. 7 is a graph illustrating the accumulation of phenylpropanolamine from the matrix patch as described in Example 8. FIG.
[160] 8 is a graph illustrating the accumulation amount of estradiol from the matrix patch as described in Example 9. FIG.
[161] 9 is a graph illustrating the accumulation amount of estradiol from the matrix patch as described in Example 10. FIG.
[162] 10 is a graph illustrating the accumulation of estradiol from the matrix patch as described in Example 11. FIG.
[163] FIG. 11 is a graph illustrating the accumulation of phenylpropanolamine from the matrix patch as described in Example 12.
[164] 12 is a graph illustrating the accumulation amount of diclofenac from the matrix patch as described in Example 16. FIG.
[165] FIG. 13 is a graph illustrating the accumulation of diclofenac from gels as described in Example 17.
[166] 14 is a graph illustrating the accumulation of testosterone from the matrix patch as described in Example 18. FIG.
[7] Accordingly, a first object of the present invention is to meet the above-described needs in the art by providing a novel method for improving the rate at which an active agent administered to a patient's human surface penetrates into and / or through the human surface. It is to let.
[8] Another object of the present invention is to provide such a method in which a hydroxide-releasing agent is used as a penetration enhancer to increase the influx of active agent through the skin or mucosal tissue of a patient.
[9] Another object of the present invention is to provide such a method of optimizing the amount of hydroxide-releasing agent used to enhance penetration while minimizing or eliminating the possibility of skin damage, irritation or sensitization.
[10] Another object of the present invention is to provide such a method wherein the active agent is a pharmacologically active agent selected from free acids, free bases, base addition salts of free acids, acid addition salts of free bases, non-ionizable drugs, peptides and proteins.
[11] Another object of the present invention is to provide such a method wherein the active agent is a cosmetically useful agent.
[12] Another object of the present invention is to provide such a method wherein said active agent is intended for local delivery and where drug administration is local.
[13] Another object of the present invention is to provide such a method wherein the active agent is intended for systemic delivery and drug administration is transdermal.
[14] Another object of the present invention is to provide a formulation and a drug delivery system for carrying out the above-mentioned method.
[15] Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows, and will be apparent to those skilled in the art upon reviewing the following, and may be learned by practice of the invention.
[16] In one aspect of the invention, a method for increasing the rate of penetration of an active agent through the body surface of a patient is provided. The method comprises administering the agent to a predetermined area of the patient's body surface in combination with a hydroxide-releasing agent in a predetermined amount effective to enhance the entry of the agent through the body surface without causing damage to the body surface. It is related. The predetermined amount of hydroxide-releasing enhancer is preferably such that the pH is in the range of about 8.0 to 13, preferably about 8.0 to 11.5, most preferably about 8.5 to 11.5, on the body surface, i.e., upon drug administration. It is an effective amount. If a skin patch is used, this is the preferred pH at the interface between the base surface of the patch (ie, the skin- or mucosal-contact surface of the patch) and the body surface. However, the optimal amount (or concentration) of any one hydroxide-releasing agent depends on the specific hydroxide-releasing agent, ie the strength, molecular weight of the base, and other factors by those skilled in the art of transdermal drug delivery. May also be considered. This optimum amount can ensure that the pH at the body surface is within the aforementioned range, i.e. within the range of about 8.0 to 13, preferably about 8.0 to 11.5, most preferably about 8.5 to 11.5. Can be determined using replicate experiments. Conventional transdermal drug delivery devices or “patches” can be used to administer the active agent, wherein the drug and hydroxide-releasing agent are generally present in the drug source or sources. However, drugs and hydroxide-releasing agents can also be administered to the body surface using liquid or semisolid formulations. Alternatively, or further, the body surface may be pretreated with a strengthening agent, for example, with a dilute solution of the hydroxide-releasing agent prior to transdermal drug administration. Such solutions generally consist of a protic solvent (eg water or alcohol) and have a pH in the range of about 8.0 to 13, preferably about 8.0 to 11.5, more preferably about 8.5 to 11.5.
[17] In another aspect of the present invention there is provided a composition for delivering a drug through a body surface using a hydroxide-releasing agent as a penetration enhancer. In general, the formulation comprises (a) a therapeutically effective amount of a drug, (b) an amount of a hydroxide-releasing agent effective to enhance the entry of the drug through the body surface without causing damage to the body surface, and (c ) Pharmaceutically acceptable carriers suitable for topical or transdermal drug administration. The composition may be in any form suitable for application to the body surface and may include, for example, creams, lotions, aqueous solutions, gels, ointments, pastes, and / or liposomes, micelles and / or microspheres. It can be prepared to contain (microsphere). The composition may be applied directly to the body surface, or may be associated with the use of a drug delivery device. In either case, it is preferred that the water be present to enhance the influx of the active agent through the patient's body surface, although not necessarily the hydroxide-releasing agent generates hydroxide ions. Thus, the formulation or drug source may be in aqueous form, i.e., contain water or be in a non-aqueous state, so that moisture evaporating from the body surface during drug administration can be retained in the formulation or transdermal system. It can be used in combination with.
[18] In another aspect of the invention, a drug delivery system is provided for topical or transdermal administration of a drug using a hydroxide-releasing agent as a penetration enhancer. The system generally comprises at least one drug source containing an amount of hydroxide-releasing agent and drug effective to enhance the influx of drugs through the body surface without causing damage to the body surface; Means for maintaining the system in a drug and enhancer delivery relationship to the body surface; And a backing layer that serves as an outer surface of the device in use.
[19] The support layer may be occluded or unoccluded, although it is preferred to be occluded. The drug source may be made of a polymeric adhesive, which in use serves as the foundation surface of the system and functions as a means for maintaining the system in the relationship of drug and enhancer delivery to the body surface. The drug source may also consist of a hydrogel or may be a sealed pouch in a "patch" -type structure, wherein the drug and hydroxide-releasing agent are present in the pouch as a liquid or semisolid formulation.
[20] I. Definition and Overview
[21] Before describing the present invention in detail, it should be understood that the present invention can be varied without being limited to a particular drug or drug delivery system. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.
[22] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. It should be known. Thus, for example, a quotation of "pharmacologically active agent" includes a mixture of two or more such compounds, and a quotation of "hydroxide-releasing agent" includes a mixture of two or more hydroxide-releasing agents.
[23] In describing and claiming the present invention, the following terminology may be used in accordance with the definitions set out below.
[24] As used herein, the terms "treating" and "treatment" are used to refer to the severity and / or reduction in the frequency of symptoms, the elimination of symptoms and / or potential causes, the occurrence of symptoms and / or the potential for symptoms. Prevention of the cause and improvement or treatment of the damage. Thus, the method of "treating" a patient according to the present invention, as the term is used herein, refers to the prevention of the disease in individuals susceptible to the disease and to the treatment of the disease in individuals exhibiting clinical symptoms. It includes everything.
[25] The term "hydroxide-releasing agent" as used herein is intended to mean an agent that releases free hydroxide ions in an aqueous environment. The formulation may contain hydroxide ions and therefore may release ions directly (eg alkali metal hydroxides), or the formulation may react chemically in an aqueous environment to generate hydroxide ions (eg metal carbonates). ).
[26] The terms "active agent", "drug" and "pharmacologically active agent" are used interchangeably herein to mean a chemical or compound that induces a desired effect and is therapeutically effective, prophylactically effective or cosmetically effective. As effective formulations are included. Also included are derivatives and analogs of such compounds, or the class of compounds specifically mentioned to induce the desired effect.
[27] A "therapeutically effective" amount means an amount sufficient to provide the desired therapeutic effect without the active agent being toxic.
[28] By "transdermal" drug delivery is meant to provide a systemic effect by administering the drug to the skin surface of the individual, allowing the drug to pass through skin tissue and into the bloodstream of the individual. The term "transdermal" refers to administration of a "transmucosal" drug, i.e., a drug administered to the surface of an individual's mucosa (e.g., under the tongue, buccal, vaginal, rectal) so that the drug passes through mucosal tissue and It is intended to include getting into the bloodstream of an individual.
[29] The term "local administration" is used in the conventional sense to mean the delivery of a local drug or pharmacologically active agent to the skin or mucous membranes, and as used means, for example, the treatment of various skin diseases. In contrast to transdermal administration, topical administration provides a local rather than systemic effect. Unless otherwise stated or implied, the terms "local drug administration" and "transdermal drug administration" are used interchangeably.
[30] The term "body surface" is used to mean skin or mucosal tissue.
[31] "Preset area" of skin or mucosal tissue refers to the area of skin or mucosal tissue through which the drug-enhancing agent is delivered, and is intended to be a defined area of intact intact living skin or mucosal tissue. The area will generally range from about 5 cm 2 to about 200 cm 2, more generally in a range from about 5 cm 2 to about 100 cm 2, preferably from about 20 cm 2 to about 60 cm 2. However, it will be understood by those skilled in the art of drug delivery that the area of skin or mucosal tissue to which the drug is administered may vary widely depending on patch arrangement, dosage, and the like.
[32] As used herein, "impregnation" or "permeation enhancement" relates to an increase in permeability of selected pharmacologically active agents to skin or mucosal tissue, that is, the agent penetrates through them (ie, through the body surface). "Flux") ratio of the formulation is increased compared to the ratio obtained in the absence of penetration enhancer. The enhanced penetration effect through the use of such enhancers can be achieved, for example, by the use of Franz diffusion apparatus known in the art and the methods used in the examples herein. It can be observed by measuring the rate of diffusion.
[33] An “effective” amount of penetration enhancer means an amount of enhancer sufficient to provide the desired increase in skin permeability, correspondingly, to the desired depth of penetration, dosage rate, and amount of drug delivered without being toxic and causing no damage. do.
[34] As used herein, "carriers" or "vehicles" refers to carrier materials suitable for transdermal drug administration. Carriers and carriers used herein include any material known in the art that is nontoxic and does not interact with other components of the composition in a detrimental manner.
[35] The term "aqueous" means an agent or drug delivery system containing water or containing water that can be applied to skin or mucosal tissue.
[36] As used herein, "peptide drug" means an active agent, drug or pharmacologically active agent comprising a peptide, polypeptide or protein. Also included are pharmacologically active derivatives and fragments of the peptide drug. For convenience of explanation, the "peptide drug" also includes one amino acid and derivatives thereof.
[37] "Peptide" means a polymer wherein the monomers are linked to each other via amide bonds. A "peptide" is generally smaller than a protein, specifically about 2 to about 10 amino acids in length. The term "peptide" includes "dipeptides" consisting of two amino acids, "tripeptides" consisting of three consecutively linked amino acids, and the like.
[38] "Polypeptide" generally means a polymer of amino acids consisting of about 10 to about 50 amino acids.
[39] As used herein, "protein" refers to a polymer of conventional amino acids consisting of at least 50 amino acids. The protein that may be used as the peptide drug in the present invention may be a naturally occurring protein, a modified naturally occurring protein, or a chemically synthesized protein which may or may not be the same as a naturally occurring protein.
[40] Accordingly, the present invention relates to methods, compositions and drug delivery systems for increasing the rate at which an active agent penetrates through the body surface of a patient, the method through which the agent passes through the body surface without causing damage to the body surface. It is associated with administration to a predetermined area of the patient's body surface in combination with a hydroxide-releasing agent in an amount effective to enhance the influx of the agent.
[41] II. The Hydroxide-Releasing Agent
[42] A "hydroxide-releasing agent" is a chemical compound that releases free hydroxide ions in the presence of an aqueous fluid. The aqueous fluid may be natural moisture on the surface of the skin, or the patch or composition used may contain additional water and / or may be used in connection with occlusive backing. Similarly, any liquid or semisolid formulation used is preferably used in combination with a layer of aqueous or occlusive material.
[43] Any hydroxide-releasing agent can be used if the compound releases free hydroxide ions in the presence of an aqueous fluid. Examples of suitable hydroxide-releasing agents include, but are not limited to, alkali metal or alkaline earth metal salts of inorganic hydroxides, inorganic oxides and weak acids. Inorganic hydroxides include, for example, alkali metal hydroxides such as sodium hydroxide, calcium hydroxide, potassium hydroxide, magnesium hydroxide, and alkaline earth metal hydroxides, ammonium hydroxide. Inorganic oxides include, for example, magnesium oxide, calcium oxide, and the like. Metal salts of weak acids are, for example, sodium acetate, sodium borate, sodium metaborate, sodium carbonate, sodium bicarbonate, sodium phosphate (tribasic), sodium phosphate (dibasic), potassium carbonate, potassium bicarbonate, potassium citrate, acetic acid Potassium, potassium phosphate (dibasic), potassium phosphate (tribasic), ammonium phosphate (dibasic) and the like. Preferred hydroxide-releasing agents are metal hydroxides such as sodium hydroxide and potassium hydroxide.
[44] It is important to optimize the amount of hydroxide-releasing agent in any patch or formulation to increase the influx of drugs through the body surface while minimizing the possibility of skin damage. Generally, this means that the pH at the body surface in contact with the agent or drug delivery system according to the present invention (ie the interface between the body surface and the agent or delivery system) is from about 8.0 to 13, preferably from about 8.0 to 11.5, Preferably it should be in the range of about 8.5 to 11.5. This, although not necessarily, generally means that the pH of the drug composition contained in the formulation or delivery system will be in the range of about 8.0 to 13, preferably about 8.0 to 11.5, more preferably about 8.5 to 11.5.
[45] For inorganic hydroxides, the amount of hydroxide-releasing agent is generally from about 0.5% to 4.0% by weight, preferably from about 0.5% to 3.0% by weight of the locally applied formulation or of the drug source or patch of the drug delivery system, More preferably about 0.75% to 2.0% by weight, and optimally about 1.0% by weight. The aforementioned amounts apply to the preparations and patches, wherein the active agent in the preparations and patches is (1) apolar molecules, ie phenylpropanolamine in the form of non-ionized, free base, and (2) the inorganic in the preparation or patch. There are no additional species that can react with hydroxides or be neutralized by inorganic hydroxides. In formulations and patches in which phenylpropanolamine is in the form of acid addition salts, there are additional species (ie, acid inactive components) in the formulation or system that can be neutralized by the hydroxide-releasing agent or react with the hydroxide-releasing agent, and inorganic The amount of hydroxide is (1) from about 0.5% to 4.0% by weight of the agent or drug source, preferably from about 0.5% by weight to the amount necessary to neutralize acid addition salts and / or other base-neutralizable species. 3.0% by weight, more preferably about 0.75% to 2.0% by weight, and optimally about 1.0% by weight. In other words, for acid addition salts of phenylpropanolamine, the inorganic hydroxide is added in an amount only sufficient to neutralize the salt (ie, from about 0.5% to 4.0%) to enhance the influx of drugs through the skin or mucosal tissue. Weight percent, preferably from about 0.5 weight percent to 3.0 weight percent, more preferably from about 0.75 weight percent to 2.0 weight percent, and optimally about 1.0 weight percent). For patches, the aforementioned percentages are given in comparison to the total dry weight of the formulation component and the adhesive, gel or liquid source.
[46] For other hydroxide-releasing agents, such as inorganic oxides and metal salts of weak acids, the amount of hydroxide-releasing agent in the formulation or drug delivery system may be substantially higher, in some cases 25 weight percent or more. And generally will range from about 2% to 20% by weight.
[47] A much higher amount of hydroxide-releasing agent can be used by adjusting the ratio and / or amount of the hydroxide-releasing agent, preferably by adjusting during its own drug delivery period.
[48] However, for all hydroxide-releasing agents in the present invention, the optimal amount of any particular agent is the strength of the base, the molecular weight of the base, and the number of ionizable sites in the drug administered and any other acidic species in the agent or patch. It will depend on other factors such as the number of. One skilled in the art can readily determine the optimal amount for any particular agent by assuring the agent or drug delivery system.
[49] III. The active agent
[50] The active agent administered can be any compound suitable for local, transdermal or transmucosal delivery and capable of inducing a desired local or systemic effect. Such materials include a wide range of classes that are commonly delivered through body surfaces and membranes, including the skin. Generally this is analgesic agents; Anesthetic agents; Antiarthritic agents; Respiratory drugs, including antiasthmatic agents; Anticancer agents including antineoplastic drugs; Anticholinergics; Anticonvulsants; Antidepressants; Antidiabetic agents; Antidiarrheals; Antihelminthics; Antihistamines; Antihyperlipidemic agents; Antihypertensive agents; Anti-infective agents such as antibiotics and antiviral agents; Antiinflammatory agents; Antimigraine preparations; Antinauseants; Antineoplastic agents; Antiparkinsonism drugs; Antipruritics; Antipsychotics; Antipyretics; Antispasmodics; Antitubercular agents; Antiulcer agents; Antiviral agents; Anxiolytics; Appetite suppressants; Attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD); Cardiovascular preparations, including calcium channel blockers, CNS agents; Beta-blockers and antiarrhythmic agents; Central nervous system stimulants; Cough and cold preparations, including decongestants; Diuretics; Genetic materials; Herbal medicines (herbal remedies); Hormone inhibitors; Hypnotics; Hypoglycemic agents; Immunosuppressive agents; Leukotriene inhibitors; Mitotic inhibitors; Muscle relaxants; Narcotic antagonists; Nicotine; Nutritional agents such as vitamins, essential amino acids and fatty acids; Ophthalmic drugs, such as antiglaucoma agents; Parasympatholytics; Peptide drugs; Psychostimulants; Sedatives; Steroids; Sympathomimetics; Tranquilizers; And vasodilators including general coronary artery, peripheral and cerebral.
[51] The amount of active agent to be administered will depend on the number of factors and will vary from subject to subject, depending upon the particular drug being administered, the particular disease or condition being treated, the severity of the condition, the age, weight and general conditions of the subject, and the judgment of the prescribing physician. Will depend.
[52] Other factors specific for transdermal drug delivery include solubility and permeability of the carrier and adhesive layer in the drug delivery device, and if a device is used, also includes time for the device to be anchored to the skin or other body surface. . The minimum amount of drug is determined by the requirement that a sufficient amount of drug be present in the device or composition to maintain the desired release rate for a given time in the application. The maximum amount for safety purposes is determined by the requirement that the amount of drug present cannot exceed the rate of release which is toxic. In general, the maximum concentration may be due to unwanted histological effects such as irritation, unacceptably high initial pulses or stickiness upon administration of the agent into the body, undesirable effects on the characteristics of the delivery device such as loss of viscosity, or It is determined by the amount of formulation that can be accommodated in the carrier without exhibiting deterioration of other properties.
[53] Preferred classes of active agents are described below.
[54] A. Pharmacologically Active Amines
[55] The active agent may be a pharmacologically active nitrogen-containing base such as a primary amine, secondary amine, or tertiary amine, or an aromatic or non-aromatic nitrogen-containing heterocycle, azo compound, imine, Or any combination of the foregoing.
[56] Examples of specific primary amines include amphetamine, norepinephrine, phenylpropanolamine (any four isomers, namely (+) norephedrine, (-) norephedrine, (+)-norshdoephedrine ) And (-)-norshdoephedrine, either individually or in combination) and pyrithiamine.
[57] Examples of secondary and tertiary amines include amiodarone, amitryptyline, azithromycin, benzphetamine, bromopheniramine, chlorambucil, Chloroprocaine, chloroquine, chlorpheniramine, chlorothen, chlorothemine, chlorpromazine, cinnarizine, clarthromycin, clomiphene, and cycle Robbenzaprine, cyclopentolate, cyclophosphamide, dacarbazine, demeclocycline, dibucaine, dicyclomine, dicyclomine, dicyclomine Ethylproprion, diltiazem, dimenhydrinate, diphenhydramine, diphenylpyraline, disopyramide, dose (doxepin), doxycycline, doxylamine, dipyridame, ephedrine, epinephrine, ethylene diamine tetraacetic acid (EDTA), erythromycin ), Flurazepam, gentian violet, hydroxychloroquine, imipramine, isoproterenol, isothipendyl, levomethadyl ( levomethadyl, lidocaine, loxarine, mechlorethamine, melphalan, methadone, methadurylene, metapheniline, metyrylene (methapyrilene), metdilazine (methdilazine), methotimeperazine (methotimeperazine), methotrexate, metoclopramide, minocycline, naftifine, nicardipine ), Nicotine (nicotine), nizatidine, orphenadrine, orphenadrine, oxybutynin, oxytetracycline, phenindamine, pheniramine, phenoxybenzamine, phenoxybenzamine Phentolamine, phenylephrine, phenyltoloxamine, procainamide, procaine, promazine, promethazine, proparacaine ), Propoxycaine, propoxyphene, pyrilamine, ranitidine, scopolamine, tamoxifen, terbinafine, tetracaine ), Tetratracycline, tonzylamine, tranadol, tranadol, triflupromazine, trimeprazine, trimethylbenzamide, trimipramine, tri Plennamin , Troleandomycin, uracil mustard, verapamil and vonedrine.
[58] Examples of non-aromatic heterocyclic amines include alprazolam, amoxapine, arecoline, asemizole, atropine, azithromycin, benzapril benzapril, benztropine, beperiden, bupracaine, buprenorphine, buspirone, butorphanol, caffeine , Capriomycin, ceftriaxone, chlorazepate, chlorcyclizine, chlordiazepoxide, chlorpromazine, chlorthiazide Ciprofloxacin, cladarabine, cladarabine, clemastine, clemizole, clindamycin, clindamycin, clofazamine, clonazepam, clonidine ( clonidine, clozapine, cocain e) codeine, cyclizine, cyproheptadine, dacarbzine, dactinomycin, decipramine, diazoxide, dioxide Dihydroergotamine, diphenidol, diphenoxylate, dipyridamole, doxapram, ergotamine, ergotamine, estazolam, famcyclovir (famciclovir), fentanyl, flavoxate, fludarabine, fluphenazine, flurazepam, fluvastin, folic acid , Ganciclovir, granisetron, guanethidine, halazepam, haloperidol, homatropine, hydrocodone, hydromord Hydromorphone, hydroxyzine, hyoscyamine, imipra (imipramine), itraconazole, keterolac, ketoconazole, ketoconazole, levocarbustine, levorphone, lincomycin, lomefloxacin, lomefloxacin, loperfloxacin Loperamide, lorazepam, losartan, loxapine, loxapine, mazindol, meclizine, meperidine, mepivacaine, Mesoridazine, metdilazine, methenamine, methimazole, metomitrimeperazine, methytrimeperazine, metysergide, metronidazole, middazole midazolam, minoxidil, mintomycin c, mitomycin c, molindone, morphine, nafzodone, nalbuphine, nalbuphine, nadixic acid, nalmefene , Naloxone, naltrexone, naphazoline, nedocromil, nico (nicotine), norfloxacin, norloxacin, ofloxacin, ondansetron, oxazepam, oxycodone, oxymetazoline, oxymorphone, phenmorine (pemoline), pentazocine, pentostatin, pentostatin, pentoxyfylline, perphenazine, phentolamine, physostigmine, pilocarpine, Pimozide, pramoxine, prazosin, prochlorperazine, promazine, promethazine, pyrrobutamine, quazine ( quazepam, quinidine, quinine, rauwolfia alkaloids, riboflavin, rifabutin, risperidone, rocuronium, scopalamine (scopalamine) scopalamine, sufentannil, tacrine, temazepam, terra Terazosin, terconazole, terfenadine, tetrahydrazoline, thiordazine, thiothixene, thilodipine, timolol , Tolazoline, tolazamide, tolazamide, tolmetin, trazodone, triazolam, triethylperazine, trifluperromazine, trihexyl Phenidyl (trihexylphenidyl), trimemeprazine, trimipamine, tubocurarine, tubulouranium, vecuronium, vidarabine, vinblastine, vinblastine (vincristine), vinorelbine and xylometazoline, but are not limited to these.
[59] Examples of aromatic heterocyclic amines include acetazolamide, acyclovir, adenosine phosphate, allopurinal, alprazolam, amoxapine, ammori Amrinone, apraclonidine, azatadine, aztreonam, bisaccodyl, bleomycin, brompheniramine, brompheniramine, buspirone, bu Toconazole, carbinoxamine, cefamandole, cefamazole, cefazole, cefixime, cefmetazole, cefonicid, cefoperazone ), Cefotaxime, cefotetan, cefpodoxime, ceftriaxone, ceftriaxone, cephapirin, chloroquine, chlorpheniramine, cimetidine, Cladarabine, clotrimazole rimazole, cloxacillin, didanosine, dipyridamole, doxazosin, doxylamine, econazole, enoxacin, and ethazole estazolam, ethionamide, famciclovir, famotidine, fluconazole, fludarabine, folic acid, ganciclovir , Hydroxychloroquine, iodoquinnol, isoniazid, isothipendyl, itraconazole, ketoconazole, lamotrigine, lanotrigine, lansoprazole, rhosoprazole Cetadine, losartan, losartan, mebendazole, mercaptopurine, mercaptopurine, methafurylene, methapyriline, methotrexate, metronidazole, Miconazole, midazolam, Minoxidil, nafzodone, naldixic acid, niacin, nicotine, nifedipine, nizatidine, omeperazole, oxprozine (oxaprozin), oxiconazole, papaverine, pentostatin, phenazopyridine, pheniramine, pilocarpine, piroxicam, pra Prazosin, primaquine, pyrazinamide, pyrilamine, pyrilmethamine, pyrimethamine, pyrithiamine, pyroxidine, quinidine, Quinine, Ribaverin, Rifampin, Rifampin, Sulfadiazine, Sulfamethizole, Sulfamethoxazole, Sulfasalzine, Sulfasoxazole, Terrase Terazosin, thiabendazole, thiamine, thioguanine, tonic Tonylylamine, timolol, trazodone, triampterene, triazolam, trimethadione, trimethoprim, trimetrexate ), Triplelenamine, tropicamide, and vidarabine, but are not limited thereto.
[60] Examples of azo compounds include phenazopyridine and sulfasalazine, while examples of imines include seppicsim, cimetidine, clofazimine, clonidine, dantrolene, pamotidine, furazolidone ( furazolidone, nitofurantoin, nitrofurazone and oxyconazole.
[61] Combinations of the aforementioned drugs and / or other forms of active agents and one or more combinations of the aforementioned drugs may also be delivered using the method according to the invention.
[62] Examples of particularly preferred nitrogen-containing drugs that can be administered using the above methods, compositions and systems according to the present invention are phenylpropanolamine and oxybutynin.
[63] Phenylpropanolamine, or 2-amino-1-phenyl-1-propanol is described, for example, in Kanfer et al. , Analytical Profiles of Drug Substances , vol. 12, K.Florey, Ed. (New York: Academic Press, 1983). Phenylpropanolamine is an sympathomimetic drug that has been used as an anorctic agent, decongestant, anti-anxiety agent, and a drug for reducing fatigue and confusion (U.S. Patent No. 5,019,594 US Pat. No. 5,260,073 to Phipps and US Pat. No. 5,096,712 to Wortman). Phenylpropanolamine has two chiral centers and therefore exists as four different isomers, which are generally (+)-norepedrine, (-)-norepedrine, (+)-nor Pseudoephedrine, and (-)-norsudoephedrine. In general, (-)-norephedrine and (+)-norshdoephedrine are recognized as more active isomers in most physiological uses. Phenylpropanolamine can be administered transdermally, ie as a mixture of any two or more of the four isomers of phenylpropanolamine, generally with (-)-norephedrine and (+)-nor Racemic mixtures of ephedrine or any one of the four isomers may be administered separately. Phenylpropanolamine is generally administered as an appetite suppressant (ie, for edible inhibition), or may be used as a decongestant, an anxiety agent, and may also be used to reduce fatigue or confusion. Most commonly, the drug is used as either anorexia nervosa or decongestant. In general, the daily dose of racemic phenylpropanolamine using the formulation and delivery system according to the invention will range from about 10 mg / day to about 250 mg / day, preferably from about 25 mg / day to about 200 mg / day.
[64] Oxybutynin is classified as an anticholinergic antipsychotic and is commonly used to treat individuals suffering from overactive bladder such as neurogenic bladder (eg, Guittard et al. US Pat. No. 5,674,895). Oxybutynin contains chiral centers and can therefore be administered either as racemate or as a single isomer. There is a discrepancy as to whether the activity of the racemate is in the S enantiomer or the R enantiomer, but the activity is believed to be mainly in the R enantiomer (Noronha-Blob (1990) J. Pharmacol. Exp. Ther. 256 (2): 562-567 and Goldenberg (1999) Clin Ther. 21 (4): 634-642.). British Patent 940,540 discloses the preparation of racemic oxybutynin. Synthesis of (S) -oxybutynin is also known. For example, S enantiomers can be obtained by esterification after degradation of the intermediate mandelic acid (Kachur et al. (1988) J. Pharmacol. Exp. Ther. 247 (3): 867 -72). The R enantiomer first prepares 4-diethylamino-2-butynyl chloride from dichlorobutin, and uses a single R enantiomer of cyclohexylphenylglycolic acid and 4-diethylamino-2-butynyl chloride prepared above. By reaction to produce an R enantiomer of 4-diethylamino-2-butynyl phenylcyclohexyl glycolate, ie, (R) -oxybutynin (Aberg) 6,123,961). Alternatively, the individual isomers can be separated from the racemic mixture of oxybutynin using techniques known in the art, such as methods based on chromatography using chiral substrates. Transdermal administration of oxybutynin is useful in a variety of situations, as can be readily understood by one of ordinary skill in the art. For example, transdermal administration of oxybutynin is useful for the treatment of urinary urgency, urinary frequency, urinary leakage, incontinence and urination pain or difficulty urination. In general, although not essential, these diseases are caused by neurogenic bladder. In addition, the compositions and drug delivery systems according to the present invention are useful for administering oxybutynin to treat other conditions and diseases in response to transdermal administration of oxybutynin. For example, oxybutynin may be administered transdermally to treat individuals suffering from detrusor hyperreflexia and detrusor instability. In general, the daily dose of racemic oxybutynin using the formulation and delivery system according to the invention will range from about 1 to 20 mg over a 24 hour period. The daily dose of the individual enantiomers of oxybutynin, ie, (S) -oxybutynin or (R) -oxybutynin, using the formulation and delivery system according to the invention is preferably less than the corresponding racemate dose Do. Specifically, the enantiomer dose is preferably in the range of about 0.5 to 15 mg over a 24 hour period.
[65] Since many amine drugs are commercially available only in salt form, ie in the form of acid addition salts, the use of hydroxide-releasing agents as penetration enhancers eliminates the need to convert the drug to the free base form prior to patch preparation. In other words, the hydroxide-releasing agent may be combined during the patch preparation with acid addition salts, thus neutralizing the drug during the preparation rather than after preparation.
[66] B. nonsteroidal antiinflammatory agents (NASIDS)
[67] Suitable nonsteroidal anti-inflammatory agents that can be used in the pharmaceutical preparations according to the present invention include, but are not limited to, ketoprofen, flurbiprofen, ibuprofen, naproxen, feh Fenoproten, benoxaprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, Propionic acid derivatives such as suprofen, alminoprofen, butibufen, fenbufen and tiaprofenic acid; Acetylsalicylic acid; Apazone; Diclofenac; Difenpiramide; Diflunisal; Etodolac; Flufenamic acid; Indomethacin; Ketorolalac; Meclofenamate; Mefenamic acid; Nabumetone; Phenylbutazone; Pyroxicam; Salicylic acid; Sulindac; Tolmetin; And combinations thereof. Preferred NSAIDs are Ivprofen, Diclofenac Sodyan, Ketoprofen, Ketorolac, Pyroxycam.
[68] The NSAIDs or NSAIDs additionally contain one or more additional active agents, such as diphenhydramine and clopheniramine, in particular antihistamines such as diphenhydramine hydrocholoride and clopheniramine maleate. antihistaminic agents; Clobetasol propionate, betamethasone benzoate, betamethasone diproprionate, diflorasone diacetate, fluosinoneide, mometasone Hydrocortisone, hydrocortisone-21-monoesters, as well as higher potencycorticosteroids such as mometasone furoate and triamcinolone acetonide, for example Hydrocortisone-21-acetate, hydrocortisone-21-butyrate, hydrocortisone-21-propionate, hydrocortisone-21-belanate (hydrocortisone-21-valerate), such as hydrocortisone-17,21-diesters Examples of the hydrocortisone-17,21-diester include hydrocortisone-17, 21-diacetate, hydrocortisone-17-acetate-21-butyrate, and hydrocortisone-17-acetate-. 21-butylate, hydrocortisone-17,21-dibutyrate, alclometasone, dexamethasone, flumethasone, flumethasone, prednisolone and Corticosteroids, including lower potency corticosteroids such as methylprednisolone; Local anesthetic agents such as phenol, benzocaine, lidocaine, prilocaine and dibucaine; Topical analgesics such as glycol salicylate, methyl salicylate, l-menthol, d, l-camphor and capsaicin ( co-administration with topical analgesics and antibiotics. Preferred additives are antibiotics as discussed in Section F below.
[69] The compounds described above can be administered transdermally using the methods, compositions and systems of the present invention to treat patients with pain or disease sensitive to NSAIDs. NASIDs are generally used as anti-inflammatory and / or analgesics in treating patients with rheumatic or arthritic disorders. The rheumatoid or arthritis diseases include, for example, rheumatoid arthritis (RA), degenerative joint disease (known as 'DJD' or 'osteoarthristis'); Juvenile rheumatoid arthritis (JRA); Psoriatic arthritis; Gouty arthritis; Ankylosing spondylitis; And lupus erythematoses such as systemic lupus erythematosus and discoid lupus erythematosus.
[70] NSAIDs can cause fever (through the anti-pyretic property of NSIDs) or myocardial infarction (MI), transient ischemic attacks, and acute superficial thrombophlebitis (platelet aggregation). (through platelet aggregation inhibition), but is not limited thereto. Furthermore, NSAIDs can include ankylosing spondylitis, bursitis, cancer-related pain, dysmenorrhea, gout, headaches, muscle pain, and tendinitis. tendonitis and pain associated with medical procedures such as dental, gynecological, oral, orthopedic, post-partum, and urological measures It can be used without limitation in single treatment or adjuvant therapy.
[71] The amount of active agent administered depends on the number of factors and also depends on the patient as mentioned above. However, for example, the daily dosage of ketorolac using the pharmaceutical formulation and system according to the present invention is approximately 10-40 mg, and the amount of pyroxicam using the pharmaceutical formulation and system according to the present invention. The daily dosage is approximately 10-40 mg, and the daily dosage of iburophene using the pharmaceutical formulation and system according to the present invention is approximately 200-1600 mg / day.
[72] C. Estrogens and Progestins
[73] Suitable estrogens that can be administered using the compositions and drug delivery systems of the present invention include estradiol (ie, 1,3,5-estratriene-3,17β-diol (1,3,5-estratriene). -3,17β-diol or "17β-estradiol" and estradiol benzoate, valerate, cypionate, heptanoate, de Esters thereof, including decanoate, acetate, and diacetate; 17α-estradiol; ethinylestradiol (ie, 17α-ethynyl Esters and ethers thereof, including estradiol (17α-ethinylestradiol), ethinylestradiol 3-acetate, ethynylestradiol 3-benzoate Estriol and Estriol Succinate inestes; polyestrol phosphate; esters and derivatives thereof, including estrone, estrone acetate, estrone sulfate, and piperazine estrone sulfate; Synthetic or natural estrogens such as quinestrol, mestranol, and conjugated equine estrogens, specifically, preferred as synthetic estrogens used in combination with the present invention. Is 17β-estradiol, ethynylestradiol or mestranol.
[74] Suitable progestins that can be delivered using the compositions and systems according to the invention include, but are not limited to, acetoxyprognenolone, allylestrenol, anagestone acetate, chlormadinone acetate, cyproterone, cyproterone acetate, desogestrel, dihydrogesterone, dimethisterone, ethisterone (17α- Ethynyltestosterone (17α-ethinyltestosterone), ethynodiol diacetate, flurogestone acetate, gestadene, hydroxyprogesterone, hydroxyprogesterone acetate (hydroxyprogesterone) acetate), hydroxyprogesterone caproate, hydroxymethylpro Hydroxymethylprogesterone, hydroxymethylprogesterone acetate, 3-ketodesogestrel, levonorgestrel, lynestrenol, medrogesterone ), Methroxyprogesterone acetate, megestrol, megestrol, megestrol acetate, merengestrol acetate, norethindrone, norethindrone acetate ), Norethisterone, norethisterone acetate, norethisterone acetate, norethynodrel, norgestimate, norgestrel, norgestrienone ), Normethisterone (normethisterone) and progesterone (but not limited to). More preferred progestins are progesterone, methoxyprogesterone, noethine drone, noethinodrel, d, l-norgestel and l-norgestrel.
[75] In female HRT, co-administration of estrogen and progestin is generally preferred, and co-administration with progestin results in no resistance to estrogen. As is known, estrogen-based therapy is known to increase the risk of endometrial hyperplasia and cancer as well as the risk of breast cancer in patients to whom the therapy is applied. . Co-administration of progestin and estrogen formulations has been found to reduce this risk. Preferred mixtures of progestin and estrogens include 17β-estradiol and hydroxyprogesterone acetate; 17β-estradiol and noethyne drone; 17β-estradiol and noethinodrel; Ethynyl estradiol and d, l-norgestrel; Ethynyl estradiol and l-norgestrel; And megestrol and hydroxyprogesterone acetate.
[76] In addition, because premenopausal women have low levels of androgens, small amounts of androgen agents, along with progestins and estrogens, to regenerate the complete hormonal profile of premenopausal women. It is preferred to administer. Suitable androgen preparations are discussed in section D. below.
[77] The aforementioned steroidal agents can be naturally occurring steroids, synthetic steroids and derivatives thereof.
[78] As mentioned above, administration of steroidal active agent mixtures is useful in a variety of situations, which can be readily understood by those skilled in the art. For example, transdermal administration of estrogen and progestin can be used in female hormone replacement therapy (HRP), which alleviates or substantially inhibits symptoms and pain resulting from changing hormone levels. Compositions and drug delivery systems according to the present invention are useful for administering estrogens and progestins in response to drug delivery of an active agent mixture to treat other pain and diseases. For example, the mixtures described above are useful for treating symptoms caused by premenstrual stress, as described above, and for female contraception. In female HRT, the woman being treated is usually a woman of childbearing age or an old age woman. Estrogen, progesterone and androgen production in the ovarian of these women are hampered by natural menopause, surgical surgery, radiation, chemical ovarian ablation or excision, or premature ovarian failure. Other instructions, including HRP and the female contraceptives, compositions, and drug delivery systems described herein, are preferably used continuously to ensure sufficient administration of the active agent. Transdermal administration according to the present invention is very effective for female HRT. That is, it reduces the incidence and pain of hot flash and night sweat, minimizes the escape of calcium from bone after menopause, and reduces the risk of death from ischemic heart disease. Generally, irritation and histological side effects such as initial pulses that are unacceptably rapid to the human body due to the agent, or loss of tackinis, viscosity or other deterioration of other qualities The maximum concentration is determined by the amount of agent that can be accommodated in the carrier without the side effects of the delivery device. However, preferred transdermal compositions and systems for HRP include about 0.5 to 10.0 mg of progestin, such as noethine drone and noethine drone acetate, 10 to 200 μg of estrogen such as 17β-estradiol, ethynyl estradiol, mestranol, etc. Can be delivered for about 24 hours or more. However, it will be understood by those skilled in the art that the preferred amount of active agent for each individual depends on the specific active agent as well as other factors; Of course, the minimum effective amount of each active agent is preferred.
[79] D. Androgen Drugs
[80] Preferred androgen preparations that can be used in the pharmaceutical preparations of the present invention include naturally occurring androgens, androsterone, androsterone acetate, androsterone propionate, androsterone benzo Androstenediol, androstenediol, androstenediol, androstenediol-3-acetate, androstenediol-17-acetate, androstenediol -Androstenediol-3,17-diacetate, androstenediol-17-benzoate, androstenediol-3-acetate-17-benzoate 3-acetate-17-benzoate), androstenedione, dehydroepiandrosterone (DHEA) (also called "prasterone"), sodium dehydroepiandro Sodium dehydroepiandrosterone sulfate, 4-dihydrotestosterone (4-HT) (called "stanolone"), 5α-dihydrotestosterone (5α-dihydrotestosterone), dromostanolone , Dromostanolone propionate, dromostanolone propionate, ethylestrenol, nandrolone phenpropionate, nandrolone decanoate, nandrolone furylpropionate furylpropionate, nandrolone cyclohexanepropionate, nandrolone benazoate, nandrolone cyclohexanecarboxylate, oxandrolone, stanozolol and Testosterone; Pharmaceutically acceptable esters of testosterone and 4-dihydrotestosterone, typically esters formed from hydroxyl groups at the C-17 position-but not limited to enanthate Propionate, Cypionate, Phenylacetate, Acetate, Isobutyrate, Buciclate, Heptanoate, Decatoate decanoate, undecanoate, caprate and isocaprate esters; And derivatives of androgens including pharmaceutically acceptable derivatives of testosterone such as methyl testosterone, testolactone, oxymetholone and fluoxymesterone However, the present invention is not limited thereto. Specifically, the preferred androgen preparations used in the present invention are testosterone and testosterone esters, such as testosterone enanthate, testosterone propiotate and testosterone sipiotate. The testosterone esters described above may be commercially available and can be readily prepared using methods known in the art or described in the literature.
[81] The above androgen preparations may be selected from the group consisting of naturally occurring androgens, synthetic androgens and derivatives thereof. Active agents can be included in the current dosage unit and selected such as pharmaceutically acceptable derivatives, analogs, esters, salts, amides, or penetration through mucosla tissue. It may be administered in the form of an agent that can be modified by adding one or more suitable functions to enhance biological properties. In general, with respect to androgen preparations, esters corresponding to salts or other derivatives are preferred. As mentioned in the previous section, the preparation of esters involves the funcionalization of hydroxyl groups and / or carboxyl groups, which can be understood by those skilled in the art of pharmaceutical chemistry and drug delivery. For example, to prepare testosterone esters, the general esterification conditions using 17-hydroxyl groups of testosterone molecules, using strong acids such as sulfuric acid, hydrochloric acid, etc., and using temperatures sufficient to reverse the reaction Reaction with a suitable organic acid under The ester can be reconverted to free acids using conventional hydrogenolysis or hydrolysis methods as needed.
[82] Androgen preparations such as testosterone (17β-hydroxyandrost-4-en-3-one, 17β-hydroxyandrost-4-en-3-one) are required for sperm production and are responsible for the overall growth of body tissues. Promote. The main clinical use of androgens is to replace or increase the secretion of androgens in hypogonadal men. Androgens may be used to treat gynecologic disorders, for example, to reduce breast engorgement during the postpartum period. Androgens can also be used to reduce protein loss after trauma, surgery, prolonged immobilization, or in the treatment of anemia, hereditary angioedema. Androgens may additionally be used to treat male osteoporosis, or as a metabolic growth stimulator in prepuberal boys.
[83] Testosterone and its derivatives are compounds that are therapeutically effective in significantly smaller amounts, generally in the range of about 5 to 10 mg / day.
[84] E. Peptidyl Drugs
[85] Peptide-based formulations that can be administered in accordance with the present invention include any pharmacologically active peptide, polypeptide or protein. Once selected, peptide-based formulations must be used that are prepared or commercially available for binding to the composition or delivery system. Peptide-based formulations can be prepared using standard synthetic methods, recombinant methods or extraction from natural products.
[86] Peptides, polypeptides and proteins can generally be synthesized using the technique of standard solid phase peptide synthesis known in the art. Synthesis in this method is a peptide chain that produces one desired amino acid residue according to the general solid phase principle, for example, the method of Merrifield, J. Amer. Chem. Soc . 85: 2149-2154, 1963. It is performed sequentially by inserting in at once. Commonly, the chemical synthesis of peptides, polypeptides and proteins results in the reactivity of various amino acid moieties with suitable protecting groups that prevent chemical reactions from occurring at these sites until the protecting groups are ultimately eliminated. To protect the side chains. It is well known to protect an α-amino group on an amino acid by reacting with a carboxyl group and then selectively removing the α-amino protecting group in order for the next reaction to take place at this site. Suitable α-amino groups and side chain protecting groups are known in the art.
[87] Peptides, polypeptides or proteins may also be prepared using recombinant techniques known in the art. That is, as will be appreciated by those skilled in the art, one can prepare DNA encoding a desired amino acid sequence, clone the DNA into an expression vector, transform a host cell, such as a bacterium, yeast or animal cell, It can be prepared using conventional recombinant techniques to express the DNA to produce peptides, polypeptides or proteins.
[88] In addition, peptides, polypeptides or proteins may be obtained from natural products, such as humans or other animals, or may be extracted from living organisms or bodies. The material is separated and purified prior to mixing into the drug delivery system or dosage form. Separation and purification techniques are known in the art, including, for example, centrifugation.
[89] Although peptide-based agents may be included in the drug delivery system of the present invention, such agents are generally coagulation factor, cytokine, endorphin, kinin, hormone, LHRH (luteinizing) hormone-releasing hormone analogues and other peptide-based agents that exhibit the desired pharmacological activity. Of course, the category is not limited thereto, but merely provided as a means for configuration. As will be appreciated by those skilled in the art, peptide-based formulations may be divided into one or more categories.
[90] Many coagulation modulators are endogenous proteins that circulate in the blood and interact with other endogenous proteins to regulate blood coagulation. Preferred coagulation modulators α ₁ - antitrypsin _{(α 1 -antitrypsin), α 2} - macroglobulin (α ₂ -macroglobulin), antithrombin Ⅲ (antithrombin Ⅲ), factor Ⅰ (fibrinogen, fibrinogen), factor Ⅱ (prothrombin, prothrombin ), Factor III (tissue prothrombin), factor V (proaccelerin), factor Ⅶ (proconvertin), factor Ⅷ (antihemophilic globurin (AHG)), factor Ⅸ ( Christmas factor; plasma thromboplastin component (PTC), factor VII (Struart-Power factor), factor VII (plasma thromboplastin antecedent, PTA) , Factor XII (Hageman factor), heparin cofactor II, kallikrein, kallikrein, plasmin, plasminogen, kallikrein precursor, protein C, Protein S, Trombomo Thrombomodulin and mixtures thereof, including both active and inactive forms of these proteins.
[91] Cytokines are proteins of a large heterogeneous group and play an important role in the function of the immune system and in the regulation of hematopoiesis, for example the production of blood or blood cell blood cells. Preferred cytokines include colony stimulating factor 4, HBNF (heparin binding neurotrophic factor), interferon-α, interferon-α-2a, interferon-α-2b, interferon α-n3, interferon-β, interferon-γ, interleukin-1, interleukin-2, interleukin-3, interleukin-4, interleukin-5, interleukin-6, interleukin-7, interleukin-8, interleukin- 9, interleukin-10, interleukin-11, interleukin-12, interleukin-13, interleukin-14, interleukin-15, interleukin-16, interleukin-17, tumor necrosis factor (TNF), TNF-α, G Granulocyte colony-stimulating factor (CSF), granulocyte-macrophage colony-stimulating factor (GMF), macrophage colony-stimulating factor (GM-CSF), mead Midkine, thymopoietin and mixtures thereof.
[92] Endorphins are generally peptides or small chain peptides that activate opiate receptors. Agonist and antagonist derivatives of naturally occurring endorphins may also be included.
[93] Endorphins and pharmacologically active derivatives are representative of demorphin, dynorphin, α-endorphin, β-endorphin, and γ-endorphin. ), σ- endorphin [Leu ^5] yen kepa Lin ^{(σ-endorphin [Leu 5]} enkephalin), [Met 5] yen kepa Lin ([Met ^5] enkephalin), the substrate P (substance P) and mixtures thereof do.
[94] Peptide hormones may be naturally occurring or may be pharmacologically active derivatives of known hormones. Peptide hormones may also be derived from humans or other zoos. Peptide hormones that can be administered using the methods, compositions and delivery systems of the invention include, for example, activin, amylin, angiotensin, atrial natriuretic peptide (ANP), (chicken, Calcitonin derived from eel, human, pig, rat, salmon, etc., calcitonin gene-related peptide, calcitonin N-terminal flanking peptide ), Cholecystokinin (CCK), ciliary neurotrophic factor (CNTF), corticotropin (adrenocorticotropin hormone (ACTH), corticotropin-releasing factor (CRF or CRH), epidermal growth factor (epidermal growth factor (EGF)), follicle-stimulating hormone (FSH), gastrin, gastrin inhibitory peptide (GIP), gastrin-releasing peptide, ghrelin (gastrin) ghrelin), Glucogon, gonadotropin-releasing factor (GnRF or GNRH), growth hormone releasing factor (GRF or GRH), human chorionic gonadotropin , hCH), inhibin A, inhibin B, insulin (derived from bovine, human pigs, etc.), leptin, lipotropin (LPH), corpus luteum Luteinizing hormone (LH), luteinizing hormone-releasing hormone (LHRH), α-melanocyte-stimulating hormone, β-melanocyte-stimulating hormone (β melanocyte-stimulating hormone, γ-melanocyte-stimulating hormone, melatonin, motilin, oxytocin (pitocin), pancreatic polypeptide , Parathyroid hormone (PTH), placental lactogen, Prolactin (PRL), prolactin-release inhiabiting factor (PIF), prolactin-releasing facor (PRF), secretin, somatotropin (growth) hormone (GH), somatostatin (SIF); growth hormone-release inhibiting factor (GIF), thyrotropin (thyroid-stimulating hormone (TSH)), thyrotropin-releasing factor (TRH or TRF), thyroxine, triiod tea Triinodothyronine, vasoactive intestinal peptide (VIP), vasopressin (antidiuretic hormone (ADH)), and mixtures thereof.
[95] In particular, preferred analogs of LHRH are buserelin, deslorelin, fertirelin, goserelin, hisstrelin, leuprolide, leuprorelin, and root. Lutrelin, nafarelin, tryptorelin and mixtures thereof.
[96] In addition, the peptide-based drug may be a kinine. In particular, preferred kinins include bradykinin, potentiator B, bradykinin potentiator C, kallidin and mixtures thereof.
[97] Other peptide-based agents that exhibit the desired pharmacological activity may also be included in the delivery system of the present invention. For example, abarelix, adenosine deaminase, anakinra, ancestim, alteplase, alglucerase, asparaginase (asparaginase), bivalirudin, bleomycin, bombesin, desmopressin acetate, des-Q14-ghrelin, dornaze-α (dornase-α), entererostatin, erythropoeitin, exendin-4, fibroblast growth factor-2, filgrastim filgrastim, β-glucocerebrosidase, gonadorelin, hyaluronidase, insulinultropin, lepirudin, lepiudin, and margarine Ⅰ magainin I), magainin II, nerve growth factor, pentigetide, thrombopoietin in), thymosin α-1, thymidin kinase (TK), tissue plasminogen activator, tryptophan hydroxylase, urokinase ( urokinase), urotensin II and mixtures thereof.
[98] In particular, preferred systemic active agents that can be administered transdermally in the present invention include LHRH analogs such as oxytocin, insulin, and leuprolide.
[99] Preferred preparations for local and topical administration include topical antibiotics, such as magainin I and magainin II, anti-fungal and anti-psoriatic agents. Antipruritic agents, antihistamines, asparaginase and antineoplastic agents such as bleomycin, local anesthetics, anti-inflammatory agents, and the like. Such compounds include, but are not limited to, a wide variety of compounds known to be topical.
[100] F. Locally administered active agents
[101] Preferred active agents for topical and topical administration are topical antibiotics, other topical anti-acne agents, anti-fungal agents, anti-psoriatic agents, antipruritic agents. And include, but are not limited to, a wide variety of compounds known to be topical, such as antihistamines, antitumor agents, local anesthetics, anti-inflammatory agents, and the like. Suitable topical antibiotics are effective against lincomycin-based antibiotics (originally antibiotics that are effective against streptomyces lincolnensis ) and tetracycline-based antibiotics ( streptomyces aurepfaciens) . Antibiotics) and sulfur-based antibiotics such as, but not limited to, sulfonamides. Lincomycin antibiotics include, for example, lincomycin itself (6,8-dideoxy-6-[[(1-methyl-4-propyl-2-pyrrolidinyl) -carbonyl] amino] -1-thio-L -Treo-alpha-D-galacto-octopyranoside (6,8-dideoxy-6-[[(1-methy1-4-propyl-2-pyrrolidinyl) -carbony1] amino] -1-thio-L -threo-α-D-galacto-octopyranoside)), clindamycin, 7-deoxy, 7-chloro derivative of lincomycin (ie, 7-chloro-6,7,8-trideoxy-6- [ [(1-Methyl-4-propyl-2-pyrrolidinyl) -carbonyl] amino] -1-thio-L-treo-alpha-D-galacto-octopyranoside (7-chloro-6, 7,8-trideoxy-6-[[(1-methyl-4-propyl-2-pyrrolidinyl) carbonyl] -amino] -1-thio-L-threo-α-D-galacto-octopyranoside)), US patent Related compounds described in 3,475,407, 3,509,127, 3,544,551 and 3,513,155 and their pharmacologically acceptable salts and esters. Tetracycline antibiotics are, for example, tetracycline itself (4- (dimethylamino) -1,4,4α, 5,5α, 6,11,12α-octahydro-3,6,12,12α-pentahydroxy-6 -Methyl-1,11-dioxo-2-naphthacene-carboxamide (4- (dimethylamino) -1,4,4α, 5,5α, 6,11,12α-octahydro-3,6,12,12α -pentahydroxy-6-methyl-1,11-dioxo-2-naphthacene-carboxamide), chlortetracycline, oxytetacycline, tetratracycline, demeclocycline, and lolitetracycline acid addition salts such as rolitetracycline, metacycline and doxycycline and their pharmaceutically acceptable salts and esters, especially hydrochloride salts. And sulfur-based antibiotics include, but are not limited to, sulfonamides sulfacetamide, sulffabenzamide, sulfadiazine sulfadoxine , Sulfamerazine, sulfamethazine, sulfamethizole, sulfamethoxazole, and their pharmacologically acceptable salts and esters, such as sulfacetamide sulfideamide sodium). Topical anti-acne agents include keratolytics such as salicyclic acid, retinoic acid (Retin-A "), and organic peroxides. The fungicides are amphotericin B, benzoic acid, buttoconazole, caprylic acid, econazole, fluconazole, itraconazole, Ketoconazole, miconazole, nystatin, salicylic acid, and terconazole.Anti-psoriasis agents include anthralin, azathio Azathioprine, calcipotriene, calcitriol, colchicine, cyclosporine, retinoids, and vitamin A. The active agents also include topical corticosteroids. Hydrocortisone ( hydrocortisone, hydrocortisone-21-acetate, hydrocortisone-21-butyrate, hydrocortisone-21-propionate, hydrocortisone-21-acetate Hydrocortisone-21-monoesters, such as 21-valerate, hydrocortisone-17, 21-diacetate, hydrocortisone- Hydrocortisone, such as 17-acetate-17-acetate-21-butyrate, hydrocortisone-17, 21-dibutyrate, and the like. One of the lower potency cortinoids such as -17,21-diesters, alclometasone, dexamethasone, flumethasone, prednisolone or methyl prednisolone Age or clobetasol propionate, betamethasone benzoate, betamethasone diproprionate, diflorasone diacetate, fluocinonide, It may be one of high potency cortinoids such as mometasone furoate, triamcinolone acetonide and the like.
[102] G. Other active agents and analogs
[103] Preferred other examples of systemic active agents for transdermal formulations and drug delivery systems of the present invention include, but are not limited to, the following compounds:
[104] Analgesics and anesthetics--hydrocodone, hydromorphone, levorphanol, oxycodone, oxymorphone, codeine, morphine, alfentanil ( alfentanil, fentanyl, meperidine, sufentannil, buprenorphine and nicomorphine;
[105] Antidepressant drugs--sertraline, paroxetine, fluoxetine, fluvoxamine, citalopram, venlafaxine and nefazodone Selective serotonin reuptake inhibitors such as); Amitriptyline, doxepin, nortriptyline, imipramine, imipramine, trimipramine, amoxapine, desipramine, protrip Tricyclic anti-depressants such as protripyline, clomipramine, mirtazapine and maprotiline; Other antidepressants such as trazodone, buspirone and bupropion;
[106] Attention deficit disorde and attention deficit hyperactivity disorder drugs--methylphenidate and pemoline;
[107] Cardiovascular preparations--enalapril, 1-carboxymethyl-3-1-carboxy-3-phenyl- (1S) -propylamino-2.3.4.5-tetrahydro-1H- (3H)- 1-benzazepine-2-one (1-carboxymethyl-3-1-carboxy-3-phenyl- (1S) -propylamino-2,3,4,5-tetrahydro-1H- (3S) -1-benzazepine- 2-one), 3- (5-amino-1-carboxy-1S-pentyl) amino-2,3,4,5-tetrahydro-2-oxo-3S-1H-1-benzazepine-1-acetic acid (3- (5-amino-1-carboxy-1S-pentyl) amino-2,3,4,5-tetrahydro-2-oxo-3S-1H-1-benzazepine-1-acetic acid) or 3- (1 -Ethoxycarbonyl-3-phenyl- (1S) -propylamino) 2,3,4,5-tetrahydro-2-oxo- (3S) -benzazepine-1-acetic acid monohydrochloride (1-ethoxycarbonyl Angiotensin converting enzyme (ACE), such as -3-pheny1- (1S) -propylamino) -2,3,4,5-tetrahydro-2-oxo- (3S) -benzazepine-1-acetic acid monohydrochloride Inhibitors; Diuretics; Pre- and afterload reducers; Cardiac glycosides, such as digoxin and digitoxin; Inotropes such as amrinone and milrinone; Verapamil, nifedipine, nifedipine, nicardipene, felodipine, isradepine, nimodipine, bepridil, amlodipine and diltia Calcium channel blockers such as diltiazem; Beta-blockers such as metoprolol; Pindolol, propafenone, propranolol, esmolol, sotolol and acebutolol; Moricizine, ibutilide, procainamide, proquinamide, quinidine, disopyramide, lidocaine, phenytoin, tocainide, mexiletin antiarrhythmics (antiarrhythmics) such as mexiletine, flecainide, encainide, brethlium, and amiodarone; Cardioprotective agents such as dexrazoxane and leucovorin; Vasodilators such as nitroglycerin; Cholinergic agents such as arecoline;
[108] CNS agents--bromocriptine, ± trans-1,3,4,4α, 5,10β-hexahydro-4-propyl-2H-1-benzopyrano-3,4- Bipyridin-9-ol-monohydrochloride (± trans-1,3,4,4α, 5,10β-hexahydro-4-propyl-2H-1-benzopyrano-3,4-bipyridine-9-ol monohydrochloride);
[109] Muscle relaxants--baclofen;
[110] Nicotine;
[111] Narcotic antagonists--naloxone, especially naloxone hydrochloride;
[112] Peripheral vascular dilators--cyclandelate, isoxsuprine and papaverine;
[113] Ophthalmic drugs--physostigmine sulfate;
[114] Respiratory drugs--e.g. Albuterol, formoterol, nikethamide, theophylline, terbutaline, oxytriphylline , Aminophylline and other xanthine derivatives;
[115] Topoimerase inhibitors--topotecan and irinotecan.
[116] Genetic material such as nucleic acids, RNA, DNA, recombinant RNA, recombinant DNA, antisense RNA, antisense DNA, ribooligonucleotides, deoxyribonucleotides, antisense riboligonucleotides, or antisense deoxyribooligonucleotides, also methods of the invention It may be delivered using pharmaceutical agents, transdermal systems.
[117] Specifically, preferred systemic active agents that can be administered transdermally in the present invention are: buprenorphine, fentanyl, sulfentanyl, terbutaline, formo Formoterol, albuterol, theophylline, estradiol, progesterone, scopolamine, enalapril, 1-carboxymethyl-3-1- Carboxy-3-phenyl- (1S) -propylamino-2,3,4,5, -tetrahydro-1H- (3S) l-benzazepine-2-one (1-carboxymethyl-3-1-carboxy- 3-pheny1- (1S) -propylamino-2,3,4,5-tetrahydro-1H- (3S) 1-benzazepine-2-one, 3- (5-amino-1-carboxy-1S-pentyl) -amino -2,3,4,5-tetrahydro-2-oxo-3S-1H-1-benzazepine-1-acetic acid (3- (5-amino-1-carboxy-1S-pentyl) amino-2,3 , 4,5-tetrahydro-2-oxo-3S-1H-1-benzazepine 1-acetic acid, 3- (1-ethoxycarbonyl-3-phenyl- (1S) -propylamino) -2,3,4 , 5-tetrahydro-2-oxo- (3 S) -benzazepine-1-acetic acid monohydrochloride (3 (1-ethoxycarbonyl-3-phenyl- (1S) -propylamino) -2,3,4,5-tetrahydro-2-oxo- (3S) -benzazepine -1-acetic acid monohydrochloride; nitroglycerin, tripolidine, tripelenamine, diphenhydramine, physostigmine, arecoline And nicotine, uncharged, nonionizable active agents are preferred. Also preferred are acidic addition salts of basic drugs, more preferably hydrochlorids salt.
[118] If salts, esters, amides, prodrugs or derivatives are pharmacologically suitable, the active agent may be administered in the form of salts, esters, amides, prodrugs, derivatives and the like. Also salts, esters, amides, prodrugs and other derivatives of the active agents are standard methods known in the art of synthetic organic chemistry such as J. E. It can be prepared according to the method of March (J. March, Advanced Organic Chemistry: Reaction, Mechanisms and Structure , 4th Ed.) (New York: Wiley-Interscience, 1992).
[119] For example, acid addition salts can be prepared from free acids, such as amine drugs, using conventional methodologies and include reacting with a suitable acid. Generally, the base form of the drug is dissolved in a polar organic solvent such as methanol or ethanol and an acid is added. The resulting salt can be obtained from solution by precipitation or by addition of a less polar polar solvent. Acids suitable for the preparation of acid addition salts are hydrochloric acid, hydrobromic acid and sulfuric acid. ), As well as inorganic acids such as nitric acid and phosphoric acid, as well as acetic acid, propionic acid, glycolic acid, pyruvic acid and oxalic acid. ), Malic acid (malic acid), malonic acid, malonic acid, succinic acid, maleic acid, maleic acid, fumaric acid, tartaric acid, tartaric acid, citric acid , Benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicycin Organic acids such as acid (salicylic acid). Acid addition salts can be reconverted to free base by treatment with a suitable base. Specifically, the acid addition salt of the active agent in the present invention is preferably a halide salt that can be prepared using hydrochloric acid or bromic acid.
[120] In contrast, the preparation of basic salts of acid moieties, which may be present in phosphodiesterase inhibitors, may be prepared by pharmaceutically acceptable bases such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, trimethylamine, It is prepared according to similar methods used. In particular, preferred basic salts in the present invention are basic metal salts such as sodium or copper salts.
[121] Preparation of esters involves the functionalization of hydroxyl and / or carboxyl groups which may be present in the molecular structure of the drug. Esters are generally moieties derived from acyl-substituted derivatives of free alcohol groups, such as carboxylic acids of the general formula RCOOH (R is alkyl, more preferably low alkyl). to be. If desired, the ester can be reconverted to free acid using hydrocracking or hydrolysis methods. In addition, amides and prodrugs may be prepared with reference to techniques or related documents known in the art. For example, the amide may be prepared from an ester using a suitable amine reactant or from anhydride or acid chloride by reacting with ammonia or low alkyl amines. The prodrugs can generally be made into compounds that are therapeutically inactivated until modified by the individual's metabolic system by covalent attachment to the moiety.
[122] Since the active agent is in its native chiral form and may be in optically isomerically pure form or in a racemic mixture, the drug may be used as a racemate or in an optically isomerically pure form to Can be mixed.
[123] The active agent administered is also cosmetically or "cosmecuetically" effective rather than pharmacologically active. Such active agents are, for example, alpha hydroxyacids, alpha ketoacids, polymeric hydroxyacids, moisture agents, collagen, marine extracts (marine) As a extract, ascorbic acid (vitamin C), α-tocopherol (vitamin E), β-tocopherol (beta) , γ- tocopherol (γ-tocopherol), δ- tocopherol (δ-tocopherol), ε- tocopherol _{(ε-tocopherol), ζ 1} - tocopherol _{(ζ 1 -tocopherol), ζ 2} - tocopherol (ζ ₂ -tocopherol), antioxidants such as η-tocopherol and retinol (vitamin A), and / or cosmetically acceptable salts, esters, amides or other derivatives thereof. Preferred tocopherol compounds are α-tocopherols. Emphasizingly cosmetic preparations include substances described in, for example, International Patent Publication Nos. WO 94/00098 and WO 94/00109, which can improve oxygen supply to skin tissue. Sunscreens may also be included.
[124] Formulations:
[125] The method of delivery of the active agent may vary, but the application of a drug delivery system or agent containing a hydroxide-releasing agent to a predetermined site of skin or other tissue is essentially sufficient for a time sufficient to provide a desirable effect on the topical site or systemic. It may include doing. The delivery method may be a direct application of a composition such as an ointment, gel, cream or the like or the use of a drug delivery device. In either case, the hydroxide-releasing agent produces hydroxide ions and therefore water must be included to enhance the influx of active agent through the patient's body surface. Thus, the formulation or drug source is in an aqueous or non-aqueous form containing water and used in combination with an occulusive overlayer so that water evaporated from the body surface can be maintained in the formulation or transdermal system during drug administration. Do it. However, in some cases, such as with a closure cover, a non-aqueous formulation may be used with or without the closure cover.
[126] Preferred formulations are such as ointments, creams, gels, lotions, pastes and the like. As can be appreciated in the field of pharmaceutical preparations, ointments are generally semisolid preparations based on petrolatum or other petroleum derivatives. As will be appreciated by those skilled in the art, the base of the particular ointment used may be prepared for optimal drug delivery, and preferably for other desirable qualities such as softeners and the like. By use with other carriers, excipients, the ointment base must be inert, stable, nonirritating and nonsensitizing. As described in pages 1399-1404 of Remington: The Science and Practice of Pharmacy, 19th Ed. (Easton, PA: Mack Publishing Co., 1995), the base of the ointment can be divided into four classes. Oleaginous bases; Emulsifiable bases; Emulsion bases; And water-soluble bases. Oily ointment bases include, for example, vegetable oils, fats from animals and semisolid hydrocarbons from petroleum. Emulsified ointment bases, also known as absorbent ointment bases, contain little or no water and include hydroxystearin sulfate, anhydrous lanolin and hydrophilic petrolatum and the like. Emulsion ointment bases are water-in-oil (W / O) emulsions or oil-in-water (O / W) emulsions, for example cetyl alcohol, glyceryl monostearate, lanolin and stearic acid (stearic acid). Preferred water soluble ointment bases are prepared from polyethylene glycols of various molecular weights; See again Remington: The Science and Practice of Pharmacy .
[127] As is known to those skilled in the art, creams are oil-in-water or water-in-oil, viscous liquids or semisolid emulsions. The cream base is water-washable, oil phase, emulsifier, and contains an aqueous state. Or the oil phase, also referred to as the "internal state", generally includes fatty alcohols such as petrolatum and cetyl alcohol or stearyl alcohol. The aqueous state, although not essential, is usually bulkier than the oil phase and generally contains a humectant. Emulsifiers in cream formulations are generally nonionic, anionic, cationic or amphoteric surfactants. As will be appreciated by those skilled in the art of pharmaceutical formulations, the gel is a semisolid, suspension-type system. Single-phase gels generally contain organic polymers that are substantially uniformly distributed through the liquid carrier in an aqueous state, and preferably comprise alcohols, and optionally oils. "Organic polymer", that is, the gel agent (gelling agents) are cross-coupled, such as the "carbomer (carbomer)," kind of polymers such as Carbopol ^{(Carbopol ),} Which are commercially available under the trademark carboxy polyalkylene (carboxypolyalkylenes) Preferred acrylic acid polymers are preferred. Hydrophilic polymers such as polyethylene oxide, polyoxyethylene-polyoxypropylene copolymers, and polyvinyalcohols; Cellulose systems such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate and methyl cellulose polymer; Gums such as tragacanth and xanthan gums; Sodium alginate; And gelatin are preferred. In order to prepare the gel uniformly, a dispersing agent such as alcohol or glycerin may be added, or the gelling agent may be dispersed by grinding, mechanical mixing or stirring or a combination thereof.
[128] Preferred lotions for the delivery of cosmetic agents are liquid or semisolid formulations which are prepared to be applied to the surface of the skin without friction, and in which solid particles comprising the active agent are generally present in a water or alcohol base. The lotion is generally a solid suspension and for the purposes of the present invention preferably comprises an oily oily emulsion. Lotion is the preferred formulation for treating large areas of the body because fluid compositions are easier to apply. In general, insoluble materials in lotions need to be finely divided. Generally, lotions contain suspending agents to produce better dispersants as well as compounds useful for localizing and retaining active agents in contact with the skin, such as methylcellulose, sodium carboxymethyl-cellulose, and the like. do.
[129] The paste is in the form of a semisolid preparation in which the active agent is suspended in a suitable base. Depending on the nature of the base, the paste is divided between fat pastes or made from a single-phase aqueous gel. In fat pastes the base is generally such as petrolatum or hydrophilic petrolatum. Pastes made from single-phase aqueous gels generally include carboxymethylcellulose or the like as a base.
[130] The formulations may also be prepared with liposomes, colloids and microspheres. Liposomes are fine vacuoles with a lipid wall comprising a lipid bilayer and may be used as drug delivery systems in the present invention. Liposomal preparations are generally preferred for poorly soluble or inexpensive pharmaceutical preparations. Liposomal preparations used in the present invention are cationic (with positive charges), anionic (with negative charges) and neutral preparations. Cationic liposomes are readily available. For example, N [1-2,3-dioleyloxy) propyl] -N, N, N-triethylammonium (N [1-2-3-dioleyloxy) propyl] -N, N, N-triethylammonium (DOTMA )), liposomes can be purchased in repo pectin ^{(Lipofectin )} trademark (GIBCO BRL, Grand Island, NY ). Similarly, anionic and neutral liposomes can be readily purchased from, for example, Avanti Polar Lipids (Birmingham, AL), or readily prepared using commercially available materials, among which phosphatidyl choline (phosphatidyl choline), cholesterol (cholesterol), phosphatidyl ethanolamine, dioleoylphosphatidyl choline (DOPC), dioleoylphosphatidyl glycerol (DOPG), dioleoyl phospho Amines (dioleoylphoshatidyl ethanolamine (DOPE)), etc. These materials can be mixed with DOTMA at appropriate ratios, and methods for making liposomes using these materials are known in the art.
[131] It is known to those skilled in the art that the micelles contain surfactant molecules whose polar heads form the outer spherical surface, while the hydrophobic hydrocarbon chains are arranged towards the center of the sphere to form a core. have. Colloidal particles are formed in aqueous solutions containing surfactants at high concentrations so that colloidal particles occur naturally. Surfactants useful for forming colloids include, but are not limited to, potassium laurate, sodium octane sulfonate, sodium decane sulfonate, and sodium dodecane sulfo Sodium dodecane sulfonate, sodium lauryl sulfate, docuate sodium, dodecyltrimethylammonium bromide, dodecyltrimethylammonium bromide, tetradecyltrimethyl Ammonium bromide, tetratradecyltrimethyl-ammonium chloride, dodecylammonium chloride, dodecylammonium chloride, polyoxy 8 dodecyl ether ), Polyoxy 12 dodecyl eth er), nonoxynol 10 and nonoxynol 30. Colloidal formulations may be used in the present invention in combination with formulations that can be applied to the source or body surface of a topical or transdermal delivery system.
[132] Microspheres may also be included in the formulations or drug delivery systems of the present invention. Like liposomes and colloids, microspheres essentially encapsulate a drug or drug-containing agent. Although not essential, they can be formed from lipids, preferably from charged lipids such as phospholipids. Preparations of lipid microspheres are known to those skilled in the art and are described in the appropriate textbooks and literature.
[133] As is known to those skilled in the art, various additives may be included in the topical formulations. For example, a solvent containing a relatively small amount of alcohol can be used to dissolve any drug substance. Other optional additives include opacifiers, antioxidants, fragrances, colorants, gelling agents, thickening agents, stabilizers, surfactants ( surfactants). Other agents, such as antimicrobials, may also be added to prevent rot during storage, ie to inhibit the growth of microorganisms such as yeast and mold. Suitable antimicrobials include methyl and propyl esters of p-hydroxybenzoic acid (ie, methyl and propyl parabens), sodium benzoate, sorbic acid, imideurea ( imidurea), and combinations thereof.
[134] For drugs with particularly low penetration rates through skin or mucosal tissues, it would be desirable to include a secondary penetration enhancer in addition to the hydroxide-releasing agent in the formulation, although it is preferred that the hydroxide-releasing agent be administered without other penetration enhancers. As with the hydroxide-releasing agent itself, any other enhancer should minimize the possibility of skin damage, irritation and systemic toxicity. Suitable secondary reinforcing agents (or "adjuvant-enhancing agents") are diethylene glycol monoethyl ether (commercially available as Transcutol ⁷ ) and diethylene glycol monomethyl ether. ether); Sodium laurate, Sodium lauryl sulfate, Cetyltrimethylammonium bromide, Benzalkonium chloride, Poloxamer (231,182, 184), Twin Surfactants such as Tween (20, 40, 60, 80) and lecithin (see US Pat. No. 4,783,450); Alcohols such as ethanol, propanol, octanol, benzyl alcohol and the like; Fatty acids such as lauric acid, oleic acid and valeric acid; Fatty acid esters such as isopropyl myristate, isopropyl palmitate, methylpropionate, and ethyl oleate; Polyols and esters thereof such as polyethylene glycol and polyethylene glycol monolaurate (PEGML; see US Pat. No. 4,568,343); Urea, dimethylacetamide (DMA), dimethylformamide (DMF), 2-pyrrolidone, 1-methyl-2-pyrrolidone (1-methyl- Amides and other nitrogen-containing compounds such as 2-pyrrolidone, ethanolamine, diethanolamine and triethanolamine; Terpenes; Alkanones; And organic acids, specifically, citric acid and succinic acid, but are not limited thereto. Less preferred, it may also be used Azon ^{(Azone )} And DMSO and C ₁₀ MSO, such as sulfoxide (sulfoxide). As mentioned earlier, Smith et al., Percutaneous Penetration Enhancers , eds. Smith et al. (CRC Press, 1995) provide an excellent overview of this field and provide for possible secondary reinforcing agents used in conjunction with the present invention. More information is provided.
[135] Formulations may also include irritation-releasing additives that reduce or eliminate the likelihood of skin irritation or skin damage caused by the drug, enhancer or other components of the formulation. Suitable stimulation-releasing additives include, for example, alpha-tocopherol; Monoamine oxidase inhibitors, specifically phenyl alcohols such as 2-phenyl-1-ethanol; Glycerin; Salicylic acids and salicylates; Ascorbic acids and ascorbates; Ionophores such as monensin; Amphiphilic amines; Ammonium chloride; N-acetylcysteine; Cis-urocanic acid; Capsaicin; And chloroquine. If added, the irritation-releasing additive may be added to the formulation of the present invention at a concentration effective to alleviate skin damage or irritation, preferably no more than about 20% by weight of the formulation, more preferably no more than about 5% by weight. Can be added.
[136] The concentration of the active agent in the formulation can vary widely and can include a wide variety of factors, including disease or treatment conditions, the nature and activity of the active agent, the desired effect, possible adverse reactions, the ability and speed of the active agent for its intended purpose, and It depends on other factors within the specific knowledge of the patient and physician. Preferred formulations range from about 0.5% to 50% by weight, or optionally contain from about 10% to 30% by weight of active agent.
[137] DRUG DELIVERY SYSTEMS:
[138] Preferred and alternative methods include the use of drug delivery systems, such as topical or transdermal “patches”. Wherein the active agent is contained within the laminated structure attached to the skin. In such a structure, the drug composition is included in a "source" located above one layer or the backing layer. The stack structure may be one source or several.
[139] In one embodiment of the invention, the source comprises a polymer matrix of a pharmaceutically acceptable adhesive that allows the system to adhere to the skin while the drug is delivered; The adhesive is preferably a pressure-sensitive adhesive (PSA) suitable for long term skin contact and must be physically and chemically compatible with the active agent, hydroxide-releasing agent and any carrier, excipient or other additive. . Examples of suitable adhesives include, but are not limited to, the following: polyethylenes; Polysiloxanes; Polyisobutylenes; Polyacrylates; Polyacrylamides; Polyurethanes; Plasticized ethylene-vinyl acetate copolymers; And polyisobutene, polybutadiene, polystyrene-isoprene copolymers, polystyrene-butadiene copolymers, and neoprene (polychloroprene) Tacky rubbers. Preferred adhesives are polyisobutylene.
[140] The backing layer functions as the primary structural component of the transdermal system and provides the device with elasticity, preferably closure. The material used for the support layer cannot absorb the components of the drug, hydroxide-releasing agent or formulation contained in the device and must be inert. The support layer preferably comprises a flexible elastomer that acts as a replenishment lid to prevent loss of drugs and / or excipients by delivery through the top layer of the patch. It would also be desirable to provide a degree of occlusion to the system as the backing layer is hydrated during use of the skin surface covered by the patch. Substances used in the occlusion layer allow the device to follow the contours of the skin and, due to the difference in skin or device flexibility or resiliency, have some potential for the device to deviate from the skin, which is a mechanical burden. Make sure that it can be worn securely on parts of the skin, such as fractures or other bends. The materials used in the support layer are, as described above, although occluded support layers are preferred, they are occluded or permeable, and generally are synthetic polymers (eg polyester, polyethylene, polypropylene, polyurethane, polyvinyridine chloride and poly). Ether amides), natural polymers (such as cellulose based materials), or macroporous textiles or nonwovens.
[141] During the storage period prior to use, the laminate structure includes a release liner. Immediately before use, the bilayer is removed from the device to allow the system to adhere to the skin. The release membrane should be made of drug / excipient impermeable material and should only be a component that protects the device before application and can be discarded. Preferably the release membrane consists of a substance that does not penetrate the pharmacologically active agent and the hydroxide-releasing agent and can be easily removed from the transdermal patch before use.
[142] In another embodiment, the drug-containing reservoir and skin contact adhesive are present in separate and distinct layers with the adhesive under the source. In this case the source may be a polymeric matrix as described above. Alternatively, the source may comprise a liquid or semisolid formulation contained in the occluded portion or "pouch", or may be a hard hydrogel source, or may have other forms. Hydrogel sources are particularly preferred in the present invention. As will be appreciated by those skilled in the art, hydrogels are polymer networks that are insoluble in water but expand upon absorption of water. That is, the hydrogel contains a hydrophilic functional group capable of absorbing water, but the hydrogel consists of a crosslinked polymer which becomes insoluble in an aqueous state. In general, the hydrogel is polyurethane, polyvinyl alcohol, polyacrylic acid, polyoxyethylene, polyvinylpyrrolidone, poly (hydroxyethyl methacryl) Consisting of crosslinked hydrophilic polymers, copolymers or combinations thereof such as poly (hydroxyethyl methacrylate, poly (HEMA)). Specifically, preferred hydrophilic polymers are HEMA and polyvinylpyrrolidone. Copolymer.
[143] For example, additional layers may be present in the drug delivery system of the invention, such as an intermediate abric layer and / or a rate-controlling membrane. The fabric layer can be used to facilitate assembly of the device, and the rate-controlling layer can be used to control the rate at which components penetrate in the device. The component may be a drug, hydroxide-releasing agent, additional enhancer, or some other component included in the drug delivery system.
[144] If present, the rate-controlling membrane can be included in one or more skin portions of the drug source in the system. Substances that can be used in the membrane are selected to limit the influx of one or more components contained in the drug formulation. Representative materials that can be used in the rate-controlling membrane are polyolefins such as polyethylene and polypropylene, polyamides, polyesters, ethylene-ethacrylate copolymers. ), Ethylene-vinyl acetate copolymer, ethylene-vinyl methylacetate copolymer, ethylene-vinyl ethylacetate copolymer, ethylene-vinyl propyl Ethylene-vinyl propylacetate copolymer, polyisoprene, polyacrylonitrile, ethylene-propylene copolymer, and the like.
[145] In general, the lower surface of the transdermal device, ie the portion in contact with the skin, has an area in the range of about 5 cm 2 to 200 cm 2, preferably 5 cm 2 to 100 cm 2, more preferably 20 cm 2 to 60 cm 2. Of course, the area will vary depending on the amount of drug delivered and the influx of drug through the body surface. Large patches are needed to accommodate many drugs, while small patches can be used to accommodate small amounts of drugs and / or drugs with relatively high penetration rates.
[146] The drug delivery system can be prepared using conventional coating or lamination techniques known to those skilled in the art. For example, an adhesive matrix system can be made by stacking the release membrane and then preparing a fluid mixture of adhesive, drug and excipient on the support layer. Similarly, an adhesive mixture may be made on the release film following lamination of the support layer. Alternatively, the drug source may be prepared without drugs or additives, and then loaded by "soaking" into the drug / excipient mixture. Generally, transdermal systems of the present invention are prepared by solvent evaporation, film casting, melt extrusion, thin film lamination, die cutting, and the like. Hydroxide-releasing agents will generally be incorporated into the device during patch manufacture rather than involved in the manufacture of the device. Therefore, for acidic addition salts of basic drugs (eg, hydrochlorides of amine drugs such as phenylpropanolamine hydrochloride), the hydroxide-releasing agent will neutralize the drug during the manufacture of the drug delivery system and consequently infiltration The hydroxide-releasing agent provided as an adjuvant results in a drug delivery system in which excess nonionic, neutral forms of the drug are present. For nonionic acidic drugs, the hydroxide-releasing agent can neutralize the drug by changing the drug into a ionic drug in salt form.
[147] In a preferred drug delivery system, an adhesive overlay that supports the drug delivery system is used to make the patch to the body surface more stable. The size of the overlay is larger than the drug source so that the adhesive can contact the body surface. An overlayer is needed because the adhesive / drug source layer may lose adhesion after several hours after the drug is applied by hydration. By combining the adhesive overlay, the delivery system remains in place for the required time.
[148] As will be appreciated by those skilled in the art of transdermal drug delivery, other types and configurations of transdermal drug delivery systems can be used in connection with the methods of the present invention, namely the use of hydroxide-releasing agents as penetration enhancers. See, eg, Ghosh, Transdermal and Topical Drug Delivery Systems (Interpharm Press, 1997), in particular Chapters 2 and 8.
[149] As a locally applied formulation according to the present invention, a composition containing a drug and a hydroxide-releasing agent in a drug source of a lamination system may contain a number of components. In some cases, the drug and hydroxide-releasing agent may be delivered "neat", ie without additional liquid. In most cases, however, the drug will be dissolved, dispersed or suspended in a suitable pharmaceutically acceptable excipient, preferably a solvent or gel. Other ingredients that may be included in the present invention are preservatives, stabilizers, surfactants and the like.
[150] Accordingly, the present invention provides new and highly effective means of increasing the influx of active agents through the body surface (skin or mucosal tissue) of the human body or animal. Hydroxide-releasing agents, as discussed herein, are employed in specific amounts relative to the agent or drug source, and include fatty acids, free bases, acidic addition salts of basic drugs, basic addition salts of acidic drugs, and non-ionized drugs. It can be used as a penetration enhancer with a wide range of drugs and drug types, including peptides and proteins. Surprisingly, the increased penetration by the present invention did not involve any notable tissue damage, irritation or sensitization. Therefore, it can be seen that the present invention is an important advance in the field of drug delivery.
[151] While certain preferred embodiments have been described so that the invention may be understood, they are intended to illustrate the invention and the scope of the invention is not so limited. Other aspects, advantages, and modifications will be apparent to those skilled in the art. In addition, the practice of the present invention may use the prior art of drug formulations, in particular topical or transdermal drug formulations, without particular mention. Such techniques are explained in detail in the literature. Goodman & Gilman ( The Pharmacological Basis of Therapeutics , 9th Ed., New York: McGraw-Hill, 1996), as well as Remington: The Science and Practice of Pharmacy , mentioned above. Reference.
[152] The following examples are provided to those skilled in the art to describe and disclose how to make and use the compounds of the invention, and are not intended to limit the scope of the invention to what their inventions are. I tried to be accurate about numbers (eg amounts, temperature, etc.), but I think there are some mistakes and errors. Unless otherwise specified, parts are parts by weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric.
[167] <Example 1>
[168] In vitro skin penetration experiments were performed using three estradiol transdermal systems. The formulation used to prepare this system is shown in Table 1. In this table, each component of the formulation is represented by weight and weight percent. The weight of sodium hydroxide for Formulations # Est-P18, # Est-P19 and # Est-P20, respectively, was 0 g, 0.0155 g and 0.025 g. Each formulation was coated on a release membrane and dried in an oven at 55 ° C. for 2 hours to remove water and other solvents. The dried DIA / release film release film was laminated to a backing film. The support layer / DIA / release film stack was then cut into 11/16 inch diameter discs. The theoretical weight percentages for each component after drying (measured assuming that all volatile components were completely removed during the drying process) are shown in Table 2.
[169] In vitro penetration of estradiol from such thin plates through human cadaver skin was performed using a Franz-type diffusion cell having a diffusion area of 1 cm 2. The volume of the receiver solution was 8 ml. The skin of the human body is cut to size and placed on a flat surface with the stratum corneum face up. The release film was peeled off from the thin layer. The backing layer / DIA film was placed and pressed onto the skin with the adhesive side against the stratum corneum. The skin / adhesive / support layer was clamped between the supply and donor chambers of the diffusion cell on the skin side against the aqueous solution. Three diffusion cells were used for each formulation.
[170] The cell was filled with 10% ethanol / 90% water solution. The aqueous solution was completely removed and replaced with fresh ethanol / water solution at each time point. Samples were analyzed by HPLC to determine the concentration of estradiol in the aqueous solution. Accumulation of estradiol penetrated through human carcass skin was calculated using the estradiol concentration measured in the aqueous solution. This was created at each time point and shown in FIG.
[171] The pH of the patch was measured using the following procedure. A round patch of 2.5 cm 2 was taken. 10 ml of pure water was pipetted into a glass vial and a stirring rod was added. The membrane was removed from the patch and placed with the patch in the vial. The vial was then placed on a stir plate and the water / patch / membrane mixture was stirred for 5 minutes. After stirring the membrane was removed from the vial and discarded. The vial was placed again on the stir plate and stirring continued for an additional 18 hours. After 18 hours, the stir bar was removed from the vial and the pH of the solution was measured using a calibrated pH meter.
[172] The measured pH for the estradiol transdermal system is shown in Table 3.
[173] Weight and weight of each component (based on total solution weight) for three estradiol transdermal administration systemsEst-P18Est-P19Est-P20 Estradiol0.0313 g (0.5%)0.0322 g (0.5%)0.0308 g (0.5%) NaOH00.0155 g (0.3%)0.025 g (0.4%) DI water00.4155 g (6.9%)0.425 g (7.0%) PIB Adhesive (30% Solids)4 g (66.3%)4 g (66.0%)4 g (65.8%) Methyl alcohol1.8 g (29.8%)1.4 g (23.1%)1.4 g (23.0%) ethanol0.2 g (3.3%)0.2 g (3.3%)0.2 g (3.3%)
[174] PIB = Polyisobutylene
[175] Weight and theoretical weight percentage of each component present in the dried film for three estradiol transdermal administration systemsEst-P18Est-P19Est-P20 Estradiol0.0313 g (2.5%)0.0322 g (2.6%)0.0308 g (2.5%) NaOH00.0155 g (1.2%)0.025 g (2.0%) PIB adhesive1.2 g (97.5%)1.2 g (96.2%)1.2 g (95.6%)
[176] PH of three estradiol transdermal administration systemsEst-P18Est-P19Est-P20 pH7.228.758.90
[177] At 24 hours, the accumulation of estradiol penetrated through human carcass skin increased from 0.22 µg / cm 2 to 7.01 µg / cm 2 when the calculated sodium hydroxide concentration in the dried patch increased from 0% to 2.0%. . The accumulation of estradiol penetrated through human corpse skin at 24 hours from a system containing 1.2% NaOH (Est-P19) was 4.55 μg / cm 2, which is a formulation without NaOH (0.22 μg / cm 2, # Est About 20 times higher than -P18). The pH of the estradiol patch measured using the procedure shown above increased from 7.22 to 8.90 when the sodium hydroxide concentration calculated from the dried patch increased from 0% to 2.0%.
[178] <Example 2>
[179] In vitro skin penetration experiments were performed using four ketoprofen transdermal systems. The formulation used to prepare this system is shown in Table 4. In this table, each component of the formulation is represented by weight and weight percent. The weight of sodium hydroxide for Formulations # Keto-P3H16, -P3H17, -P3H18 and -P3H19 respectively was 0 g, 0.19 g, 0.215 g and 0.225 g. Each formulation was coated on a release membrane and dried in an oven at 55 ° C. for 2 hours to remove water and other solvents. The dried DIA / release film release film was laminated to a backing film. The support layer / DIA / release film stack was then cut into 11/16 inch diameter discs. The theoretical weight percent of each component after drying (measured assuming all volatile components were completely removed during the drying process) is shown in Table 5.
[180] In vivo infiltration of ketoprofen from this thin plate through the skin of the human cadaver was performed using a Franz diffusion cell with a diffusion area of 1 cm 2. The skin of the human body is cut to a suitable size and placed on a flat surface with the stratum corneum face up. The release film was peeled off from the thin layer. The support layer / DIA film was placed and pressed onto the skin with the adhesive side against the stratum corneum. The skin / adhesive / support layer was clamped between the supply and reception chambers of the diffusion cells on the skin side against the receiving solution. Three diffusion cells were used for each formulation.
[181] General saline was used as the aqueous solution. The volume of the aqueous solution was 8 ml. The whole aqueous solution was collected and replaced with fresh saline at each time. The collected aqueous solution was analyzed by HPLC to determine the concentration of ketoprofen. The accumulation of ketoprofen penetrated through the skin of the human body was calculated using the ketoprofen concentration measured in the aqueous solution. This was made for each elapsed time and is shown in FIG.
[182] Ketoprofen is a free acid and therefore reacts with NaOH. The concentration of NaOH in the system after the reaction is completed depending on the amount of ketoprofen added. The NaOH concentration remaining after the reaction is completed is defined as 'excess NaOH concentration', which is calculated by the following equation.
[183] [ _Excess NaOH] = [ _Total NaOH]-[ _{Amount required for neutralization of} NaOH]
[184] Excess NaOH concentrations for the four ketoprofen systems, # Keto-P3H16, -P3H17, -P3H18 and -P3H19 were calculated and shown in Table 6.
[185] The pH of each patch was measured using the procedure of Example 1. The results are shown in Table 6.
[186] Weight and weight percent of each component (based on total solution weight) for four ketoprofen transdermal administration systemsKeto-P3H16Keto-P3H17Keto-P3H18Keto-P3H19 Ketoprofen1.2 g (16.7%)1.2 g (15.8%)1.2 g (15.7%)1.2 g (15.7%) NaOH00.19 g (2.5%)0.215 g (2.8%)0.225 g (2.9%) DI water00.19 g (2.5%)0.215 g (2.8%)0.225 g (2.9%) PIB adhesive (30% solids)4 g (55.6%)4 g (52.8%)4 g (52.4%)4 g (52.3%) Methyl alcohol2 g (27.8%)2 g (26.4%)2 g (26.2%)2 g (26.1%)
[187] Weight and theoretical weight percentage of each component present in the dried film for four ketoprofen transdermal administration systemsKeto-P3H16Keto-P3H17Keto-P3H18Keto-P3H19 Ketoprofen1.2 g (50%)1.2 g (45.9%)1.2 g (45.9%)1.2 g (45.7%) NaOH00.19 g (7.3%)0.215 g (8.2%)0.225 g (8.6%) PIB adhesive1.2 g (50%)1.2 g (46.3%)1.2 g (45.9%)1.2 g (45.7%)
[188] Excess NaOH Concentration and pH of Four Ketoprofen Transdermal Administration SystemsKeto-P3H16Keto-P3H17Keto-P3H18Keto-P3H19 Excess NaOH Concentration 0.05%1.00%1.38% pH3.688.6010.1010.57
[189] Although patch # Keto-P3H17 containing 7.3% NaOH (Table 5), the accumulation of ketoprofen (61.7 μg / cm 2, FIG. 2) that penetrated through the skin of the human body at 24 hours elapsed was NaOH free. Only slightly higher than the formulation (Keto-P3H16, 35.2 μg / cm 2). This would be due to the consumption of NaOH by the reaction between NaOH and ketoprofen, which reduced NaOH concentration to only 0.05% as excess NaOH concentration (Table 6). These results show that the penetration of ketoprofen can be enhanced with excess NaOH concentrations as low as 0.05%.
[190] At 24 hours, the accumulation of ketoprofen penetrated through the skin of the human body increased from 61.7 µg / cm 2 to 402.7 µg / cm 2 when the excess NaOH concentration calculated in the dried patch increased from 0.05% to 1.38%. It became. The accumulation of ketoprofen penetrated through the skin of the human body at 24 hours after preparation (Keto-P3H18, 315.8 μg / cm 2) containing 1.0% excess NaOH resulted in a preparation containing excess NaOH concentration of 0.05% ( Keto-P3H17, 61.7 μg / cm 2) about 5 times higher.
[191] The pH of the ketoprofen patch measured using the procedure of Example 1 increased from 8.60 to 10.57 when the excess NaOH concentration calculated from the dried patch increased from 0.05% to 1.38%.
[192] <Example 3>
[193] In vitro skin penetration experiments were performed using four phenylpropanolamine hydrochloride transdermalsystems. The formulation used to prepare this system is shown in Table 7. In this table, each component of the formulation is represented by weight and weight percent. The weights of sodium hydroxide for Formulations # PPA-N7, -N1, -N2 and -N5 respectively were 0g, 0.165g, 0.195g and 0.23g. Each formulation was coated on a release membrane and dried in an oven at 55 ° C. for 2 hours to remove water and other solvents. The dried DIA / release film release film was laminated to a backing film. The support layer / DIA / emission film stack was then cut into 11/16 inch diameter round discs. The theoretical weight percent of each component after drying (measured assuming that all volatile components were completely removed during the drying process) is shown in Table 8.
[194] Ex vivo infiltration of PPA-HCl from this thin plate through human cadaver skin was performed using a Franz-type diffusion cell with a diffusion area of 1 cm 2. The volume of the receiver solution was 8 ml. The skin of the human body is cut to a suitable size and placed on a flat surface with the stratum corneum face up. The release film was peeled off from the thin layer. The support layer / DIA film was placed and pressed onto the skin with the adhesive side against the stratum corneum. The skin / adhesive / support layer was clamped between the supply and reception chambers of the diffusion cells on the skin side against the receiving solution. Three diffusion cells were used for each formulation.
[195] The cell was filled with DI water. The aqueous solution was completely removed and replaced with fresh DI water at each time. Samples were analyzed by HPLC to determine the concentration of PPA-HCl in the aqueous solution. The accumulated amount of PPA-HCl penetrated through the skin of the human body was calculated using the PPA-HCl concentration measured in the aqueous solution. This was created for each elapsed time and is shown in FIG.
[196] PPA-HCl is a free base acid addition salt, so it reacts with NaOH. The concentration of NaOH in the system after the reaction is completed depending on the amount of PPA-HCl added. The NaOH concentration remaining after the reaction is completed is defined as 'excess NaOH concentration' and is calculated as described in the above example. The excess NaOH concentrations for the four PPA-HCl systems, # PPA-N7, -N1, -N2 and -N5 were calculated and shown in Table 9.
[197] The pH of each patch was measured by the method of Example 1. The results are shown in Table 6.
[198] Weight and weight percent of each component (based on total solution weight) for four PPA-HCl transdermal administration systemsPPA-N7PPA-N1PPA-N2PPA-N5 PPA-HCl0.75 g (8.5%)0.75 g (8.2%)0.75 g (8.1%)0.75 g (8.1%) NaOH00.165 g (1.8%)0.195 g (2.1%)0.23 g (2.5%) DI water1.1 g (12.4%)1.265 g (13.8%)1.295 g (14.0%)1.33 g (14.3%) Propylene glycol0.5 g (5.6%)0.5 g (5.4%)0.5 g (5.4%)0.5 g (5.4%) Methyl alcohol1 g (11.3%)1 g (10.9%)1 g (10.8%)1 g (10.7%) Heptane1.5 g (16.9%)1.5 g (16.3%)1.5 g (16.2%)1.5 g (16.1%) PIB Adhesive (30% Solids)4 g (45.2%)4 g (43.6%)4 g (43.3%)4 g (43.0%)
[199] Weight and theoretical weight percentage of each component present in the dried film for the PPA-HCl transdermal administration systemPPA-N7PPA-N1PPA-N2PPA-N5 PPA-HCl0.75 g (30.6%)0.75 g (28.7%)0.75 g (28.4%)0.75 g (28.0%) NaOH00.165 g (6.3%)0.195 g (7.4%)0.23 g (8.6%) PIB adhesive1.2 g (49.0%)1.2 g (45.9%)1.2 g (45.4%)1.2 g (44.8%) Propylene glycol0.5 g (20.4%)0.5 g (19.1%)0.5 g (18.9%)0.5 g (18.7%)
[200] Excess NaOH Concentration and pH of Four PPA-HCl Transdermal SystemsPPA-N7PPA-N1PPA-N2PPA-N5 Excess NaOH Concentration 0.20%1.33%2.62% pH7.3310.0810.1610.88
[201] Although patch # PPA-N1 containing 6.3% NaOH (Table 8), the accumulation of PPA-HCl (1.35 mg / cm 2, FIG. 3) penetrated through the skin of the human body 24 hours after the preparation was Only slightly higher than the formulation without NaOH (PPA-N7, 0.56 mg / cm 2). This would be due to the consumption of NaOH by the reaction between NaOH and PPA-HCl, as shown in Table 9 which reduced NaOH concentration to only 0.20% as excess NaOH concentration. These results show that the permeation of PPA-HCl can be improved with excess NaOH concentration as low as 0.20%.
[202] At 24 hours, the accumulation of PPA-HCl penetrated through the skin of the human body increased from 1.35 mg / cm 2 to 5.99 mg / cm 2 when the calculated excess NaOH concentration in the dried patch increased from 0.20% to 2.62%. It became. The accumulated amount of PPA-HCl penetrated through the skin of the human body at 24 hours from the preparation containing 1.33% of excess NaOH (PPA-N2, 5.2 mg / cm 2) was determined to contain the excess NaOH concentration of 0.20% ( PPA-N1, 1.35 mg / cm 2) about 5 times higher.
[203] The pH of the PPA-HCl patch increased from 10.08 to 10.88 when the excess NaOH concentration calculated in the dried patch increased from 0.20% to 2.62%. The irritation of the skin can be related to the pH of the patch and depends on the excess NaOH concentration.
[204] <Example 4>
[205] Studies on the irritation of human skin were performed using the seven transdermal administration systems listed below.
[206] Patch # Keto-IT1 (does not contain ketoprofen and NaOH)
[207] Patch # Keto-IT2 (containing ketoprofen, no NaOH)
[208] Patch # Keto-IT7
[209] Patch # Keto-IT8
[210] Patch # Keto-IT9
[211] Patch # Keto-IT10
[212] Patch with mineral oil
[213] Patches containing mineral oil were used as controls and were occluded chambers (Hilltop, Cincinnati, OH) containing mineral oil placed with paper tape. The following procedure was used to make the system except the system containing mineral oil. Formulations prepared with this system are shown in Table 10, which includes the weight and weight percent of each component in the formulation. The sodium hydroxide in each of the # Keto-IT7, -IT8, -IT9 and BIT10 formulations was 0.6 g, 0.65 g, 0.69 g, 0.73 g. Each formulation was coated on a release membrane and dried in an oven at 55 ° C. for 2 hours to remove water and other solvents. The dried DIA / release film release film was laminated to a backing film. The support layer / DIA / release film stack was then cut into 2 inch diameter round discs. The theoretical weight percent of each component after drying is shown in Table 2, which is calculated assuming that all volatile components have been completely removed during drying.
[214] Healthy people were also included in skin irritation experiments. Each subject had the seven patches listed above on their arms for 24 hours. To make the system safe and blocked for 24 hours, a 7/8 inch diameter adhesive film was applied over each system except for the mineral oil patch. After 24 hours, the patch was removed and the skin was recorded in 0-4 steps. The recorded steps are listed below. The skin was recorded again at 48 hours.
[215] 0 = negative
[216] + = Unclear response (0.5)
[217] 1 = erythema
[218] 2 = erythema and hardening
[219] 3 = erythema, hardening and hydrophobic
[220] 4 = blister
[221] Skin penetration experiments were performed from # Keto-IT7, -IT8, -IT9 and BIT10 formulations. Franz diffusion cells with a diffusion area of 1 cm 2 were used for the experiment. The skin of the human body is cut to a suitable size and placed on a flat surface with the stratum corneum face up. The release film was peeled off from the thin layer. The support layer / DIA film was placed and pressed onto the skin with the adhesive side against the stratum corneum. The skin / adhesive / support layer was clamped between the supply and reception chambers of the diffusion cells on the skin side against the receiving solution. Three diffusion cells were used for each formulation.
[222] General saline was used as the aqueous solution. The volume of the aqueous solution was 8 ml. The aqueous solution was collected at 24 hours and the concentration of ketoprofen was analyzed by HPLC. The amount of ketoprofen transmitted through the skin of the human body was calculated using the ketoprofen concentration measured in the aqueous solution. This is shown in Table 12.
[223] Excess NaOH concentrations for the four ketoprofen formulations, # Keto-IT7, -IT8, -IT9 and BIT10 were calculated as described in Example 2 and are shown in Table 12.
[224] The pH of the patch was measured using the procedure of Example 1, and the pH measured for each ketoprofen transdermal administration system is also shown in Table 12.
[225] Weight and weight percent of each component (based on total solution weight) for four ketoprofen transdermal administration systemsKeto-it7Keto-it8Keto-it9Keto-IT10 Ketoprofen2.4 g (14.0%)2.4 g (14.0%)2.4 g (13.9%)2.4 g (13.8%) NaOH0.6 g (3.5%)0.65 g (3.8%)0.69 g (4.0%)0.73 g (4.2%) DI water0.6 g (3.5%)0.65 g (3.8%)0.69 g (4.0%)0.73 g (4.2%) PIB Adhesive (30% Solids)8 g (46.8%)8 g (46.5%)8 g (46.3%)8 g (46.1%) Tetraglycol0.5 g (2.9%)0.5 g (2.9%)0.5 g (2.9%)0.5 g (2.9%) Isopropylmyristate0.4 g (2.3%)0.4 g (2.3%)0.4 g (2.3%)0.4 g (2.3%) Methylsalicylate0.6 g (3.5%)0.6 g (3.5%)0.6 g (3.5%)0.6 g (3.5%) Methyl alcohol4 g (23.4%)4 g (23.3%)4 g (23.3%)4 g (23.0%)
[226] Weight and theoretical weight percentage of each component present in the dried film for four ketoprofen transdermal administration systemsKeto-it7Keto-it8Keto-it9Keto-IT10 Ketoprofen2.4 g (34.8%)2.4 g (34.5%)2.4 g (34.3%)2.4 g (34.1%) NaOH0.6 g (8.7%)0.65 g (9.4%)0.69 g (9.9%)0.73 g (10.4%) PIB Adhesive (30% Solids)2.4 g (34.0%)2.4 g (34.5%)2.4 g (34.3%)2.4 g (34.1%) Tetraglycol0.5 g (7.2%)0.5 g (7.2%)0.5 g (7.2%)0.5 g (7.1%) Isopropylmyristate0.4 g (5.8%)0.4 g (5.8%)0.4 g (5.7%)0.4 g (5.7%) Methylsalicylate0.6 g (8.7%)0.6 g (8.6%)0.6 g (8.6%)0.6 g (8.5%)
[227] Excess NaOH concentration, accumulation of ketoprofen through the skin at 24 hours, and pH of the four ketoprofen transdermal administration systemsKeto-it7Keto-it8Keto-it9Keto-IT10 pH10.0610.8111.0411.18 Excess NaOH Concentration3.22%3.92%4.47%5.01% Accumulation of ketoprofen through the skin at 24 hours0.170.340.541.52
[228] The accumulation of ketoprofen penetrated through the skin of the human body at 24 hours increased from 0.17 mg / cm 2 to 1.52 mg / cm 2 when the excess NaOH concentration calculated in the dried patch increased from 3.22% to 5.01%. It became. The excess NaOH concentration and accumulation of ketoprofen through the skin at 24 hours and patch pH for Keto-P3H18 were 0.34 mg / cm 2 and 10.81, respectively, which was that of Keto-P3H18 shown in Example 2 (0.32 mg / cm 2). , pH = 10.10). However, the excess NaOH concentration (3.92%) for Keto-IT8 was higher than that of Keto-P3H18 (1.00%), due to the consumption of NaOH through reaction between NaOH and components rather than ketoprofen from Keto-IT8 preparation. Will be.
[229] The recording of the stimuli obtained indicated that the stimuli from this patch were insignificant.
[230] Example 5
[231] In vitro skin penetration experiments were performed using four ibuprofen transdermal gels. The formulation used to prepare this gel is shown in Table 13. In this table, each component of the formulation is represented by weight and weight percent. The weight of sodium hydroxide for Formulations # Ibu-GH81, -GH82, -GH83 and -GH84 respectively was 0g, 0.115g, 0.135g and 0.15g.
[232] Ex vivo infiltration of PPA-HCl from the gel through the skin of the human cadaver was performed using a Franz diffusion cell with a diffusion area of 1 cm 2. The volume of the receiver solution was 8 ml. The skin of the human body was cut to size and clamped between the supply and reception chambers of the diffusion cell with the stratum corneum back to the donor solution. Three diffusion cells were used for each formulation.
[233] General saline was used as the aqueous solution. The volume of the aqueous solution was 8 ml. The whole aqueous solution was collected and replaced with fresh saline at each time point. The collected aqueous solution was analyzed by HPLC to determine the concentration of ibuprofen. The accumulation of ibuprofen penetrated through the skin of the human body was calculated using the ibuprofen concentration measured in the aqueous solution. This was created for each time point, and is shown in FIG.
[234] The excess NaOH concentrations for the four ibuprofen gels, # Ibu-GH81, -GH82, -GH83 and -GH84 were calculated and shown in Table 14.
[235] The pH of each gel was measured using the procedure of Example 1. The results are shown in Table 14.
[236] Weight and weight percent of each component, based on the weight of the total solution, for the four ibuprofen gelsIbu-GH81Ibu-GH82Ibu-GH83Ibu-GH84 Ibuprofen0.6 g (36.8%)0.6 g (32.3%)0.6 g (31.6%)0.6 g (31.1%) NaOH00.115 g (6.2%)0.135 g (7.1%)0.15 g (7.8%) ethanol0.4 g (24.5%)0.4 g (21.5%)0.4 g (21.1%)0.4 g (20.7%) DI water0.6 g (36.8%)0.715 g (38.4%)0.735 g (38.7%)0.75 g (38.9%) HPMCP0.03 g (1.8%)0.03 g (1.6%)0.03 g (1.6%)0.03 g (1.6%)
[237] HPMCP = hydroxypropyl methyl cellulose phthalate
[238] Excess NaOH Concentration and pH of Four Ibuprofen Transdermal GelsIbu-GH81Ibu-GH82Ibu-GH83Ibu-GH84 Excess NaOH Concentration 0%0.98%1.74% pH4.576.5811.8312.22
[239] When the excess NaOH concentration calculated from the gel increased from 0% to 1.74%, the accumulation of ibuprofen through the skin of the human body increased from 0.33 mg / cm 2 to 5.74 mg / cm 2 at 24 hours. The accumulated amount of ibuprofen (Ibu-GH83, 1.12 mg / cm 2) penetrated through the skin of the human body 24 hours after the formulation with excess NaOH concentration of 0.98% was obtained from the formulation with excess NaOH concentration of 0% ( Ibu-GH82, 0.33 mg / cm 2), about three times higher.
[240] When the excess NaOH concentration calculated in the gel increased from 0% to 1.74%, the pH of the ibuprofen patch measured using the procedure of the previous example increased from 6.58 to 2.22. Skin irritation may be related to the pH of the gel and is dependent on excess NaOH concentration.
[241] <Example 6>
[242] In vitro skin penetration experiments were performed using four phenylpropanolamine hydrogen chloride (PPA-HCl) transdermal administration systems. The formulations used to prepare this system are shown in Table 15. In this table, each component of the formulation is represented by weight and weight percent. The weight of sodium carbonate (Na ₂ CO ₃ ) of each formulation, # PPA-PC1, -PC2, -PC3, and -PC4, was 0 g, 0.29 g, 0.44 g, 0.74 g. Matrix patches were prepared using the same procedure as described in Example 3 and the values were obtained. The theoretical weight percent of each component after drying (measured assuming that all volatile components were completely removed during the drying process) is shown in Table 16. The accumulation of PPA-HCl through the skin of the human body was calculated using the measured PPA-HCl concentration in the aqueous solution. This is shown in Table 17 and FIG.
[243] PPA-HCl is a free acid, so it reacts with Na ₂ CO ₃ . The concentration of Na ₂ CO _{3 in} the system after the reaction is completed depending on the amount of PPA-HCl added. The Na ₂ CO ₃ concentration remaining after the reaction is completed is defined as 'excess Na ₂ CO ₃ concentration', which is calculated by the following equation.
[244] [ _{Excess amount of} Na ₂ CO ₃ ] = [ _{Total amount of} Na ₂ CO ₃ ]-[ _{Amount required for} Na ₂ CO _{3 neutralization} ]
[245] Excess Na ₂ CO ₃ concentrations for the four PPA-HCl systems, # PPA-PC1, -PC2, -PC3 and -PC4 were calculated and shown in Table 18.
[246] The pH of each patch was measured using the procedure of Example 1. The results are shown in Table 18.
[247] Weight and weight percent of each component (based on total solution weight) for four PPA-HCl systemsPPA-PC1PPA-PC2PPA-PC3PPA-PC4 PPA-HCl0.5 g (6.7%)0.5 g (5.7%)0.5 g (5.6%)0.5 g (5.5%) Na ₂ CO ₃ 00.29 g (3.3%)0.44 g (5.0%)0.74 g (8.1%) DI water1.0 g (13.5%)2.0 g (23.0%)2.0 g (22.6%)2.0 g (21.9%) Methyl alcohol0.5 g (6.7%)0.5 g (5.7%)0.5 g (5.6%)0.5 g (5.5%) Propylene glycol0.2 g (2.7%)0.2 g (2.3%)0.2 g (2.3%)0.2 g (2.2%) HPMC0.01 g (0.1%)0.01 g (0.1%)0.01 g (0.1%)0.01 g (0.1%) Heptane1.2 g (16.2%)1.2 g (13.8%)1.2 g (13.6%)1.2 g (45.2%) PIB Adhesive (30% Solids)4 g (54.0%)4 g (46.0%)4 g (45.2%)4 g (54.2%)
[248] Weight and theoretical weight percentage of each component present in the dried film for four PPA-HCl systemsPPA-PC1PPA-PC2PPA-PC3PPA-PC4 PPA-HCl0.5 g (26.2%)0.5 g (22.7%)0.5 g (21.3%)0.5 g (18.9%) Na ₂ CO ₃ 00.29 g (13.2%)0.44 g (18.7%)0.74 g (27.9%) Propylene glycol0.2 g (10.5%)0.2 g (9.1%)0.2 g (8.5%)0.2 g (7.5%) HPMC0.01 g (0.5%)0.01 g (0.5%)0.01 g (0.4%)0.01 g (0.4%) PIB adhesive1.2 g (62.8%)1.2 g (54.5%)1.2 g (51.1%)1.2 g (45.3%)
[249] Accumulation of PPA-HCl penetrated through human carcass skin for the PPA-HCl transdermal administration system (µg / cm 2)PPA-PC1PPA-PC2PPA-PC3PPA-PC4 5 hours152.868.081.1144.8 15 hours359.5222.7400.8631.2 19 hours442.7295.7551.5864.3 24 hours545.1410.4705.61147.5
[250] Excess Na ₂ CO ₃ Concentration and pH of PPA-HCl Transdermal SystemPPA-PC1PPA-PC2PPA-PC3PPA-PC4 Excess Na ₂ CO ₃ concentration-0.4%6.7%16.7% pH6.549.819.8610.17
[251] Although patch # PPA-PC2 containing 13.2% Na ₂ CO ₃ (Table 16), the accumulation of PPA-HCl (410.4 μg / cm 2, Table 17) penetrated through the skin of the human body at 24 hours after It was lower than that of the formulation without Na ₂ CO ₃ (PPA-PC1, 545.1 μg / cm 2). This would be due to the consumption of Na ₂ CO ₃ by the reaction between Na ₂ CO ₃ and PPA-HCl, which reduced Na ₂ CO ₃ concentration to only 0.4% as excess Na ₂ CO ₃ concentration (Table 6). ).
[252] When the calculated excess Na ₂ CO ₃ concentration in the dried patch increased from 0.4% to 16.7%, the accumulation of PPA-HCl penetrated through the skin of the human body at 24 hours was 1147.5 μg / cm at 410.4 μg / cm 2. Increased to 2 cm 2. These results show that although the required excess Na ₂ CO ₃ concentration is higher than that of NaOH, the penetration of PPA-HCl can be improved by Na ₂ CO ₃ . Na ₂ CO ₃ is a weak base compared to NaOH, Na ₂ CO ₃ will need a large amount because Na ₂ CO ₃ has a higher molecular weight than NaOH.
[253] The pH of the PPA-HCl patch measured using the above procedure increased from 9.81 to 10.17 when the excess Na ₂ CO ₃ concentration calculated in the dried patch increased from 0.4% to 16.7%.
[254] <Example 7>
[255] In vitro skin penetration experiments were performed using four phenylpropanolamine hydrogen chloride (PPA-HCl) transdermal administration systems. The formulations used to prepare this system are shown in Table 19. In this table, each component of the formulation is represented by weight and weight percent. The weight of tripotassium phosphate (K ₃ PO ₄ ) for each formulation, # PPA-PK1, -PK2, -PK3 and -PK4, was 0 g, 0.57 g, 0.6 g, 0.66 g. Matrix patches were prepared using the same procedure as described in Example 3 and the values were obtained. The theoretical weight percent of each component after drying (measured assuming that all volatile components were completely removed during the drying process) is shown in Table 20. The accumulation of PPA-HCl through the skin of the human body was calculated using the measured PPA-HCl concentration in the aqueous solution. This is shown in Table 21 and FIG.
[256] PPA-HCl is a free acid, so it reacts with K ₃ PO ₄ . The concentration of K ₃ PO _{4 in} the system after the reaction is completed depending on the amount of PPA-HCl added. The K ₃ PO ₄ concentration remaining after completion of the reaction is defined as 'excess K ₃ PO ₄ concentration', which is calculated by the following equation.
[257] [K ₃ PO _{4 excess} ] = [K ₃ PO _{4 total} ]-[ _{Quantity required for} K ₃ PO _quadruple ]
[258] Excess concentrations K ₃ PO ₄ for the four PPA-HCl systems, # PPA-PK1, -PK2, -PK3 and -PK4 were calculated and shown in Table 8.
[259] The pH of each patch was measured using the procedure of Example 1. The results are shown in Table 22.
[260] Weight and weight percent of each component (based on total solution weight) for four PPA-HCl systemsPPA-PK1PPA-PK2PPA-PK3PPA-PK4 PPA-HCl0.5 g (6.6%)0.5 g (6.1%)0.5 g (6.1%)0.5 g (6.1%) K ₃ PO ₄ 00.57 g (7.0%)0.6 g (7.3%)0.66 g (8.0%) DI water1.0 g (13.2%)1.0 g (12.2%)1.0 g (12.2%)1.0 g (12.1%) Propylene glycol0.5 g (6.6%)0.5 g (6.1%)0.5 g (6.1%)0.5 g (6.1%) Methyl alcohol0.5 g (6.6%)0.5 g (6.1%)0.5 g (6.1%)0.5 g (6.1%) PIB Adhesive (30% Solids)4 g (52.6%)4 g (49.0%)4 g (48.8%)4 g (48.4%) HPMC0.1 g (1.3%)0.1 g (1.2%)0.1 g (1.2%)0.1 g (1.2%) Heptane1 g (13.2%)1 g (12.2%)1 g (12.2%)1 g (12.1%)
[261] Weight and theoretical weight percentage of each component present in the dried film for four PPA-HCl systemsPPA-PC1PPA-PC2PPA-PC3PPA-PC4 PPA-HCl0.5 g (21.7%)0.5 g (17.4%)0.5 g (17.2%)0.5 g (16.9%) K ₃ PO ₄ 00.57 g (19.9%)0.6 g (20.7%)0.66 g (22.3%) Propylene glycol0.5 g (21.7%)0.5 g (17.4%)0.5 g (17.2%)0.5 g (16.9%) PIB adhesive1.2 g (52.2%)1.2 g (41.8%)1.2 g (41.4%)1.2 g (40.5%) Heptane0.1 g (4.3%)0.1 g (3.5%)0.1 g (3.4%)0.1 g (3.4%)
[262] Accumulation of PPA-HCl penetrated through human carcass skin for the PPA-HCl transdermal administration system (µg / cm 2)PPA-PK1PPA-PK2PPA-PK3PPA-PK4 5 hours94.7660.0421.6362.9 16 hours445.91701.31420.31607.5 20 hours576.81919.21633.11872.5 24 hours680.52055.21762.92021.1
[263] Excess K ₃ PO ₄ Concentration and pH of PPA-HCl Transdermal SystemPPA-PK1PPA-PK2PPA-PK3PPA-PK4 Excess K ₃ PO ₄ concentration-0.2%1.2%3.2% pH6.759.689.6210.08
[264] The accumulation of PPA-HCl penetrated through the skin of the human body at 24 hours after PPA-PK2 (2055.2 μg / cm 2, Table 21) with a calculated K ₃ PO ₄ concentration of 0.2% was calculated as K ₃ PO _4. 3 times higher than that from the formulation without (PPA-PK1, 680.5 μg / cm 2). These results show that infiltration of PPA-HCl can be enhanced at excess K ₃ PO ₄ concentrations as low as 0.2%.
[265] The accumulation of PPA-HCl through the skin of the human body at 24 hours was the same as when the excess K ₃ PO ₄ concentration in the dried patch increased from 0.2% to 3.2% (Tables 21 and 22).
[266] The pH of the PPA-HCl patch measured using the above procedure was increased when the K ₃ PO ₄ concentration in the dried patch increased from 0% to 19.9% (or greater than 0.2% K ₃ PO ₄ concentration, Tables 20 and 22). ), Increased from 6.75 to 9.68. However, the pH of PPA-HCl remained as it was when the excess K ₃ PO ₄ concentration increased from 0.2% to 3.2% in the dried patch.
[267] <Example 8>
[268] In vitro skin penetration experiments were performed using four phenylpropanolamine hydrogen chloride (PPA-HCl) transdermal administration systems. The formulations used to prepare this system are shown in Table 23. In this table, each component of the formulation is represented by weight and weight percent. The weight of tripotassium phosphate (K ₃ PO ₄ ) for each formulation, # PPA-PK1R, -PK2R, -PK5 and -PK6, was 0 g, 0.57 g, 0.73 g, 1.05 g. Matrix patches were prepared using the same procedure as described in Example 3 and the values were obtained. The theoretical weight percent of each component after drying (measured assuming that all volatile components were completely removed during the drying process) is shown in Table 24. The accumulation of PPA-HCl through the skin of the human body was calculated using the measured PPA-HCl concentration in the aqueous solution. This is shown in Table 25 and FIG.
[269] The excess K ₃ PO ₄ concentrations for the four PPA-HCl systems, # PPA-PK1R, -PK2R, -PK5 and -PK6 were calculated using the procedure of Example 7, and the results are shown in Table 26.
[270] The pH of each patch was measured using the procedure of Example 1 and the results are shown in Table 26.
[271] Weight and weight percent of each component (based on total solution weight) for four PPA-HCl transdermal administration systemsPPA-PK1RPPA-PK2RPPA-PK5PPA-PK6 PPA-HCl0.5 g (6.9%)0.5 g (6.4%)0.5 g (6.3%)0.5 g (6.1%) K ₃ PO ₄ 00.57 g (7.3%)0.73 g (9.2%)1.05 g (12.1%) DI water1.0 g (13.9%)1.0 g (12.9%)1.0 g (12.6%)1.0 g (12.1%) Methyl alcohol0.5 g (6.9%)0.5 g (6.4%)0.5 g (6.3%)0.5 g (6.1%) Propylene glycol0.2 g (2.8%)0.2 g (2.6%)0.2 g (2.5%)0.2 g (2.4%) HPMC0.01 g (0.1%)0.01 g (0.1%)0.01 g (0.1%)0.01 g (0.1%) Heptane1 g (13.9%)1 g (12.9%)1 g (12.6%)1 g (12.1%) PIB Adhesive (30% Solids)4 g (55.5%)4 g (51.4%)4 g (50.4%)4 g (48.4%)
[272] Weight and theoretical weight percentage of each component present in the dried film for four PPA-HCl transdermal administration systemsPPA-PK1RPPA-PK2RPPA-PK5PPA-PK6 PPA-HCl0.5 g (26.2%)0.5 g (20.2%)0.5 g (18.9%)0.5 g (16.5%) K ₃ PO ₄ 00.57 g (23.6%)0.73 g (27.7%)1.05 g (35.5%) Propylene glycol0.2 g (10.5%)0.2 g (8.1%)0.2 g (7.6%)0.2 g (6.8%) HPMC0.01 g (0.5%)0.01 g (0.4%)0.01 g (0.4%)0.01 g (0.3%) PIB adhesive1.2 g (62.8%)1.2 g (48.4%)1.2 g (45.5%)1.2 g (40.5%)
[273] Accumulation of PPA-HCl penetrated through human carcass skin for the PPA-HCl transdermal administration system (µg / cm 2)PPA-PK1RPPA-PK2RPPA-PK5PPA-PK6 5 hours336.8553.1291.5186.7 16 hours879.51702.41172.5873.1 20 hours1091.22031.21711.51204.3 24 hours1324.02378.42222.71628.0
[274] Excess K ₃ PO ₄ Concentration and pH of PPA-HCl Transdermal SystemPPA-PK1RPPA-PK2RPPA-PK5PPA-PK6 Excess K ₃ PO ₄ concentration-0.2%6.2%16.4% pH79.7210.1710.44
[275] The accumulated amount of PPA-HCl penetrated through the skin of the human body at 24 hours for PPA-PK2R (2378.4 μg / cm 2, Table 25) with a calculated excess K ₃ PO ₄ concentration of 0.2% was K ₃ PO ₄ 2 times higher than that from the formulation without (PPA-PK1R, 1324.0 μg / cm 2). These results showed that the permeation of PPA-HCl was enhanced at excess K ₃ PO ₄ concentrations as low as 0.2%.
[276] The accumulation of PPA-HCl across the skin of the human body at 24 hours was the same as when the excess K ₃ PO ₄ concentration in the dried patch increased from 0.2% to 6.2% (Tables 25 and 26). When the excess K ₃ PO ₄ concentration in the dried patch increased from 6.2% to 16.4% (Table 26), the accumulation of PPA-HCl through the skin of the human body at 24 hours decreased from 2222.7 to 1628.0 μg / cm 2. . This decrease in flow rate is due to the high concentration of K ₃ PO _{4 making} the adhesive matrix more hydrophobic and the decrease in the amount of K ₃ PO ₄ that can be dissolved even in small amounts of water on the skin.
[277] The pH of the PPA-HCl patch measured using the above procedure was increased when the K ₃ PO ₄ concentration in the dried patch increased from 0% to 23% (or greater than 0.2% K ₃ PO ₄ concentration, Tables 24 and 26). ), Increased from 7 to 9.72. However, the pH of PPA-HCl increased from 9.72 to 10.44 when the excess K ₃ PO ₄ concentration in the dried patch increased from 0.2% to 6.4%.
[278] Example 9
[279] In vitro skin penetration experiments were performed using four estradiol transdermal administration systems. The formulations used to prepare this system are shown in Table 27. In this table, each component of the formulation is represented by weight and weight percent. The weight of tripotassium phosphate (K ₃ PO ₄ ) for each formulation, # Est-PK1, -PK2, -PK3 and -PK4, was 0 g, 0.1 g, 0.3 g, 0.48 g. Matrix patches were prepared using the same procedure as described in Example 1 and the values were obtained. The theoretical weight percent of each component after drying (measured assuming that all volatile components were completely removed during the drying process) is shown in Table 28. The accumulation of estradiol across the skin of the human body was calculated using the estradiol concentration measured in the aqueous solution. This is shown in Table 29 and FIG.
[280] Since estradiol is was not expected to react with the K ₃ PO _4, K ₃ PO ₄ as shown in Table 28 is the same as the excess K ₃ PO ₄ concentration.
[281] The pH of each patch was measured using the procedure of Example 1 and the results are shown in Table 30.
[282] Weight and weight percent (based on weight of total solution) of each component for four estradiol transdermal administration systemsEst-PK1Est-PK2Est-PK3Est-PK4 Estradiol0.03 g (0.5%)0.03 g (0.5%)0.03 g (0.5%)0.03 g (0.4%) Methyl alcohol0.5 g (8.0%)0.5 g (7.8%)0.5 g (7.6%)0.5 g (7.4%) K ₃ PO ₄ 00.1 g (1.6%)0.3 g (4.6%)0.48 g (7.1%) DI water0.5 g (8.0%)0.5 g (7.8%)0.5 g (7.6%)0.5 g (7.4%) Propylene glycol0.25 g (4.0%)0.25 g (3.9%)0.25 g (3.8%)0.25 (3.7%) PIB Adhesive (30% Solids)4 g (63.7%)4 g (62.7%)4 g (60.8%)4 g (59.2%) Heptane1 g (15.9%)1 g (15.7%)1 g (15.2%)1 g (14.8%)
[283] Weight and theoretical weight percentage of each component present in the dried film for four estradiol transdermal administration systemsEst-PK1Est-PK2Est-PK3Est-PK4 Estradiol0.03 g (2.0%)0.03 g (1.9%)0.03 g (1.7%)0.03 g (1.5%) K ₃ PO ₄ 00.1 g (6.3%)0.3 g (16.9%)0.48 g (24.5%) Propylene glycol0.25 g (16.9%)0.25 g (15.8%)0.25 g (14.0%)0.25 (12.8%) PIB adhesive1.2 g (81.1%)1.2 g (76.0%)1.2 g (67.4%)1.2 g (61.2%)
[284] Accumulation of estradiol penetrated through the skin of the human body for the estradiol transdermal administration system (µg / cm 2)Est-PK1Est-PK2Est-PK3Est-PK4 5 hours0.21.22.11.5 16.5 hours0.43.97.63.7 20 hours0.54.68.84.4 24 hours0.65.610.25.3
[285] Excess K ₃ PO ₄ concentration and pH of the four estradiol transdermal administration systemsEst-PK1Est-PK2Est-PK3Est-PK4 Excess K ₃ PO ₄ concentration0%6.3%16.9%24.5% pH6.48.8910.839.87
[286] The accumulation of estradiol penetrated through the skin of the human body at the 24 hour passage for Est-PK2 (5.6 μg / cm 2, Table 9) with a calculated concentration of excess K ₃ PO ₄ of 6.3% was determined by K ₃ PO ₄ . 9 times higher than that from the formulation without (Est-PK1, 0.6 μg / cm 2). These results showed that the permeation of estradiol is enhanced by K ₃ PO ₄ . The accumulation of estradiol across the skin of the human body at 24 hours increased from 5.6 to 10.2 when the excess K ₃ PO ₄ concentration in the dried patch increased from 6.3% to 16.9% (Tables 29 and 30). When the excess K ₃ PO ₄ concentration in the dried patch increased from 16.9% to 24.5% (Table 30), the accumulation of PPA-HCl through the skin of the human body at 24 hours elapsed from 10.2 to 5.3 μg / cm 2. Reduced to. This decrease in flow rate is due to the high concentration of K ₃ PO _{4 making} the adhesive matrix more hydrophobic and the decrease in the amount of K ₃ PO ₄ that can be dissolved even in small amounts of water on the skin.
[287] The pH of the estradiol patch measured using the above procedure increased from 6.4 to 10.83 when the K ₃ PO ₄ concentration in the dried patch increased from 0% to 16.9%. However, the pH of estradiol decreased from 10.83 to 9.87 when the excess K ₃ PO ₄ concentration in the dried patch increased from 16.9% to 24.5%.
[288] <Example 10>
[289] In vitro skin penetration experiments were performed using four estradiol transdermal administration systems. The formulations used to prepare this system are shown in Table 31. In this table, each component of the formulation is represented by weight and weight percent. The weight of sodium carbonate (Na ₂ CO ₃ ) of each formulation, # Est-PC1, -PC2, -PC3, and -PC4, was 0g, 0.11g, 0.3g, 0.45g. It was prepared using the same procedure as described and the value was obtained. The theoretical weight percent of each component after drying (measured assuming that all volatile components were completely removed during the drying process) is shown in Table 32. The accumulation of estradiol across the skin of the human body was calculated using the estradiol concentration measured in the aqueous solution. This is shown in Table 33 and FIG.
[290] Since estradiol was not expected to react with Na ₂ CO ₃ , the Na ₂ CO ₃ shown in Table 28 is equal to the excess Na ₂ CO ₃ concentration.
[291] The pH of each patch was measured using the procedure of Example 1. The results are shown in Table 18.
[292] Weight and weight percent (based on total solution weight) of each component for the four estradiol transdermal administration systemsEst-PC1Est-PC2Est-PC3Est-PC4 Estradiol0.03 g (0.5%)0.03 g (0.4%)0.03 g (0.4%)0.03 g (0.4%) Na ₂ CO ₃ 00.11 g (1.6%)0.3 g (4.1%)0.45 g (6.1%) DI water0.5 g (8.0%)1.2 g (16.9%)1.2 g (16.5%)1.2 g (16.2%) Methyl alcohol0.5 g (8.0%)0.5 g (7.1%)0.5 g (6.9%)0.5 g (6.7%) PIB Adhesive (30% Solids)4 g (63.7%)4 g (56.4%)4 g (55.0%)4 g (53.8%) Propylene glycol0.25 g (4.0%)0.25 g (3.5%)0.25 g (3.4%)0.25 g (3.4%) Heptane1 g (15.9%)1 g (14.1%)1 g (13.7%)1 g (13.5%)
[293] Weight and theoretical weight percentage of each component present in the dried film for four estradiol transdermal administration systemsEst-PC1Est-PC2Est-PC3Est-PC4 Estradiol0.03 g (2.0%)0.03 g (1.9%)0.03 g (1.7%)0.03 g (1.6%) Na ₂ CO ₃ 00.11 g (6.9%)0.3 g (16.9%)0.45 g (23.3%) PIB adhesive1.2 g (81.1%)1.2 g (75.5%)1.2 g (67.4%)1.2 g (62.2%) Propylene glycol0.25 g (16.9%)0.25 g (15.7%)0.25 g (14.0%)0.25 g (13.0%)
[294] Accumulation of estradiol penetrated through human corpse skin for estradiol transdermal administration system (µg / cm 2)Est-PC1Est-PC2Est-PC3Est-PC4 5 hours0.10.40.10.1 16.5 hours0.20.90.40.6 20 hours0.31.10.61.0 24 hours0.31.41.01.4
[295] Excess Na ₂ CO ₃ Concentration and pH for Four Estradiol Transdermal SystemsEst-PC1Est-PC2Est-PC3Est-PC4 Excess Na ₂ CO ₃ concentration0%6.9%16.9%23.3% pH7.489.8710.5110.49
[296] Accumulation of excess Na ₂ CO ₃ with a concentration of 6.9% calculated on 24 hours time for Est-PC2 (1.4㎍ / ㎠, Table 33) penetrate through the skin of the human body estradiol is the Na ₂ CO ₃ 4 times higher than that from the formulation without (Est-PK1, 0.6 μg / cm 2). These results showed that Na ₂ CO ₃ could enhance the penetration of estradiol.
[297] At 24 hours, the accumulation of estradiol across the skin of the human body remained about the same as the excess Na ₂ CO ₃ concentration in the dried patches increased from 6.9% to 23.3% (Tables 33 and 34). . This reaction is due to the fact that the amount of Na ₂ CO ₃ that can be dissolved in a small amount of water on the skin remained about the same for Est-PC2, Est-PC3 and Est-PC4.
[298] The pH of the estradiol patch measured using the above procedure increased from 7.48 to 10.51 when the Na ₂ CO ₃ concentration in the dried patch increased from 0% to 16.9%. However, the pH of estradiol remained about the same when the excess Na ₂ CO ₃ concentration in the dried patch increased from 16.9% to 23.3%.
[299] <Example 11>
[300] In vitro skin penetration experiments were performed using four estradiol transdermal systems. The formulations used to prepare this system are shown in Table 35, where each component of the formulation is represented by weight and weight percent. The weight of magnesium oxide (MgO) was 0g, 0.11g, 0.3g and 0.45g for # Est-PM1, -PM2, -PM3 and -PM4 formulations, respectively. Matrix patches were prepared and evaluated in the same manner as in Example 1. The theoretical weight percentages for each component after drying (measured assuming that all volatile components were completely removed during the drying process) are shown in Table 36. Accumulation of estradiol penetrated through human corpse skin was measured using the estradiol concentration measured on the aqueous solution, and is shown in Table 37 and FIG. 10.
[301] Since estradiol is not expected to react with MgO, the MgO concentrations listed in Table 36 are equal to the excess MgO concentrations.
[302] The pH of each patch was measured using the method of Example 1, and the results are shown in Table 38.
[303] Weight and weight percent of each component (based on total solution weight) for four estradiol transdermal administration systemsEst-PM1Est-PM2Est-PM3Est-PM4 Estradiol0.03 g (0.5%)0.03 g (0.4%)0.03 g (0.4%)0.03 g (0.4%) MgO00.11 g (1.6%)0.3 g (4.1%)0.45 g (6.1%) DI water0.5 g (8.0%)1.2 g (16.9%)1.2 g (16.5%)1.2 g (16.2%) Methyl alcohol0.5 g (8.0%)0.5 g (7.1%)0.5 g (6.9%)0.5 g (6.7%) PIB Adhesive (30% Solids)4 g (63.7%)4 g (56.4%)4 g (55.0%)4 g (53.8%) Propylene glycol0.25 g (4.0%)0.25 g (3.5%)0.25 g (3.4%)0.25 g (3.4%) Heptane1 g (15.9%)1 g (14.1%)1 g (13.7%)1 g (13.5%)
[304] Weight and theoretical weight percentage of each component present in the dried film for four estradiol transdermal administration systemsEst-PM1Est-PM2Est-PM3Est-PM4 Estradiol0.03 g (2.0%)0.03 g (1.9%)0.03 g (1.7%)0.03 g (1.6%) MgO00.11 g (6.9%)0.3 g (16.9%)0.45 g (23.3%) PIB adhesive1.2 g (81.1%)1.2 g (75.5%)1.2 g (67.4%)1.2 g (62.2%) Propylene glycol0.25 g (16.9%)0.25 g (15.7%)0.25 g (14.0%)0.25 g (13.0%)
[305] Estradiol accumulation (μg / cm ² ) penetrated through human carcass skin for estradiol transdermal administration systemEst-PM1Est-PM2Est-PM3Est-PM4 4.75 hours0.080.090.050.02 15.75 hours0.210.310.190.13 19.75 hours0.260.410.260.19 23.75 hours0.320.530.360.27
[306] Excess MgO Concentration and pH in Four Estradiol Transdermal SystemsEst-PM1Est-PM2Est-PM3Est-PM4 Excess MgO Concentration0%6.9%16.9%23.3% pH7.488.959.6610.28
[307] For Est-PM2 (0.53 μg / cm ² , Table 37) with an excess MgO concentration of 6.9%, the accumulation of estradiol penetrated through human carcass skin at 24 hours was K ₃ PO ₄ (Est-PM1, 0.32 μg / cm ² ) was slightly higher than in the absence of formulation. This result means that MgO enhances the penetration of estradiol.
[308] In dried patches, when the excess MgO concentration increased from 6.9% to 23.3% (Tables 23 and 24), the accumulation of estradiol penetrated through the human body skin at 24 hours was 0.53 μg / cm ^2. Decreased to 0.27 μg / cm ² . This behavior is probably due to the higher concentrations of MgO that make the adhesive matrix more hydrophobic and reduce the amount of MgO that can be dissolved by a small amount of water in the upper layers of the skin.
[309] When the MgO concentration in the dried patch increased from 0% to 23.3%, the pH of the estradiol patch measured by the method described above increased from 7.48 to 10.28.
[310] <Example 12>
[311] In vitro skin penetration experiments were performed using four phenylpropanolamine hydrochloride (PPA-HCl) transdermal administration systems. The formulations used to prepare this system are listed in Table 39, where each component of the formulation is expressed in weight and weight percent. The weight of magnesium hydroxide (MgO) was 0g, 0.11g, 0.26g and 0.50g for # PPA-PM1, -PM2, -PM3 and -PM4 formulations, respectively. Matrix patches were prepared and evaluated in the same manner as in Example 3. The theoretical weight percent for each component after drying (measured assuming that all volatile components were completely removed during the drying process) is shown in Table 40. Accumulation of PPA-HCl infiltrated through human body skin was calculated using the PPA-HCl concentration measured on the aqueous solution, and is shown in Table 41 and FIG. 11.
[312] PPA-HCl reacts with MgO because it is a free base salt. After the reaction is complete, the MgO concentration in the system is determined by the amount of PPA-HCl added. The remaining MgO concentration after completion of the reaction is defined as "excess MgO concentration" and is calculated by the following formula.
[313] [MgO _Excess ] = [MgO _{Total Amount} ]-[ _{Amount Required for} MgO _{Neutralization} ]
[314] The excess MgO concentrations for the four PPA-HCl systems, # PPA-PM1, -PM2, -PM3 and -PM4, were calculated and shown in Table 42 below.
[315] The pH of the patch was measured by the method of Example 1 and the results are shown in Table 42.
[316] Weight and weight percent of each component (based on total solution weight) for four PPA-HCl transdermal administration systemsPPA-PM1PPA-PM2PPA-PM3PPA-PM4 PPA-HCl0.5 g (6.9%)0.5 g (6.0%)0.5 g (5.9%)0.5 g (5.7%) MgO00.11 g (1.3%)0.26 g (3.1%)0.50 g (5.7%) DI water1.0 g (13.9%)2.0 g (24.0%)2.0 g (23.6%)2.0 g (22.9%) Methyl alcohol0.5 g (6.9%)0.5 g (6.0%)0.5 g (5.9%)0.5 g (5.7%) Propylene glycol0.2 g (2.8%)0.2 g (2.4%)0.2 g (2.4%)0.2 g (2.3%) HPMC0.02 g (0.3%)0.02 g (0.2%)0.02 g (0.2%)0.02 g (0.2%) PIB Adhesive (30% Solids)4 g (55.4%)4 g (48.0%)4 g (47.2%)4 g (45.9%) Heptane1.0 g (13.9%)1.0 g (12.0%)1.0 g (11.8%)1.0 g (11.5%)
[317] Weight and theoretical weight percentage of each component present in the dried film for four PPA-HCl transdermal administration systemsPPA-PM1PPA-PM2PPA-PM3PPA-PM4 PPA-HCl0.5 g (26.0%)0.5 g (24.6%)0.5 g (22.9%)0.5 g (20.7%) MgO00.11 g (5.4%)0.26 g (11.9%)0.50 g (20.7%) Propylene glycol0.2 g (10.4%)0.2 g (9.9%)0.2 g (9.2%)0.2 g (8.3%) HPMC0.02 g (1.0%)0.02 g (1.0%)0.02 g (0.9%)0.02 g (0.8%) PIB adhesive1.2 g (62.5%)1.2 g (59.1%)1.2 g (55.0%)1.2 g (49.6%)
[318] PPA-HCl accumulation (μg / cm ² ) penetrated through human carcass skin for PPA-HCl transdermal administration systemPPA-PM1PPA-PM2PPA-PM3PPA-PM4 5 hours18.7296.8222.1489.4 15 hours77.8621.51362.91255.2 19 hours102.7711.41920.91524.9 24 hours129.8801.92533.41831.3
[319] Excess MgO Concentration and pH in Four PPA-HCl Transdermal SystemsPPA-PM1PPA-PM2PPA-PM3PPA-PM4 Excess MgO Concentration 0.1%7.0%16.2% pH7.899.6010.0910.10
[320] For PPA-PM2 (801.9 μg / cm ² , Table 41) with an excess MgO concentration of 0.1%, the accumulation of PPA-HCl infiltrated through human carcass skin at 24 hours elapsed before MgO (PPA-PM1, 129.8 μg). / cm ² ) was about 6 times higher than in the absence of the formulation. These results indicate that penetration of PPA-HCl is enhanced when the excess MgO concentration is as low as 0.1%.
[321] In the dried patches, when the excess MgO concentration increased from 0.1% to 7.0% (Table 41 and Table 42), the accumulation of PPA-HCl penetrated through human body skin at 24 hours was 801.9 μg / cm Increased from ² to 2533.4 μg / cm ² . In dried patches, when the concentration of excess MgO was increased from 7.0% to 16.2% (Table 42), the accumulation of PPA-HCl penetrated through the human body skin at 24 hours elapsed from 2533.4 to 1831.3 μg / cm Decreased to ² . This decrease in flow rate is probably due to the higher concentrations of MgO that make the adhesive matrix more hydrophobic and because the amount of MgO that can be dissolved by a small amount of water in the upper layers of the skin is reduced.
[322] In dried patches, when the MgO concentration was increased from 0% to 5.4% (or greater than 0.1% MgO concentration, Table 40 and Table 42), the pH of the PPA-HCl patch measured using the method described above was 7.89 to 9.60. Increased. In dried patches, the pH of PPA-HCl was approximately the same when the excess MgO concentration increased further from 0.1% to 16.2% (Table 42).
[323] Example 13
[324] Ex vivo skin penetration experiments were performed using leuprolide solutions. The formulations used to prepare these solutions are listed in Table 43, in which each component of the formulation is expressed in weight and weight percent. The weight of sodium hydroxide was 0g, 0.0125g and 0.0275g for # Leu-S1, # Leu-S2 and # Leu-S3 formulations, respectively. Each formulation was mixed until the solution was even.
[325] In vitro permeation experiments of each leuprolide solution through human corpse skin were performed using Franz-type diffusion cells with a 1 cm ² diffusion area. The volume of the aqueous solution was 8 ml. Human carcass skin was cut to a suitable size and placed on a flat surface with the stratum corneum facing up. The skin was fixed between the supply and reception chambers of the diffusion cell and the stratum corneum was allowed to dry. The leuprolide solution was applied to the stratum corneum using a micro-pipette. Each formulation was administered in amounts of 25 μl and 50 μl for a total of six test groups. The storage room was sealed against air by using a parafilm wrap to keep the water from spilling. Three diffusion cells were used for each test group, for a total of 18 cells.
[326] The cell was charged with DI (deionized) water with aqueous solution. Bubbles of DI water were removed. At each time point the aqueous solution was completely removed and replaced with fresh DI water. A sample of the aqueous solution was taken and analyzed by high pressure liquid chromatography (HPLC) to determine the leuprolide concentration. Accumulation of leuprolides through human carcass skin (Table 44) was calculated using the leuprolide concentrations measured in the aqueous solution at each time point.
[327] Weight and weight percent of ingredients (based on total solution weight) for three leuprolide transdermal administration systemsLeu-S1Leu-S2 *Leu-S3 * Lyuprolead0.003 g (0.4%)6.4 × 10 ^-4 g (0.18%)6.4 × 10 ^-4 g (0.16%) DI water0.45 g (64.0%)0.28 g (80.9%)0.33 g (80.3%) NaOH0 g (0.0%)0.0125 g (3.6%)0.0275 g (6.7%) Propylene glycol0.25 g (35.6%)0.053 g (15.3%)0.053 g (13.0%)
[328] * Solutions Leu-S2 and Leu-S3 were prepared using 0.15g Leu-S1 with the correct amount of NaOH and DI water added. Percentages cannot be calculated at 100% because of rounding.
[329] Accumulation of leuprolide penetrated through human body skin from 25 μl and 50 μl solutions containing NaOH at 5 and 24 hours (μg / cm ² )Leu-S125 μlLeu-S225 μlLeu-S325 μlLeu-S150μLLeu-S250 μlLeu-S350 μl 5 hours0.380.520.580.320.620.3 24 hours0.523.214.430.328.5810.8
[330] In the dried patch, when the concentration of sodium hydroxide increased from 0% to 6.7%, at 24 hours, the accumulation of leuprolide penetrated through the human carcass skin at a dose of 25 μl was 0.52 μg / cm. Increased from ² to 4.43 μg / cm ² . When the concentration of sodium hydroxide in the leuprolide solution increased from 0% to 6.7%, at 24 hours, the accumulation of leuprolide penetrated through the human carcass skin at a dose of 50 μl was 0.32 μg / cm. Increased from ² to 10.8 μg / cm ² . At 24 hours, the accumulation of leuprolide penetrated through human carcass skin in the 50 μl dose group containing 3.6% NaOH (Leu-S2) was 8.58 μg / cm ² . This amount was about 27 times higher than in the formulation without NaOH (0.32 μg / cm ² , # Leu-S1).
[331] <Example 14>
[332] In vitro penetration experiments of oxytocin through human carcass skin were performed using Franz-type diffusion cells with a 1 cm ² diffusion area. The volume of the aqueous solution was 8 ml. Human carcass skin was cut to a suitable size and placed on a flat surface with the stratum corneum side facing up. The skin was fixed between the supply and reception chambers of the diffusion cells. 18 diffusion cells were used in this experiment. Aqueous 2% NaOH solution (50 μl) was administered to the supply cell of 9 cells (cells # 1 to # 9), and a 4% NaOH aqueous solution (50 μl) was applied to the other 9 cells (cells # 10 to # 18) Administered. After applying NaOH solution, the feed chamber was covered with parafilm.
[333] After 5 hours, the NaOH solution was washed from the skin pieces for three cells treated with 2% NaOH solution (# 1 to # 3 cells) and three cells treated with 4% NaOH solution (# 10 to # 12 cells). It was. After 10 hours, the NaOH solution was washed from the skin pieces for three cells treated with 2% NaOH solution (# 4 to # 6 cells) and three cells treated with 4% NaOH solution (# 13 to # 15 cells). It was. After 24 hours, the NaOH solution was washed from the skin pieces for three cells treated with 2% NaOH solution (# 7 to # 9 cells) and three cells treated with 4% NaOH solution (# 16 to # 18 cells). It was. To wash the NaOH solution, the aqueous solution was removed and replaced with fresh DI water. This process was repeated twice. DI water was added to the feed chamber to dilute the NaOH solution and then the feed solution was removed. This process was repeated several times.
[334] After washing the NaOH solution in the skin fragments, the solution in the supply chamber was completely removed and replaced with 50 μl of oxytocin solution. The components of the formulation to which the oxytocin solution was added are shown in Table 45 below. After application of the oxytocin solution, the feed chamber was covered with parafilm.
[335] The cells were filled using DI water as the aqueous solution. Air was removed from the DI water. At each time point, the aqueous solution was completely removed and replaced with fresh DI water. After taking a sample, the oxytocin concentration on the aqueous solution was analyzed by HPLC. Accumulation of oxytocin through human body skin was calculated using the oxytocin concentration measured in the aqueous solution at each time point, and is shown in Table 46.
[336] Oxytocin Solution Formulation Oxytocin0.005g DI water0.6g Propylene glycol0.6g
[337] Accumulation of oxytocin penetrated through the human body skin from oxytocin solution (µg / cm ² )Skin pretreated with 4% NaOH for 5 hoursSkin pretreated with 4% NaOH for 15 hoursSkin pretreated with 4% NaOH for 24 hours 5 hours118.95202.28193.82 15 hours200.66222.45232.72 24 hours225.52231.58236.80
[338] <Example 15>
[339] In vitro penetration experiments of oxytocin through human carcass skin were performed using Franz-type diffusion cells with a 1 cm ² diffusion area. The volume of the aqueous solution was 8 ml. Human carcass skin was cut to a suitable size and placed on a flat surface with the stratum corneum side facing up. The skin was fixed between the supply and reception chambers of the diffusion cells. 18 diffusion cells were used in this experiment. A 0.25% aqueous NaOH solution (50 μl) was administered to the donor chamber of nine cells (cells # 1 to # 9), and a 1.0% aqueous NaOH solution (50 μl) was supplied to the other nine cells (cells # 10 to # 18). Was administered. After applying NaOH solution, the feed chamber was covered with parafilm.
[340] After 5 hours, the NaOH solution was washed from the skin pieces for three cells treated with 0.5% NaOH solution (# 1 to # 3 cells) and three cells treated with 1.0% NaOH solution (# 10 to # 12 cells). It was. After 11 hours, the NaOH solution was washed from the skin pieces for three cells treated with 0.25% NaOH solution (# 4 to # 6 cells) and three cells treated with 1.0% NaOH solution (# 13 to # 15 cells). It was. After 24 hours, the NaOH solution was washed from the skin pieces for three cells treated with 0.25% NaOH solution (# 7 to # 9 cells) and three cells treated with 1.0% NaOH solution (# 16 to # 18 cells). It was. To wash the NaOH solution, the aqueous solution was removed and replaced with fresh DI water. This process was repeated twice. DI water was added to the feed chamber to dilute the NaOH solution, at which time the feed solution was removed. This process was repeated several times until the pH of the feed solution reached 8 or less.
[341] After washing the NaOH solution in the skin fragments, the solution in the supply chamber was completely removed and replaced with 50 μl of oxytocin solution. The components of the formulations with added oxytocin solution are shown in Table 47. After application of the oxytocin solution, the feed chamber was covered with parafilm.
[342] The cells were filled using DI water as the aqueous solution. Air was removed from the DI water. At each time point, the aqueous solution was completely removed and replaced with fresh DI water. After taking a sample, the oxytocin concentration on the aqueous solution was analyzed by HPLC. Accumulation of oxytocin through human body skin was calculated using the oxytocin concentration measured in the aqueous solution at each time point, and is shown in Table 48.
[343] Oxytocin Solution Formulation Oxytocin0.005g DI water0.6g Propylene glycol0.6g
[344] Accumulation of oxytocin penetrated through the human body skin from oxytocin solution (µg / cm ² )Skin pretreated with 1.0% NaOH for 5 hoursSkin pretreated with 1.0% NaOH for 11 hoursSkin pretreated with 1.0% NaOH for 24 hours 4.25 hours0.4553.4213.23 14.75 hours0.9767.9721.06 24 hours0.9775.3630.97
[345] <Example 16>
[346] In vitro skin penetration experiments were performed using four diclofenac sodium transdermal administration systems. The formulations used to prepare this system are listed in Table 49, where each component of the formulation is expressed in weight and weight percent. The weight of sodium hydroxide (NaOH) was 0g, 0.035g, 0.05g and 0.1g for # Diclo-P10, -P11, -P12 and -P13 formulations, respectively. Each formulation was covered with a release liner and dried for 2 hours in an oven maintained at 55 ° C. to remove water and other solvents. The dried DIA / release film release film was laminated to a backing film. The backing / drug-in-adhesive / release liner laminate was cut into 11/16 inch diameter discs. The theoretical weight percent (calculated assuming volatile components were removed during drying) for each component after drying is shown in Table 50.
[347] In vitro penetration experiments of Diclofenac Sodium infiltrated into human carcass skin from these plates were performed using Franz-type diffusion cells with a 1 cm ² diffusion area. The volume of the aqueous solution was 8 ml. Human carcass skin was cut to a suitable size and placed on a flat surface with the stratum corneum side facing up.
[348] The backing layer / DIA film was placed and pressed onto the skin with the adhesive side against the stratum corneum. The skin / adhesive / backing laminate was fixed between the supply and diffusion chambers of the diffusion cell with the skin side facing towards the aqueous solution. Three diffusion cells were used for each formulation.
[349] The cell was filled with a solution of 10% ethanol and 90% water. At each time point the aqueous solution was completely removed and replaced with fresh ethanol / water solution. After taking a sample, the concentration of dietofenac sodium in the aqueous solution was analyzed by HPLC. Accumulation of Diclofenac Sodium through human carcass skin was calculated using Diclofenac Sodium concentration measured in the aqueous solution and is shown in Table 51 and FIG. 12.
[350] Since Diclofenac Sodium is not thought to react with NaOH, the NaOH concentrations shown in Table 50 are the same as the excess NaOH concentrations.
[351] The pH of the patch was measured by the following method. Holes were drilled in a 2.5 cm ² round patch. Pipette 10 ml purified water into the glass vial and stir bar into the glass vial. The liner was removed from the patch and placed in the vial with the patch. The vial was placed on a stir plate and the water / patch / membrane mixture was mixed for 5 minutes until the membrane was removed from the vial. The vial was placed back on the stir plate and mixed again for 18 hours. After 18 hours, the solution was removed from the stir bar vial and the pH of the solution was measured using a calibrated pH meter.
[352] The pH measured for the Diclofenac Sodium Transdermal System is shown in Table 52 below.
[353] Weight and Weight Percent of Each Component (Based on Total Solution Weight) for Four Diclofenac Sodium Transdermal SystemsDiclo-P10Diclo-P11Diclo-P12Diclo-P13 Diclofenac Sodium0.6 g (9.2%)0.6 g (9.1%)0.6 g (9.0%)0.6 g (9.0%) Propylene glycol0.9 g (13.9%)0.9 g (13.7%)0.9 g (13.6%)0.9 g (13.4%) NaOH00.035 g (0.5%)0.05 g (0.8%)0.1 g (1.5%) PIB Adhesive (30% Solids)4 g (61.5%)4 g (60.9%)4 g (60.6%)4 g (59.7%) Heptane1 g (15.4%)1 g (15.2%)1 g (15.2%)1 g (14.9%) DI water00.035 g (0.5%)0.05 g (0.8%)0.1 g (1.5%)
[354] Weight and theoretical weight percentage of each component present in the dried film for four diclofenac sodium transdermal administration systemsDiclo-P10Diclo-P11Diclo-P12Diclo-P13 Diclofenac Sodium0.6 g (22.2%)0.6 g (21.9%)0.6 g (21.8%)0.6 g (21.4%) Propylene glycol0.9 g (33.3%)0.9 g (32.9%)0.9 g (32.7%)0.9 g (32.1%) NaOH00.035 g (1.3%)0.05 g (1.8%)0.1 g (3.6%) PIB Adhesive (30% Solids)1.2 g (44.4%)1.2 g (43.9%)1.2 g (43.6%)1.2 g (42.9%)
[355] PPA-HCl accumulation (μg / cm ² ) through human carcass skin for Diclofenac sodium transdermal administration systemDiclo-P10Diclo-P11Diclo-P12Diclo-P13 5 hours0.5659.01437.82010.5 10.5 hours4.71587.62619.32992.9 20 hours18.82273.73263.03513.1 24 hours28.42439.63420.63647.3
[356] Excess NaOH Concentration and pH in Four Diclofenac Sodium Transdermal SystemsDiclo-P10Diclo-P11Diclo-P12Diclo-P13 Excess NaOH concentration (% by weight)01.31.83.6 pH7.1710.5910.7211.28
[357] In the dried patches, when the calculated excess NaOH concentration increased from 0% to 3.6%, the accumulation of diclofenac sodium penetrated through the human corpse skin at 24 hours elapsed from 28.4 μg / cm ² to 3647.3 μg / cm Increased to ^two . At 24 hours, the accumulation of diclofenac sodium penetrated through human carcass skin in a system containing 1.3% NaOH (Diclo-P11) was 2439.6 μg / cm ² . This amount is about 85 times higher than in the formulation without NaOH (28.4 μg / cm ² , # Diclo-P10).
[358] The pH of Diclofenac Sodium, measured by the method described above, increased from 7.17 to 11.28 when the calculated excess NaOH concentration increased from 0% to 3.6% in dried patches.
[359] <Example 17>
[360] In vitro skin penetration experiments were performed using four diclofenac sodium transdermal gels. The formulations used to prepare these gels are listed in Table 53, where each component of the formulation is expressed in weight and weight percent. The weight of sodium hydroxide (NaOH) was 0g, 0.02g, 0.03g and 0.05g for # Diclo-DG25, -DG27, -DG28 and -DG29 formulations, respectively.
[361] In vitro penetration experiments of diclofenac sodium from these gels into human carcass skin were performed using Franz-type diffusion cells having a diffusion area of 1 cm ² . The human carcass skin was cut to the appropriate size and fixed between the supply and reception chambers of the diffusion cell with the stratum corneum face towards the donor solution. Three diffusion cells were used for each formulation.
[362] A solution of 10% ethanol and 90% water was used as the aqueous solution. The volume of the aqueous solution was 8 ml. At each time point the aqueous solution was removed and replaced with fresh ethanol / water solution. Dietofenac sodium concentration in the selected aqueous solution was analyzed by HPLC. Accumulation of Diclofenac Sodium through human carcass skin was calculated using Diclofenac Sodium concentration measured in the aqueous solution and is shown in Table 54 and FIG. 13.
[363] Since Diclofenac Sodium does not seem to react with NaOH, the NaOH concentrations shown in Table 53 are equal to the excess NaOH concentration.
[364] Weight and Weight Percent of Each Component (Based on Total Solution Weight) for Four Diclofenac Sodium Transdermal GelsDiclo-DG25Diclo-DG27Diclo-DG28Diclo-DG29 Diclofenac Sodium0.3 g (14.1%)0.3 g (13.8%)0.3 g (13.7%)0.3 g (13.50%) Propylene glycol0.6 g (28.2%)0.6 g (27.6%)0.6 g (27.4%)0.6 g (26.9%) ethyl alcohol1 g (46.9%)1 g (46.1%)1 g (45.7%)1 g (44.8%) DI water0.2 g (9.4%)0.22 g (10.1%)0.23 g (10.5%)0.25 g (11.2%) HPMC0.03 g (1.4%)0.03 g (1.4%)0.03 g (1.4%)0.03 g (1.3%) NaOH00.02 g (0.9%)0.03 g (1.4%)0.05 g (2.2%)
[365] PPA-HCl accumulation (μg / cm ² ) through human carcass skin for Diclofenac Sodium Transdermal GelDiclo-DG25Diclo-DG27Diclo-DG28Diclo-DG29 5 hours16.850.6175.9585.2 10.5 hours29.8147.5503.51499.8 20 hours53.4252.3896.41988.1 24 hours65.3270.41023.32036.8
[366] Excess NaOH Concentration of Four Diclofenac Sodium Transdermal GelsDiclo-DG25Diclo-DG27Diclo-DG28Diclo-DG29 Excess NaOH concentration (% by weight)00.91.42.2
[367] On the gel, when the calculated excess NaOH concentration increased from 0% to 2.2% (Table 55), the accumulation of diclofenac sodium penetrated through the human corpse skin at 24 hours elapsed from 65.3 μg / cm ² to 2036.8 μg. increased to / cm ² . At 24 hours, the accumulation of diclofenac sodium penetrated through the human carcass skin from a gel containing 0% NaOH (Diclo-DG27) was 270.4 μg / cm ² . This amount is about 4 times higher than in the formulation without NaOH (65.3 μg / cm ² , # Diclo-DG25).
[368] Example 18
[369] In vitro skin penetration experiments were performed using four testosterone transdermal administration systems. The formulations used to prepare this system are listed in Table 56, where each component of the formulation is expressed in weight and weight percent. The weight of sodium hydroxide (NaOH) was 0g, 0.02g, 0.04g and 0.075g for # Test-P91, -P92, -P93 and -P94 formulations, respectively. Each formulation was covered with a release liner and dried for 2 hours in an oven maintained at 55 ° C. to remove water and other solvents. The dried DIA / release film release film was laminated to a backing film. The backing / drug-in-adhesive / release liner laminate was cut into 11/16 inch diameter discs. The theoretical weight percent (calculated assuming volatile components were removed during drying) for each component after drying is shown in Table 57.
[370] In vitro penetration of testosterone from these plates through human carcass skin was performed using Franz-type diffusion cells with a 1 cm ² diffusion area. The volume of the aqueous solution was 8 ml. Human carcass skin was cut to a suitable size and placed on a flat surface with the stratum corneum side facing up. The release film was peeled off from the thin layer. The backing layer / DIA film was placed on a piece of skin with the adhesive side facing towards the stratum corneum layer. The skin / adhesive / backing laminate was fixed between the supply and reception chambers of the diffusion cell with the skin side facing towards the aqueous solution. Three diffusion cells were used for each formulation.
[371] The cell was filled with a solution of 10% ethanol and 90% water. At each time point the aqueous solution was completely removed and replaced with fresh ethanol / water solution. After taking the sample, the testosterone concentration in the aqueous solution was analyzed by HPLC. Accumulation of testosterone through human carcass skin was calculated using testosterone concentrations measured in the aqueous solution, and are shown in Table 58 and FIG. 14.
[372] Since testosterone does not seem to react with NaOH, the NaOH concentrations shown in Table 57 are the same as the excess NaOH concentrations.
[373] The pH of the patch was measured by the following method. Holes were drilled in a 2.5 cm ² round patch. Pipette 10 ml purified water into the glass vial and stir bar into the glass vial. The membrane was removed from the patch and placed in the vial with the patch. The vial was placed on a stir plate and the water / patch / membrane mixture was mixed for 5 minutes until the membrane was removed from the vial. The vial was placed back on the stir plate and mixed again for 18 hours. After 18 hours, the stir bar was removed from the vial and the pH of the solution was measured using a calibrated pH meter. The pH measured for the testosterone transdermal administration system is shown in Table 59 below.
[374] Weight and weight percent of each component (based on total solution weight) for four testosterone transdermal administration systemsTest-p91Test-p92Test-p93Test-p94 Testosterone0.3 g (4.8%)0.3 g (4.7%)0.3 g (4.7%)0.3 g (4.7%) ethyl alcohol0.5 g (7.9%)0.5 g (7.9%)0.5 g (7.8%)0.5 g (7.8%) Propylene glycol0.5 g (7.9%)0.5 g (7.9%)0.5 g (7.8%)0.5 g (7.8%) NaOH00.02 g (0.3%)0.04 g (0.6%)0.075 g (1.2%) DI water00.02 g (0.3%)0.04 g (0.6%)0.075 g (1.2%) PIB Adhesive (30% Solids)4 g (63.5%)4 g (63.1%)4 g (62.7%)4 g (62.0%) Heptane1 g (15.9%)1 g (15.8%)1 g (15.7%)1 g (15.5%)
[375] Weight and theoretical weight percentage of each component present in the dried film for the four testosterone transdermal administration systemsTest-p91Test-p92Test-p93Test-p94 Testosterone0.3 g (15.0%)0.3 g (14.9%)0.3 g (14.7%)0.3 g (14.5%) Propylene glycol0.5 g (25.0%)0.5 g (24.8%)0.5 g (24.5%)0.5 g (24.1%) NaOH00.02 g (1.0%)0.04 g (2.0%)0.075 g (3.6%) PIB adhesive1.2 g (60.0%)1.2 g (59.4%)1.2 g (58.8%)1.2 g (57.8%)
[376] Testosterone accumulation (μg / cm ² ) through human carcass skin for testosterone transdermal administration systemTest-p91Test-p92Test-p93Test-p94 5 hours1.97.336.176.1 16.25 hours4.328.578.0147.8 20 hours5.336.689.5168.8 25 hours7.449.9108.0199.4
[377] Excess NaOH Concentration and pH in Four Testosterone Transdermal SystemsTest-p91Test-p92Test-p93Test-p94 Excess NaOH concentration (% by weight)01.02.03.6 pH7.149.1710.0410.32
[378] In the dried patches, when the calculated excess NaOH concentration increased from 0% to 3.6%, the accumulation of testosterone penetrated through the human carcass skin at 24 hours passed from 7.4 μg / cm ² to 199.4 μg / cm ^2. Increased to. At 24 hours, the accumulation of testosterone penetrated through human carcass skin in a system containing 1.0% NaOH (Test-P92) was 49.9 μg / cm ² . This amount was about 6 times higher than in the formulation without NaOH (7.4 μg / cm ² , # Test-P91). This result means that the penetration of testosterone can be increased when the excess NaOH concentration is as low as 1.0%.
[379] The pH of testosterone measured using the method described above increased from 7.14 to 10.32 when the calculated excess NaOH concentration increased from 0% to 3.6% in the dried patch.
[380] Example 19
[381] In vitro skin penetration experiments were performed using an oxybutynin HCl transdermal administration system. The formulations used to prepare this system are listed in Table 60, where each component of the formulation is expressed in weight and weight percent. The weight of sodium hydroxide (NaOH) was 0.15g, 0.25g and 0.35g for # Oxy-P1, -P2 and -P3 formulations, respectively. Each formulation was covered with a release liner and dried for 2 hours in an oven maintained at 55 ° C. to remove water and other solvents. The dried DIA / release film release film was laminated to a backing film. The backing / drug-in-adhesive / release liner laminate was cut into 11/16 inch diameter discs. The theoretical percent weight (calculated assuming volatile components were removed during drying) for each component after drying is shown in Table 61.
[382] In vitro penetration experiments of oxybutynin HCl into human carcass skin from these hands were performed using Franz-type diffusion cells having a diffusion area of 1 cm ² . The volume of the aqueous solution was 8 ml. Human carcass skin was cut to a suitable size and placed on a flat surface with the stratum corneum side facing up. The release film was peeled off from the thin layer. The backing layer / DIA film was placed on a piece of skin with the adhesive side facing towards the stratum corneum. The skin / adhesive / backing laminate was fixed between the supply and reception chambers of the diffusion cell with the skin side facing towards the aqueous solution. Three diffusion cells were used for each formulation.
[383] The cell was filled with a solution of 10% ethanol and 90% water. At each time point the aqueous solution was completely removed and replaced with fresh ethanol / water solution. After taking the sample, the oxybutynin HCl concentration in the aqueous solution was analyzed by HPLC. Accumulation of oxybutynin HCl through human body skin was calculated using the oxybutynin HCl concentration measured in the aqueous solution and is shown in Table 62.
[384] Weight and weight percent of each component (based on total solution weight) for three oxybutynin HCl transdermal administration systemsOxy-P1Oxy-P2Oxy-P3 Oxybutynin HCl0.5 g (6.5%)0.5 g (6.3%)0.5 g (6.2%) DI water0.65 g (8.4%)0.75 g (9.5%)0.85 g (10.5%) NaOH0.15 g (1.9%)0.25 g (3.2%)0.35 g (4.3%) Propylene glycol0.3 g (3.9%)0.3 g (3.8%)0.3 g (3.7%) Triton X 1000.1 g (1.3%)0.1 g (1.3%)0.1 g (1.2%) PIB Adhesive (30% Solids)4 g (51.9%)4 g (50.6%)4 g (49.4%) Methyl alcohol1 g (13.0%)1 g (12.7%)1 g (12.3%) Heptane1 g (13.0%)1 g (12.7%)1 g (12.3%)
[385] Weight and theoretical weight percentage of each component present in the dried film for three oxybutynin HCl transdermal administration systemsOxy-P1Oxy-P2Oxy-P3 Oxybutynin HCl0.5 g (15.4%)0.5 g (14.9%)0.5 g (14.5%) NaOH0.15 g (4.6%)0.25 g (7.5%)0.35 g (10.1%) Propylene glycol0.3 g (9.2%)0.3 g (9.0%)0.3 g (8.7%) Triton X 1000.1 g (3.1%)0.1 g (3.0%)0.1 g (2.9%) PIB adhesive1.2 g (36.9%)1.2 g (35.8%)1.2 g (34.8%) Methyl alcohol1 g (30.8%)1 g (29.9%)1 g (29.0%)
[386] Oxybutynin HCl accumulation (μg / cm ² ) through human carcass skin for oxybutynin HCl transdermal administration systemOxy-P1Oxy-P2Oxy-P3 5 hours691.02108.71399.5 10.5 hours1259.42615.91865.9 24 hours1747.72853.52322.8
[387] When the NaOH concentration in the dried patch to increase from 4.6% to 10.1%, 24 hours at the time of the accumulated amount of oxybutynin HCl through the human body, the skin will vary at 1747.7㎍ / cm ² to 2322.8㎍ / cm ² It became.
[388] Example 20
[389] In vitro skin penetration experiments were performed using four diclofenac sodium transdermal administration systems. The formulations used to prepare this system are listed in Table 63, where each component of the formulation is expressed in weight and weight percent. The weight of sodium hydroxide (NaOH) was 0g, 0.01g, 0.02g and 0.05g for # Dclo-P64, -P86, -P65 and -P87 formulations, respectively. Each formulation was covered with a release liner and dried for 2 hours in an oven maintained at 55 ° C. to remove water and other solvents. The dried DIA / release film release film was laminated to a backing film. The backing / drug-in-adhesive / release liner laminate was cut into 11/16 inch diameter discs. Theoretical weight percentages for each component after drying (calculated assuming volatile components were removed during drying) are shown in Table 64.
[390] In vitro penetration experiments of Diclofenac Sodium into human carcass skin from these hands were performed using Franz-type diffusion cells with a 1 cm ² diffusion area. The volume of the aqueous solution was 8 ml. Human carcass skin was cut to a suitable size and placed on a flat surface with the stratum corneum side facing up. The release film was peeled off from the thin layer. The backing layer / DIA film was placed on a piece of skin with the adhesive side facing towards the stratum corneum. The skin / adhesive / backing laminate was fixed between the supply and reception chambers of the diffusion cell with the skin side facing towards the aqueous solution. Twelve diffusion cells were used for each formulation.
[391] The cell was filled with a solution of 10% ethanol and 90% water. At each time point, pH was measured at the interface between the skin fragments and patches of the three diffusion cells. For pH measurement, the aqueous solution was removed, the clamp and feed chamber were removed, and the forceps were used to remove the patch from the skin piece. The skin pieces were placed in a holding room, and the pH of the solution in the skin was measured by placing a microelectrode directly on the surface of the skin pieces. The pH measured at the skin / patch interface is shown in Table 65. For the other cells, the aqueous solution was completely removed and replaced with fresh ethanol / water solution. After taking the sample, the diclofenac sodium concentration in the aqueous solution was analyzed by HPLC. The pH of the collected aqueous solution was measured using a pH meter. Accumulation of Diclofenac Sodium through human carcass skin was calculated using Diclofenac Sodium concentration measured in aqueous solution and is shown in Table 66. The pH of the aqueous solution is shown in Table 67.
[392] Since Diclofenac Sodium does not seem to react with NaOH, the NaOH concentrations listed in Table 64 are the same as the excess NaOH concentrations.
[393] The pH of the patch was measured by the following method. Holes were drilled in a 2.5 cm ² round patch. Pipette 10 ml purified water into the glass vial and stir bar into the glass vial. The membrane was removed from the patch and placed in the vial with the patch. The vial was placed on a stir plate and the water / patch / membrane mixture was mixed for 5 minutes until the membrane was removed from the vial. The vial was placed back on the stir plate and mixed again for 18 hours. After 18 hours, the stir bar was removed from the vial and the pH of the solution was measured using a calibrated pH meter. The pH measured for the Diclofenac Sodium Transdermal System is shown in Table 68 below.
[394] Weight and Weight Percent of Each Component (Based on Total Solution Weight) for Four Diclofenac Sodium Transdermal SystemsDiclo-P64Diclo-P86Diclo-P65Diclo-P87 Diclofenac Sodium0.6 g (9.2%)0.6 g (9.2%)0.9 g (9.2%)0.6 g (9.1%) Propylene glycol0.9 g (13.8%)0.9 g (13.8%)0.9 g (13.8%)0.9 g (13.6%) NaOH00.01 g (0.2%)0.02 g (0.3%)0.05 g (0.8%) PIB Adhesive (30% Solids)4 g (61.5%)4 g (61.3%)4 g (61.2%)4 g (60.6%) Heptane1 g (15.4%)1 g (15.3%)1 g (15.3%)1 g (15.2%) DI water00.01 g (0.2%)0.02 g (0.3%)0.05 g (0.8%)
[395] Weight and theoretical weight percentage of each component present in the dried film for four diclofenac sodium transdermal administration systemsDiclo-P64Diclo-P86Diclo-P65Diclo-P87 Diclofenac Sodium0.6 g (22.2%)0.6 g (22.1%)0.9 g (22.1%)0.6 g (21.8%) Propylene glycol0.9 g (33.3%)0.9 g (33.2%)0.9 g (33.1%)0.9 g (32.7%) NaOH00.01 g (0.4%)0.02 g (0.7%)0.05 g (1.8%) PIB adhesive1.2 g (44.4%)1.2 g (44.3%)1.2 g (44.1%)1.2 g (43.6%)
[396] PH measured at the interface between the skin and the patch at each time point for the Diclofenac Sodium Transdermal SystemDiclo-P64Diclo-P86Diclo-P65Diclo-P87 3 hours*11.0*10.3 6 hours*11.011.29.8 10 hours8.510.910.710.2 24 hours*9.710.19.4
[397] * Not enough solution at the interface to measure
[398] Diclofenac Sodium Accumulation (μg / cm ² ) through Human Carcass Skin for Diclofenac Sodium Transdermal SystemDiclo-P64Diclo-P86Diclo-P65Diclo-P87 3 hours7.51.533.4257.7 6 hours39.618.3269.3793.3 10 hours63.249.3654.41652.2 24 hours34.6227.71733.83257.7
[399] PH measured in aqueous solution at each time point for the Diclofenac Sodium Transdermal SystemDiclo-P64Diclo-P86Diclo-P65Diclo-P87 3 hours8.18.09.310.8 6 hours7.47.97.710.0 10 hours7.07.67.37.7 24 hours7.08.97.59.6
[400] Excess NaOH Concentration and pH in Four Diclofenac Sodium Transdermal SystemsDiclo-P64Diclo-P86Diclo-P65Diclo-P87 Excess NaOH concentration (% by weight)00.40.71.8 pH7.408.9910.7110.38
[401] When the calculated excess NaOH concentration increased from 0% to 1.8% in the dried patch (Table 64), the accumulated amount of Diclofenac Sodium penetrated through the human body skin at 24 hours was 34.6 μg / cm ^2. Increased from to 3257.7 μg / cm ² . At 24 hours, the accumulation of diclofenac sodium penetrated through human carcass skin in a system containing 0.4% NaOH (Diclo-P86) was 227.7 μg / cm ² . This amount is about 6 times higher than in the formulation without NaOH (34.6 μg / cm ² , # Diclo-P64). This result means that the penetration of Diclofenac Sodium can be increased when the NaOH concentration is as low as 0.4%.
[402] Although the concentration of NaOH increased from 0.4% to 1.8%, the pH measured at the interface between the skin and the patch was approximately the same as in Table 67. The lower the amount of solution at the interface, the higher the NaOH concentration. Since there is not a sufficient amount of solution in the upper part of the skin, it was difficult to measure the pH of the skin fragment and patch interface for each formulation when NaOH was not present or when the concentration of NaOH was low.
[403] At low NaOH concentrations, it was difficult to measure pH at the skin and patch interface, so the pH of the aqueous solution was measured at each time point. The pH of the aqueous solutions described in Table 67 indicates that the pH is determined by the time interval between sampling, the NaOH concentration on the patch and the time point measured. As the concentration of NaOH in the patch increased from 0.4% to 1.8%, the pH at 3 hours increased from 8.0 to 10.8.
[404] The pH of Diclofenac Sodium Patch measured using this method increased from 7.40 to 10.38 when the dried patch patch, calculated excess NaOH concentration increased from 0% to 1.8% (Table 68).

权利要求:
Claims (51)
[1" claim-type="Currently amended] Administration of a drug-release agent applied to the body surface in combination with the drug to a topical site on the patient's body surface in a predetermined amount effective to enhance the influx of the drug through the topical site of the body surface without causing damage to the body surface A method of enhancing the influx of drugs through the body surface, including.
[2" claim-type="Currently amended] The method of claim 1, wherein the predetermined amount of hydroxide-releasing agent is an amount effective to bring the pH of the local body site in the range of about 8 to 13 during drug administration.
[3" claim-type="Currently amended] The method of claim 2 wherein the pH is between 8 and 11.5.
[4" claim-type="Currently amended] The method of claim 1 wherein the body surface is skin.
[5" claim-type="Currently amended] The method of claim 1 wherein the body surface is mucosal tissue.
[6" claim-type="Currently amended] The method of claim 1 wherein the drug and the hydroxide-releasing agent are applied simultaneously to the body surface.
[7" claim-type="Currently amended] The method of claim 1 wherein the drug and the hydroxide-releasing agent are present in a single pharmaceutical formulation.
[8" claim-type="Currently amended] 8. The method of claim 7, wherein the pharmaceutical formulation is in aqueous form.
[9" claim-type="Currently amended] The method of claim 8, wherein the pharmaceutical formulation has a pH of about 8-13.
[10" claim-type="Currently amended] 10. The method of claim 9, wherein the pH is about 8 to 11.5.
[11" claim-type="Currently amended] 9. The method of claim 8, wherein the aqueous formulation is selected from the group consisting of creams, gels, lotions and pastes.
[12" claim-type="Currently amended] The method of claim 1, wherein a hydroxide-releasing agent is administered to a localized portion of the body surface prior to administration of the drug, wherein the hydroxide releasing agent has a pH of about 8 to 13 and consists of a protic solvent in an aqueous solution.
[13" claim-type="Currently amended] The method of claim 1 wherein the hydroxide-releasing agent is selected from the group consisting of inorganic hydroxides, inorganic oxides, metal salts of weak acids, and mixtures thereof.
[14" claim-type="Currently amended] The method of claim 13 wherein the hydroxide-releasing agent is an inorganic hydroxide.
[15" claim-type="Currently amended] 15. The method of claim 14, wherein the inorganic hydroxide is selected from the group consisting of ammonium hydroxide, alkaline metal hydroxides, alkaline earth metal hydroxides, and mixtures thereof.
[16" claim-type="Currently amended] 16. The method of claim 15, wherein the inorganic hydroxide is selected from the group consisting of ammonium hydroxide, sodium hydroxide, calcium hydroxide, potassium hydroxide, magnesium hydroxide and mixtures thereof.
[17" claim-type="Currently amended] The method of claim 16 wherein the inorganic hydroxide is sodium hydroxide.
[18" claim-type="Currently amended] The method of claim 13, wherein the hydroxide-releasing agent is an inorganic oxide.
[19" claim-type="Currently amended] The method of claim 13 wherein the hydroxide-releasing agent is a metal salt of a weak acid.
[20" claim-type="Currently amended] 15. The amount of inorganic hydroxide in the formulation according to claim 14, which is the sum of (a) the amount necessary to neutralize any acidic species in the formulation plus (b) an amount equal to about 0.5% to 4.0% by weight of the formulation. How to.
[21" claim-type="Currently amended] The method of claim 20, wherein the drug is an acidic drug in the form of a free acid, and wherein the amount of (a) is an amount necessary to neutralize the acidic drug and other acidic species in the formulation.
[22" claim-type="Currently amended] 22. The method of claim 21, wherein the drug is a basic drug in free base form.
[23" claim-type="Currently amended] The method of claim 2, wherein the drug is a base addition salt of an acidic compound.
[24" claim-type="Currently amended] 2. The drug and hydroxide-releasing agent of claim 1, wherein the drug and hydroxide-releasing agent are administered by applying a drug delivery device to a localized portion of the patient's body surface to form a body surface-transmitting device interface, wherein the device is administered with the drug and the hydroxide-releasing agent. And an outer backing layer which, in use, serves as an outer surface of the device.
[25" claim-type="Currently amended] The method of claim 1, wherein the drug is administered in combination with an additional penetration enhancer.
[26" claim-type="Currently amended] The method of claim 1, wherein the drug and the hydroxide-releasing agent are administered without any additional penetration enhancer.
[27" claim-type="Currently amended] (a) a therapeutically effective amount of a drug;
(b) an amount of a hydroxide-releasing agent effective to enhance the influx of the drug through a topical portion of the body surface without causing damage to the body surface; And
(c) Pharmaceutically acceptable carriers suitable for topical or transdermal drug administration:
A composition useful for drug delivery through a body surface comprising an aqueous formulation of a.
[28" claim-type="Currently amended] 29. The composition of claim 27, wherein the pH is about 8-13.
[29" claim-type="Currently amended] 29. The composition of claim 28, wherein the pH is about 8 to 11.5.
[30" claim-type="Currently amended] The composition of claim 27 consisting of a cream, gel, or paste.
[31" claim-type="Currently amended] 28. The composition of claim 27, wherein the composition is substantially free of additional penetration enhancers.
[32" claim-type="Currently amended] 28. The composition of claim 27, wherein the composition is substantially free of inorganic solvents.
[33" claim-type="Currently amended] 29. The composition of claim 27, wherein the hydroxide-releasing agent is selected from the group consisting of inorganic hydroxides, inorganic oxides, metal salts of weak acids and mixtures thereof.
[34" claim-type="Currently amended] 34. The composition of claim 33, wherein the hydroxide-releasing agent is an inorganic hydroxide.
[35" claim-type="Currently amended] 35. The composition of claim 34, wherein said inorganic hydroxide is selected from the group consisting of ammonium hydroxide, alkali metal hydroxides, alkaline earth calcitic hydroxides, and mixtures thereof.
[36" claim-type="Currently amended] 36. The composition of claim 35, wherein the inorganic hydroxide is selected from the group consisting of ammonium hydroxide, sodium hydroxide, calcium hydroxide, potassium hydroxide, magnesium hydroxide and mixtures thereof.
[37" claim-type="Currently amended] 37. The composition of claim 36, wherein the inorganic hydroxide is sodium hydroxide.
[38" claim-type="Currently amended] 34. The composition of claim 33, wherein the hydroxide-releasing agent is an inorganic oxide.
[39" claim-type="Currently amended] 34. The composition of claim 33, wherein the hydroxide-releasing agent is a metal salt of a weak acid.
[40" claim-type="Currently amended] 35. The amount of inorganic hydroxide in a formulation according to claim 34, which is the total amount of (a) the amount necessary to neutralize any acidic species in the formulation plus (b) an amount equal to about 0.5% to 4.0% by weight of the formulation. Composition.
[41" claim-type="Currently amended] The composition of claim 27, wherein the drug is an acid addition salt of a basic compound and the amount of (a) is an amount necessary to neutralize any other acid species and acid addition salt in the formulation.
[42" claim-type="Currently amended] 28. The composition of claim 27, wherein the drug is an acidic drug in free acid form and the amount of (a) is an amount necessary to neutralize the acidic drug and any other acidic species in the formulation.
[43" claim-type="Currently amended] The composition of claim 27, wherein the drug is a basic drug in the form of a free base.
[44" claim-type="Currently amended] The composition of claim 27 wherein the drug is a basic addition salt of an acidic compound.
[45" claim-type="Currently amended] 28. The composition of claim 27, wherein the drug is nonionic.
[46" claim-type="Currently amended] (a) at least one drug source containing an amount of a hydroxide-releasing agent and a drug effective to enhance the influx of the drug through a topical portion of the body surface without causing damage to the body surface;
(b) means for maintaining the system in a drug and enhancer delivery relationship to the body surface; And
(c) a backing layer that serves as the outer surface of the device in use:
System for topical or transdermal administration of a drug comprising a.
[47" claim-type="Currently amended] 47. The system of claim 46, wherein said support layer is occluded.
[48" claim-type="Currently amended] 47. The system of claim 46, wherein said drug source comprises a polymeric adhesive.
[49" claim-type="Currently amended] 49. The system of claim 48, wherein said polymeric adhesive is provided as a means for maintaining a system in the relationship of drug and fortifier delivery to body service.
[50" claim-type="Currently amended] 47. The system of claim 46, wherein said drug source comprises a hydrogel.
[51" claim-type="Currently amended] 47. The system of claim 46, wherein the drug source consists of a sealed pouch containing the drug and a hydroxide-releasing agent in a liquid or semisolid formulation.

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EP0275716B1|1995-08-09|Transdermal estrogen/progestin dosage unit, and fertility control kit comprising said dosage unit.

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EP0721348B1|1999-09-01|Monoglyceride/lactate ester permeation enhancer

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US7214381B2|2007-05-08|Composition for transdermal and/or transmucosal administration of active compounds that ensures adequate therapeutic levels

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US5314694A|1994-05-24|Transdermal formulations, methods and devices

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EP0341202B1|1992-07-29|Transdermal monolithic systems

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US6004578A|1999-12-21|Permeation enhances for transdermal drug delivery compositions, devices and methods

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US5122382A|1992-06-16|Transdermal contraceptive formulations, methods and devices

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ES2494853T3|2014-09-16|Transdermal Administration System

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US4743249A|1988-05-10|Dermal and transdermal patches having a discontinuous pattern adhesive layer

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CA2163003C|2003-01-28|Solubilizer and external preparations containing the same

同族专利:

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公开号 | 公开日

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KR100795237B1|2008-01-15|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1999-12-16|Priority to US46509899A

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1999-12-16|Priority to US09/465,098

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2000-05-11|Priority to US56988900A

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2000-05-11|Priority to US09/569,889

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2000-06-30|Priority to US60789200A

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2000-06-30|Priority to US09/607,892

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2000-12-14|Priority to US09/738,395

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2000-12-14|Priority to US09/738,395

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2000-12-14|Priority to US09/738,410

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2000-12-14|Priority to US09/738,410

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2000-12-15|Application filed by 더마트랜드 인코포레이티드

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2002-10-31|Publication of KR20020082468A

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2008-01-15|Application granted

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2008-01-15|Publication of KR100795237B1

优先权:

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申请号 | 申请日 | 专利标题

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US46509899A| true| 1999-12-16|1999-12-16|

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US09/465,098|1999-12-16|

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US56988900A| true| 2000-05-11|2000-05-11|

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US09/569,889|2000-05-11|

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US60789200A| true| 2000-06-30|2000-06-30|

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US09/607,892|2000-06-30|

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US09/738,410|US6586000B2|1999-12-16|2000-12-14|Hydroxide-releasing agents as skin permeation enhancers|

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US09/738,410|2000-12-14|

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US09/738,395|2000-12-14|

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US09/738,395|US6719997B2|2000-06-30|2000-12-14|Transdermal administration of pharmacologically active amines using hydroxide-releasing agents as permeation enhancers|