Transdermal preparation containing antioxidants

Abstract

To provide transdermal absorption preparations in which a sufficient amount of drug to express the desired efficacy is stably retained in the paste and which have skin irritation reduced as much as possible.SOLUTION: Provided is a transdermal absorption preparation containing a drug and a stabilizer in a base, in which the stabilizer is selected from the group consisting of thiosulfate, sulfite, bisulfite, and nitrite. The transdermal absorption preparation preferably further contains glycerin.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to transdermal absorption preparations such as tape preparations and patch preparations (referring to a dosage form in which a reservoir layer containing a drug and an adhesive layer are laminated), which are used to apply a required drug to the skin and administer it to the subcutaneous tissue or the systemic circulation system through the biological membrane.

Background Art

[0002] Generally, in the case of oral administration of drugs, the absorbability of drugs is affected by factors such as the pH value in the stomach or intestine and the presence or absence of contents, so it is difficult to always keep the absorption amount of drugs constant, and it is also difficult to gradually administer a certain amount of drugs over a long period of time. In oral administration, since the absorption amount is not constant, side effects may sometimes occur due to a sudden increase in blood concentration, and in the case of drugs with a short half-life, the duration of the effective blood concentration becomes short, and sufficient drug efficacy may not be maintained for a long time. Furthermore, in injection administration, there are problems such as pain during administration and inconvenience of the administration method. In the case of preparations for local action, it is necessary to maintain a certain concentration of the drug in the subcutaneous tissue through the stratum corneum.

[0003] Therefore, in order to solve these problems, the development of transdermal absorption preparations has been actively promoted because a constant effective blood concentration can be maintained over a long period of time, and improvements in simplicity, functionality, etc. can be expected. Since this type of transdermal absorption preparation administers drugs to the systemic circulation system through the stratum corneum of the skin, which originally has a barrier function to prevent the invasion of foreign substances into the body, it is not always easy to administer an amount of drug sufficient to exhibit the desired drug efficacy. Usually, measures such as adding an absorption promoter to the base to enhance the permeability of the drug or increasing the adhesive area are taken.

[0004] When transdermal formulations are applied as patches, they have the side effect of irritating the skin during application, so it is preferable to keep the application area as small as possible. To reduce such side effects, it is desirable to reduce the application area of ​​the patch by improving the skin permeability of the drug through the addition of absorption enhancers. For this reason, many proposals have been made regarding absorption enhancers, which are added to formulations to promote the transdermal absorption of drugs (for example, Patent Documents 1 and 2). In addition, when the drug itself is a substance with poor stability, many studies have been conducted on stabilizers to prevent decomposition during storage (for example, Patent Document 3). In the case of transdermal formulations containing rotigotine, a method for producing such formulations is known that includes a step of mixing rotigotine and an antioxidant in a weight ratio of 1:0.0001 to 0.1 (Patent Document 4). The antioxidant in Patent Document 4 is one or more substances selected from the group consisting of tocopherol and its esters, ascorbic acid, ascorbyl palmitate, 2,5-dihydroxybenzoic acid, butylhydroxytoluene, butylhydroxyanisole, and propyl gallate. Furthermore, in a transdermal patch containing rotigotine comprising a support, a drug-containing layer, and a release liner, a transdermal patch is known in which the drug-containing layer contains (1) a rubber-based adhesive, (2) rotigotine or a salt thereof, and (3) an inhibitor of the formation of rotigotine degradation products (Patent Document 5). In Patent Document 5, mercaptobenzimidazole and sulfites are used as the inhibitor of rotigotine degradation products. In the case of fentanyl-containing transdermal formulations, there is a known patch comprising a support and an adhesive layer laminated on at least one surface of the support, wherein the adhesive layer contains at least one selected from the group consisting of fentanyl and its salts, an adhesive base, and an antioxidant having a sulfur atom in its molecule (Patent Document 6). In Patent Document 6, the antioxidant having a sulfur atom in its molecule is at least one selected from the group consisting of 2-mercaptobenzimidazole and sodium pyrosulfite. [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] Special Publication No. 10-507199 (Patent No. 3228341) [Patent Document 2] International Publication No. 2011 / 049038 (Patent No. 5913981) [Patent Document 3] JP-A-3-261722 (Patent No. 3002493) [Patent Document 4] Special Publication No. 2017-515871 [Patent Document 5] Japanese Patent Publication No. 2013-079220 (Japanese Patent No. 5856424) [Patent Document 6] International Publication No. 2017 / 073516 (Patent No. 6453481) [Overview of the project] [Problems that the invention aims to solve]

[0006] This invention relates to a transdermal formulation containing a stabilizer. The stabilizer improves the stability of the drug in the adhesive layer. However, the addition of the stabilizer to the adhesive base should not result in a decrease in adhesiveness or an increase in skin irritation. Therefore, it is necessary to select the optimal stabilizer considering the target drug, the adhesive base used, and other factors. Furthermore, since stabilizers act on the skin during the period that the transdermal formulation is applied to the skin, they must not cause skin irritation. Many stabilizers have been used to date. Typical stabilizers include antioxidants such as BHT (dibutylhydroxytoluene), tocopherol, vitamin C and its derivatives, and hydroquinone. Thiosulfites and sulfites have strong reducing properties and powerful antioxidant effects. However, these compounds are inorganic salts and have poor compatibility with rubber-based adhesives and acrylic-based adhesives, which are common bases for transdermal formulations. They tend to aggregate into parts within the base, making it difficult for them to exert a stabilizing effect. In view of the above circumstances, the object of the present invention is to provide a transdermal formulation that stably retains a sufficient amount of drug in the ointment to exhibit the desired pharmacological effect. [Means for solving the problem]

[0007] While diligently investigating novel stabilizers, the inventors discovered that inorganic reducing substances such as thiosulfates and sulfites provide excellent stability for many drugs and have low skin irritation. These compounds are poorly soluble in many organic solvents and have extremely poor compatibility with rubber-based adhesives, acrylic-based adhesives, and silicone-based adhesives, which are bases for transdermal formulations. Therefore, even when thiosulfates and sulfites are incorporated, they do not disperse uniformly and are less effective due to crystal precipitation. The inventors discovered that by further coexisting these inorganic salts with glycerin, thiosulfates and sulfites can be uniformly and finely dispersed in the base, thereby exhibiting the antioxidant effect of reducing inorganic salts, and thus completed the present invention. Thiosulfates and sulfites are well-known reducing agents and have long been used in cosmetics, food, and medical applications, with a wealth of safety data. However, while it is conceivable that adding these substances to transdermal formulations could impart stability to drugs, their inorganic salt nature makes them inconvenient to use. Although there is one reported case of sulfites being used in transdermal formulations (Patent No. 5856424), the addition of thiosulfates was completely unknown.

[0008] The present invention is as follows: [1] A transdermal absorption preparation comprising a drug and a stabilizer in a base, wherein the stabilizer is selected from the group consisting of thiosulfates, sulfites, bisulfites, and nitrites. [2] The transdermal formulation according to [1], wherein the base is one or more selected from the group consisting of acrylic adhesives, rubber adhesives, and silicone adhesives. [3] The transdermal preparation according to [1] or [2], wherein the content of the stabilizer in the total weight of the ointment containing the drug is 0.01 to 2% by weight. [4] A transdermal absorption preparation comprising a drug and a stabilizer in a base, wherein the stabilizer is selected from the group consisting of thiosulfates, sulfites, bisulfites, and nitrites, and further comprises glycerin. [5] The transdermal preparation described in [4], wherein the glycerin content is 0.01 to 20% by weight of the ointment containing the drug. [6] The transdermal formulation according to [4] or [5], wherein a drug, a stabilizer, and glycerin are present together in the adhesive base, and the amount of glycerin added is 1.5 to 2000 parts by weight per 1 part by weight of the stabilizer. [7] A transdermal absorption preparation according to [4] or [5], wherein a drug, a stabilizer, and glycerin are present together in the adhesive base, the amount of glycerin added is 1.5 to 2000 parts by weight per 1 part by weight of the stabilizer, and further contains an absorption enhancer. [8] A transdermal preparation according to any one of [1] to [7], wherein the drug is rotigotine or a salt thereof. [9] A transdermal preparation according to any one of [1] to [3], wherein the drug is rotigotine or a salt thereof, and further comprises an absorption enhancer.

[10] The transdermal formulation according to [9], wherein the absorption enhancer is selected from the group consisting of cetyl alcohol, diethanolamide laurate, isopropyl myristate (IPM), isopropyl palmitate (IPP), and stearic acid.

[11] The transdermal preparation according to [9] or

[10] , wherein the drug is rotigotine or a salt thereof, and the adhesive base is a mixture of polyisobutylene (PIB) and an acrylic compound containing cetyl alcohol.

[12] The transdermal formulation according to [9] or

[10] , wherein the drug is rotigotine or a salt thereof, and the adhesive base comprises styrene-isoprene-styrene block copolymer (SIS) and an acrylic mixture containing IPM.

[13] A transdermal preparation according to any one of [1] to [7], wherein the drug is fentanyl or a salt thereof.

[14] A transdermal preparation according to any one of [1] to [3], wherein the drug is fentanyl or a salt thereof, and further comprises an absorption enhancer.

[15] The transdermal formulation according to

[14] , wherein the absorption enhancer is selected from the group consisting of cetyl alcohol, lauric acid diethanolamide, isopropyl myristate (IPM), isopropyl palmitate (IPP), and stearic acid.

[16] The transdermal formulation according to

[14] or

[15] , wherein the drug is fentanyl or a salt thereof, and the base is a styrene-isoprene-styrene block copolymer (SIS) adhesive.

[17] A method for producing a transparent or translucent coating solution, comprising the step of mixing a rubber-based or acrylic adhesive solution with a drug; a stabilizer selected from the group consisting of thiosulfates, sulfites, bisulfites, and nitrites; and glycerin.

[18] A method for producing a coating solution, comprising the steps of mixing a drug, a stabilizer selected from the group consisting of thiosulfates, sulfites, bisulfites, and nitrites, and glycerin into a rubber-based or acrylic adhesive solution, and further mixing in a sucrose fatty acid ester. [Effects of the Invention]

[0009] The thiosulfates, sulfites, etc. (hereinafter referred to as thiosulfates, etc.) which are stabilizers contained in the transdermal preparation of the present invention are neutral compounds having a reducing anion. When the drug is a basic compound, it is considered to interact with anions such as thiosulfates to be stabilized and suppress decomposition. Furthermore, by using a combination of thiosulfates, etc. with known absorption promoters, the drug release amount per unit area and per unit time and the drug transferability into the skin can be extremely improved. This is considered to be because the above absorption promoter changes the physical properties of the base and penetrates into the skin to reduce the barrier function of the stratum corneum. As a result, the drug partition coefficient between the base and the skin changes, or the drug diffusion rate in the skin is increased, the drug release amount is improved, and the required amount of the drug can easily penetrate the skin and be absorbed into the body circulation system. Therefore, in the case of a tape preparation, a transdermal preparation having a larger effective dose than a conventional product of the same area can be obtained as compared with a conventional drug-containing transdermal preparation. In other words, the same effect as that of the conventional product can be obtained with a transdermal preparation having a smaller area than the conventional product. Therefore, even in a person sensitive to skin irritation, the occurrence of erythema is avoided, or the area of erythema is reduced. And since the area of the preparation can be small, the sticking operation is easy and there is no discomfort due to sticking.

Brief Description of Drawings

[0010] [Figure 1] Chromatogram of the rotigotine patch extract of Comparative Example 2 [Figure 2] Chromatogram of the rotigotine patch extract of Example 1 [Figure 3] Chromatogram (A) of the fentanyl patch extract of Example 3 and chromatogram (B) of the fentanyl patch extract of Comparative Example 4

Modes for Carrying Out the Invention

[0011] As stabilizers in the transdermal absorption preparation of the present invention, thiosulfates, sulfites, bisulfites, and nitrites can be mentioned. Examples of the salts include salts with alkali metals and salts with alkaline earth metals, and sodium salts are preferred. Thiosulfates and the like may be used alone or in combination with known absorption promoters. The addition amount of thiosulfates and the like is preferably 0.01 to 5% by weight in the base (total weight of the paste), and more preferably 0.02 to 2% by weight. If the addition amount in the base is less than 0.01% by weight, the stabilizing effect on the drug is weak, and if it exceeds 5% by weight, problems such as crystal precipitation in the base are likely to occur. Another feature of the present invention is to add a salt dissolution aid when blending thiosulfates and the like into the base. Inorganic salts such as sodium thiosulfate and sodium sulfite are extremely polar, and therefore have poor compatibility with rubber-based adhesives and acrylic-based adhesives. Also, they are completely insoluble in solvents such as ethyl acetate, toluene, and cyclohexane, which are solvents for these adhesives. Therefore, it is extremely difficult to dissolve the drug and the adhesive and uniformly disperse thiosulfates and the like in the solution. The inventors of the present invention have found that when glycerin coexists when uniformly micro-dispersing thiosulfates and the like in the adhesive solution, it is uniformly micro-dispersed in the adhesive solution, and even in the dried transdermal absorption preparation, it is stably micro-dispersed in the base and exhibits the stabilizing effect of the drug. The addition amount of glycerin is 0.01 to 20% by weight in the base (total weight of the paste), and more preferably 0.02 to 10% by weight. If the addition amount in the base is less than 0.01% by weight, the solution stabilizing effect during uniform dispersion of thiosulfates and the like in the base or the coating solution for production is weak, and if it exceeds 20% by weight, bleeding occurs on the surface of the adhesive paste, and inappropriate matters such as a decrease in adhesive strength are likely to occur. Furthermore, the addition amount of glycerin is preferably 1.5 to 2000 parts by weight with respect to 1 part by weight of thiosulfates and the like.

[0012] In the transdermal absorption formulation of the present invention, absorption enhancers can be used in combination. Examples of absorbance enhancers that can be used in combination include 1-dodecylcycloheptan-2-one, oleyl alcohol, cetyl alcohol, oleic acid, stearic acid, lauric acid, sodium lauryl sulfate, lauric methanolamide, lauric diethanolamide, 1-methyl-2-pyrrolidone, isopropyl myristate (IPM), isopropyl palmitate (IPP), triacetin, lactic acid, polyoxyethylene alkyl ether phosphate, etc., with cetyl alcohol, lauric diethanolamide, isopropyl myristate (IPM), isopropyl palmitate (IPP), and stearic acid being preferred. For promoting the absorption of basic drugs, triacetin, diisopropanolamine, etc., are preferred. The amount of these added is preferably 1 to 20% by weight of the base (total weight of the ointment). If the amount added to the base is less than 1% by weight, the enhancing effect is weak, and if it exceeds 20% by weight, the effect on the skin is strong and tends to cause irritation.

[0013] The amount of drugs and absorption enhancers added to the above-mentioned base corresponds to the amount added to the formulation itself in the case of ointments, creams, and liniments; to the amount added to the portion of the formulation excluding the support and release paper, i.e., the adhesive base portion, in the case of tapes and poultices; and to the amount added to the base contained in the reservoir layer and / or adhesive layer in the case of patches.

[0014] The base of the transdermal formulation used in the present invention is an adhesive base in the case of tapes and poultices, and a non-adhesive base in the case of ointments, creams, patches, and liniments.

[0015] The above-mentioned adhesive base is not particularly limited, as long as it has a general adhesive composition that can dissolve drugs and has pressure-sensitive adhesion that allows it to adhere to skin or mucous membranes for a long period of time at room temperature. Preferred adhesive bases include bases made of acrylic adhesives, bases made of rubber adhesives, and bases made of silicone adhesives. These may be used individually or in combination of two or more types.

[0016] Examples of acrylic adhesives used in acrylic adhesive bases include homopolymers and copolymers of alkyl (meth)acrylates obtained from an aliphatic alcohol having 1 to 18 carbon atoms, particularly preferably 4 to 18 carbon atoms, and (meth)acrylic acid, as well as copolymers of alkyl (meth)acrylates with other functional monomers.

[0017] Examples of functional monomers include monomers having hydroxyl groups, monomers having carboxyl groups, monomers having amide groups, monomers having amino groups, etc. Copolymerizable monomers can also be used, such as vinyl acetate, styrene, α-methylstyrene, vinyl chloride, acrylonitrile, ethylene, propylene, and butadiene. It is preferable that the adhesive contains 50% by weight or more of alkyl (meth)acrylate as a (co)polymerizing component.

[0018] Acrylic adhesives are typically prepared by solution polymerization of the required monomers in the presence of a polymerization initiator. However, the polymerization method is not limited to this. The polymerization reaction conditions are selected appropriately, mainly depending on the type of monomer.

[0019] Examples of rubber-based adhesives used in rubber-based adhesive bases include those prepared by adding 100 parts by weight of a rubber elastic material such as natural rubber, styrene-isoprene-styrene block copolymer (SIS), styrene-butadiene-styrene block copolymer, styrene-olefin-styrene block copolymer, polyisoprene, polybutene, polyisobutylene (PIB), or ethylene-vinyl acetate copolymer, to 20 to 200 parts by weight of a tackifier such as rosin resin, polyterpene resin, coumarone-indene resin, petroleum resin, or terpene-phenol resin, and optionally, appropriate amounts of softeners such as liquid polybutene, mineral oil, lanolin, liquid polyisoprene, or liquid polyacrylate, fillers such as titanium dioxide, or antioxidants such as butylhydroxytoluene.

[0020] Examples of silicone-based adhesives used in silicone-based adhesive bases include those whose main component is polydimethylsiloxane.

[0021] The above adhesive may contain, as needed, various additives such as plasticizers, fillers, and antioxidants.

[0022] Examples of the non-stick base include beeswax, oils and fats, lanolin, white petrolatum, paraffin, Plastibase, higher fatty acids, higher alcohols, emulsifiers, macrogol, and carboxyvinyl polymers.

[0023] The drug (bioactive substance) used in this invention can be any substance that can permeate biological membranes percutaneously.

[0024] Examples of drugs include, for example, antipyretics, anti-inflammatory drugs, analgesics, steroidal anti-inflammatory drugs, nonsteroidal anti-inflammatory drugs, narcotic analgesics, anticonvulsants, antipsychotics, antidepressants / anxiolytics, antiparkinsonian drugs, antidementia drugs, hypnotics, sedatives, antispasmodics, muscle relaxants, autonomic nervous system agents, cerebral circulation / metabolism improvers, cardiac stimulants, antianginal drugs, antihypertensives / arrhythmics drugs, vasodilators, antihypertensives, vasopressors, diuretics, respiratory stimulants, antitussives / expectorants, bronchodilators, asthma / nasal allergy treatments, respiratory drugs, cold remedies, antiemetics, antacids, anti-ulcers, and laxatives. Examples include antidiarrheal and antiintestinal agents, liver agents, pancreatic disease treatment agents, choleretic agents, female hormones, male hormones, hypothalamic and pituitary hormones, ovulation inducers, diabetes insipidus treatment agents, thyroid hormones, anabolic hormones, antithyroid agents, calcium metabolizers, anti-inflammatory enzymes, antihistamines, anti-rheumatic agents, gout treatment agents, hypoglycemic agents, vitamins, hematopoietic agents, hemostatic agents, hyperlipidemia treatment agents, antibiotics, antitumor agents, immunosuppressants, antidotes, emetics, anthelmintics, antiparasitic agents, hemorrhoid treatment agents, genitourinary agents, local anesthetics, and anticoagulants.

[0025] Examples of antipyretic, anti-inflammatory, and analgesic drugs include indomethacin, salicylic acid, glycol salicylate, aspirin, acetaminophen, diclofenac sodium, ibuprofen, sulindac, naproxen, and ketoprofen.

[0026] Examples of steroidal anti-inflammatory drugs include hydrocortisone, prednisolone, fluocinolone acetonide, fludroxycortide, and methylprednisolone.

[0027] Examples of narcotic analgesics include morphine, oxycodone, and fentanyl. Fentanyl may be in free form or as a salt, and may be an inorganic or organic salt, as long as it is a pharmaceutically acceptable salt. For example, fentanyl citrate is one such example. In this invention, it is preferable to use fentanyl citrate.

[0028] Examples of vasodilators include diltiazem, verapamil, pentaerythritol tetranitrate, dipyridamole, isosorbide dinitrate, nifedipine, and nitroglycerin.

[0029] Examples of drugs used to treat hypertension and arrhythmias include propanolol, atenolol, pindolol, quinidine sulfate, ajmaline, alprenolol hydrochloride, metoprolol tartrate, nadolol, timolol maleate, and disopyramide.

[0030] Examples of antihypertensive drugs include clonidine hydrochloride, captopril, and bnitrolol hydrochloride.

[0031] Examples of cough suppressants and expectorants include procaterol hydrochloride and terbutaline sulfate.

[0032] Examples of antitumor agents include 5-fluorouracil, 1-(2-tetrahydrofuryl)-5-fluorouracil, and mitomycin C.

[0033] Examples of local anesthetics include benzocaine, procaine, lidocaine, and tetracaine.

[0034] Examples of hormone preparations include steroid hormones such as estrogen, estradiol, testosterone, progesterone, and prostaglandins, as well as peptide hormones such as insulin.

[0035] Examples of asthma and nasal allergy treatments include ketotifen fumarate, azelastine hydrochloride, and sodium cromoglycate.

[0036] Examples of antihistamines include cycloheptadine hydrochloride, diphenhydramine hydrochloride, fenbenzamine, and mequitazine.

[0037] Examples of anticoagulants include heparin.

[0038] Examples of antispasmodics include scopolamine and clofluperol.

[0039] Examples of cerebral circulation and metabolism improving agents include vinpocetine, flunarizine hydrochloride, nicardipine hydrochloride, brocinocamine fumarate, dihydroergotoxin mesylate, ifenprodil tartrate, and isoxuprine hydrochloride.

[0040] Examples of antidepressants and anti-anxiety drugs include maprotiline hydrochloride, etizolam, diazepam, bromazepam, amitriptyline hydrochloride, and mianserin hydrochloride.

[0041] Examples of anti-dementia drugs include donepezil and rivastigmine.

[0042] Examples of antiparkinson's disease agents include ropinirole (hydrochloride) and rotigotine. Rotigotine may be in the free form or as a salt, and may be an inorganic or organic salt, as long as it is a pharmaceutically acceptable salt. For example, rotigotine hydrochloride is one such example. In this invention, it is preferable to use the free form of rotigotine.

[0043] Examples of vitamin D preparations include alfacalcidol and ergocalciferol.

[0044] Examples of blood glucose-lowering agents include glibenclamide and gliclazide.

[0045] Examples of anti-ulcer agents include clovride malate, famotidine, and glycopyrronium bromide.

[0046] Examples of sleeping pills include phenobarbital and amobarbital.

[0047] Examples of antibiotics include tetracycline and chloramphenicol.

[0048] In the present invention, the transdermal absorption of various drugs can be promoted. Therefore, whether the drug is a basic drug or an acidic drug, a formulation with excellent transdermal absorption can be produced by combining it with the composition of the present invention. However, from the viewpoint of using thiosulfates or the like as stabilizers, it is desirable to select a basic drug. A basic drug is a drug that has a basic functional group such as an amino group (primary, secondary, or tertiary) in its molecule and exhibits basicity as a compound, while an acidic drug is a drug that has an acidic functional group such as a carboxyl group in its molecule and exhibits acidity as a compound. Rotigotine and its salts for anti-Parkinson's disease, and fentanyl and its salts, which are analgesics, are examples of basic compounds.

[0049] The amount of these drugs added varies depending on the type of drug and the intended use of the transdermal formulation, but is preferably 0.1 to 30% by weight. The saturation solubility of the drug in the base varies depending on the composition of the base. High drug release can be obtained by making the drug miscible in the base at a concentration as close as possible to its saturation solubility and preventing crystal precipitation. However, even if drug crystals precipitate in the base, it does not pose any particular problem. It is also possible to encapsulate the drug or absorption enhancer, or to provide a storage layer for the drug or absorption enhancer.

[0050] The transdermal formulations used in the present invention include tapes, poultices, patches, creams, liniments, and ointments.

[0051] However, the drugs and stabilizers in the reservoir layer may also be included in the adhesive layer.

[0052] The above-mentioned cream, ointment, and liniment are drug-containing pastes, slurries, or liquids obtained by uniformly mixing the drug, stabilizers, and additives such as absorption enhancers, which may be added as needed, with the non-adhesive base.

[0053] The tape preparation has an adhesive base containing a drug, a stabilizer, and additives such as an absorption enhancer as needed, provided on one side of a support, and a preferred adhesive base is one that adheres well to the skin.

[0054] The above-described patch is prepared by applying a layer of the adhesive base, which contains a drug, a stabilizer, water, and additives such as an absorption enhancer as needed, to one side of a support. A preferred adhesive base is one that has good affinity for water. If the adhesive base has poor tackiness, it can be fixed to the skin surface with an adhesive bandage or tape.

[0055] The above-described patch is constructed by sequentially laminating a non-adhesive reservoir layer and an adhesive layer consisting of the adhesive onto one side of a support, wherein the reservoir layer holds the non-adhesive base containing the drug, stabilizers, and additives such as absorption enhancers as needed. This reservoir layer is applied to the skin via the adhesive layer, and the drug in the reservoir layer is absorbed transdermally through the adhesive layer.

[0056] Creams and ointments may contain lipid-soluble solvents, purified water, water-soluble solvents, pH adjusters, etc. Examples of lipid-soluble solvents include liquid paraffin, isopropyl myristate, and diethyl sebacate, while examples of water-soluble solvents include ethanol, glycerin, and propylene glycol.

[0057] The support material used for tapes, poultices, and patches is flexible, yet provides self-support to the transdermal formulation and prevents the volatilization and migration of the drug in the adhesive base layer and reservoir layer. Examples of support material include cellulose acetate, ethylcellulose, polyethylene terephthalate, plasticized vinyl acetate-vinyl chloride copolymer, nylon, ethylene-vinyl acetate copolymer, plasticized polyvinyl chloride, polyurethane, polyethylene, polyvinylidene chloride, and aluminum. These materials can be used, for example, as a single sheet or film or as a laminate of two or more layers. Materials other than aluminum may be used as woven or nonwoven fabrics. The support material is preferably made of a material that conforms to the skin surface, and a laminate film of polyethylene terephthalate and ethylene-vinyl acetate copolymer is particularly preferred. The thickness of the support is preferably 5 to 100 μm.

[0058] A tape is formed by forming an adhesive base layer on one side of the above-mentioned support, and a patch is formed by sequentially laminating a reservoir layer and an adhesive layer on one side of the above-mentioned support. In the patch, an appropriate control film may be present between the reservoir layer and the adhesive layer.

[0059] In preparing adhesive tapes, the conventional methods for manufacturing adhesive tapes can be applied to form the adhesive base layer. A typical example is the solvent coating method, but other methods such as the hot melt coating method and the electron beam curing emulsion coating method are also used. To form the adhesive base layer using the solvent coating method, for example, a drug, stabilizer, and additives such as an absorption enhancer (if necessary) are dissolved or dispersed in a suitable solvent, and the resulting solution or dispersion is directly applied to one side of a support and dried to form an adhesive base layer of the required thickness. Alternatively, this solution or dispersion may be applied onto a protective release paper, and after drying, the resulting adhesive base layer may be adhered to the support. The thickness of the adhesive base layer varies depending on the intended use, but is preferably 10 to 200 μm.

[0060] Tapes typically have a release liner on their adhesive surface to protect the surface of their adhesive base layer until use. Patches also have a release liner on the adhesive surface of their adhesive layer. A film of polyethylene terephthalate treated with silicone is often used as the release liner, but the release liner is not limited to this. The thickness of the release liner is 1000 μm or less, preferably 30 to 200 μm.

[0061] To manufacture a poultice, a sticky base, a drug, a stabilizer, water, and additives such as absorption enhancers, which may be added as needed, are uniformly mixed, and the resulting drug-containing paste is applied in layers to one side of a support. The drug-containing paste may also contain other additives such as purified water, humectants, inorganic fillers, viscosity modifiers, crosslinking agents, and anti-aging agents. Examples of humectants include glycerin and propylene glycol, and examples of inorganic fillers include kaolin, bentonite, zinc oxide, and titanium dioxide.

[0062] The resulting transdermal formulations in various dosage forms are typically applied directly to the surface of the skin or mucous membranes for the purpose of administering the drug to the circulatory system via the skin or mucous membranes. Furthermore, these transdermal formulations may also be applied to the skin or mucous membranes for the purpose of treating diseases of the skin or mucous membranes. [Examples]

[0063] The present invention will be described in more detail below with reference to examples. However, the present invention is not limited to these examples, and various modifications are possible without departing from the technical spirit of the invention. Hereafter, "parts" refers to "parts by weight." Furthermore, the evaluation and measurement methods for the skin transfer test, skin irritation test, and skin permeability test shown in the results are as follows.

[0064] Preparation of transdermal absorption formulations (Rotigotine transdermal preparation) The method for producing the transdermal formulation of Example 1 is as follows. Examples 0, 2, and the comparative example were produced in accordance with Example 1. The compositions are shown in Table 1. Aqueous solutions were prepared using predetermined amounts of cyclohexane solutions of (1) and (2), ethyl acetate solution of (3), toluene solutions of (5) and (6), and a mixture of (7), (8) and (9). Predetermined amounts of ethyl acetate solution of (3), ethanol solution of (11), and toluene solution of (12) were added to these solutions. Further, THF solution of (4) was added and the mixture was thoroughly stirred to obtain a coating solution. The coating solution was applied to a 40 μm thick PET film and dried to obtain a tape-type transdermal absorption preparation with a 50 μm thick adhesive layer.

[0065] [Table 1]

[0066] [Table 2]

[0067] (Fentanyl transdermal preparation) The method for producing the transdermal formulation of Example 3 is as follows. Example 4 and the comparative example were produced in accordance with Example 3. The compositions are shown in Table 3. A predetermined amount of SIS polymer, alicyclic saturated hydrocarbon resin, and liquid paraffin were dissolved in cyclohexane to prepare a base solution. A predetermined amount of lauric acid diethanolamide was dissolved in methanol, and a predetermined amount of fentanyl citrate was added to prepare a drug solution. The drug solution was added to the base solution, and an aqueous solution of sodium sulfite or sodium bisulfite was added, followed by the addition of glycerin. The mixture was thoroughly stirred and mixed to prepare a coating solution. The coating solution was applied to a 40 μm thick PET film and dried to obtain a tape-type transdermal absorption preparation with a 50 μm thick adhesive layer.

[0068] [Table 3]

[0069] [Table 4]

[0070] (Rotigotine transdermal preparation) A transdermal formulation containing rotigotine in an acrylic adhesive base, or an acrylic adhesive base, was prepared according to Example 1. The composition is shown in Table 5.

[0071] [Table 5]

[0072] The transdermal drug absorption and drug stability tests were conducted as follows.

[0073] Drug transdermal absorption test Human excised skin was placed in a Franz-type diffusion cell circulating 37°C water. PBS buffer solution (pH 7.4) was supplied to the receiver (dermis) side and stirred with a magnetic stirrer. The resulting transdermal formulation was applied to the donor (stratum corneum) side, and a permeability test was performed. After 12 and 24 hours, the mixture in the receiver was collected, and the drug concentration was measured by high-performance liquid chromatography (HPLC) to determine the cumulative amount of drug permeated the skin. The cumulative amount of drug was the average of the results from n=3 tests.

[0074] Drug stability testing The prepared tape formulations were punched out into 2 cm diameter circles, sealed in aluminum laminate bags, and stored at 60°C for 1 week in Examples 1 and 2, and Comparative Examples 1 and 2. They were stored for 3 days in Examples 3 and 4, and Comparative Examples 1 and 2. They were stored at 60°C for 4 weeks in Examples 5 and 6, and Comparative Examples 3 and 4. After that, the tape formulations were immersed in ethanol, etc., for 4 hours to extract the drug, and the drug content was measured by HPLC. Heat storage resulted in the appearance of analogous substance peaks derived from substances thought to be related to the drug. As a measure of stability, the expression level of analogous substance peaks was measured simultaneously with the drug content measurement. The expression status of rotigotine analogous substances is shown in Figure 1 as a chromatogram from the test results for the sample of Comparative Example 2, and the chromatogram for Example 1 is shown in Figure 2. Similarly, the expression status of fentanyl analogous substances is shown in Figure 3B as a chromatogram from the test results for the sample of Comparative Example 4, and the chromatogram for Example 3 is shown in Figure 3A.

[0075] Rotigotine HPLC conditions Detector: UV absorbance spectrophotometer (measurement wavelength: 225 nm) Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 25 cm is packed with 5 μm octadecylsilylated silica gel for liquid chromatography. (CAPCELL PAK C18 or a column with equivalent performance) Pre-column: SecurityGuard C8, 3.0 mm × 4.0 mm, 5 μm (Phenomenex) Column temperature: Constant temperature around 40°C Mobile phase A: 100 mL of buffer solution (pH 4.5) of 50 mM NaH2PO4 and 2.5 mM sodium 1-octanesulfonate, mixed with 53.8 mL of acetonitrile. Flow rate: 1.0 mL per minute Sample temperature: A constant temperature around 4°C Area measurement range: Up to 25 minutes after injection

[0076] Fentanyl HPLC conditions Detector: UV absorbance spectrophotometer (measurement wavelength: 210 nm) Column: A stainless steel tube with an inner diameter of 3.0 mm and a length of 10 cm is packed with 3 μm octylsilylated silica gel for liquid chromatography. (InertSustain C8 HP or a column with equivalent performance) Pre-column: SecurityGuard C8, 3.0 mm × 4.0 mm, 5 μm (Phenomenex) Column temperature: Constant temperature around 25°C Mobile phase A: 0.02 mol / L phosphate buffer at pH 2.5 Mobile phase B: Acetonitrile Mobile phase delivery: The concentration gradient is controlled by changing the mixing ratio of mobile phases A and B as follows.

[0077] [Table 6]

[0078] Flow rate: 0.6 mL per minute Sample temperature: A constant temperature around 4°C Area measurement range: Up to 36 minutes after injection

[0079] A transdermal drug absorption test was performed using the obtained transdermal tape formulation, and the results are shown in Table 7.

[0080] [Table 7]

[0081] Table 6 shows that the addition of thiosulfate and glycerin significantly improves the drug stability of the transdermal rotigotine formulation.

Claims

1. In a transdermal formulation comprising a drug and a stabilizer in a base, The drug is rotigotine or a salt thereof, or fentanyl or a salt thereof. The stabilizer is selected from the group consisting of thiosulfates, sulfites, and bisulfites. The base material is one or more selected from the group consisting of acrylic adhesives and rubber adhesives. A transdermal absorption preparation characterized in that the base further contains glycerin, and the amount of glycerin added is 1.5 to 2000 parts by weight per 1 part by weight of the stabilizer.

2. The transdermal formulation according to claim 1, wherein the content of the stabilizer in the total weight of the ointment containing the drug is 0.01 to 2% by weight.

3. The transdermal formulation according to claim 1 or 2, wherein the glycerin content is 0.01 to 20% by weight of the total weight of the ointment containing the drug.

4. The transdermal formulation according to claim 1 or 2, further comprising an absorption enhancer in the base of the adhesive.

5. The transdermal formulation according to claim 4, wherein the absorption enhancer is selected from the group consisting of cetyl alcohol, lauric acid diethanolamide, isopropyl myristate (IPM), isopropyl palmitate (IPP), and stearic acid.

6. The transdermal formulation according to claim 5, wherein the drug is rotigotine or a salt thereof, and the adhesive base is a mixture of polyisobutylene (PIB) and an acrylic system, and contains cetyl alcohol.

7. The transdermal formulation according to claim 5, wherein the drug is rotigotine or a salt thereof, and the adhesive base comprises an IPM in which styrene-isoprene-styrene block copolymer (SIS) and an acrylic mixture.

8. The transdermal formulation according to claim 5, wherein the drug is fentanyl or a salt thereof, and the base is a styrene-isoprene-styrene block copolymer (SIS) adhesive.

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