Antioxidant-containing transdermal absorption preparation

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 agents and patch agents (referring to dosage forms in which a drug-containing reservoir layer 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 conditions 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 administer a certain amount of drugs gradually 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 intended for local action, it is necessary to maintain a certain concentration of the drug in the subcutaneous tissue through the stratum corneum of the skin.

[0003] Therefore, in order to solve these problems, the development of transdermal absorption preparations has been actively promoted for reasons such as being able to maintain a constant effective blood concentration over a long period of time and expecting improvements in simplicity, functionality, etc. 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 entry of foreign substances into the body, it is not always easy to administer a sufficient amount of drugs 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 the transdermal preparation is a patch, since it has a side effect of irritating the skin during application, it is preferable that the application area be as small as possible. In order to reduce such side effects, it is desired to reduce the application area of the patch by improving the skin permeability of the drug by adding a penetration enhancer. Therefore, many proposals have been made regarding penetration enhancers for adding specific compounds to the preparation to promote the transdermal absorption of the drug (for example, Patent Documents 1 and 2). Also, in the case of a drug that is a substance with poor stability, many studies have been made regarding stabilizers for preventing decomposition during storage (for example, Patent Document 3). In the case of a rotigotine-containing transdermal preparation, a method for producing a transdermal preparation including a step of mixing rotigotine and an antioxidant at a weight ratio of 1:0.0001 to 0.1 is known (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. Also, in a rotigotine-containing transdermal patch comprising a support, a drug-containing layer, and a release liner, a transdermal patch in which the drug-containing layer contains (1) a rubber-based adhesive, (2) rotigotine or a salt thereof, and (3) an inhibitor for suppressing the generation of decomposition products of rotigotine is known (Patent Document 5). The inhibitor for suppressing the generation of decomposition products of rotigotine in Patent Document 5 uses mercaptobenzimidazole and sulfite. In the case of a fentanyl-containing transdermal preparation, a 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 the molecule is known (Patent Document 6). In Patent Document 6, the antioxidant having a sulfur atom in the 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] Japanese Patent Publication No. 10-507199 (Patent No. 3228341) [Patent Document 2] International Publication No. 2011 / 049038 (Patent No. 5913981) [Patent Document 3] Japanese Unexamined Patent Application Publication No. 3-261722 (Patent No. 3002493) [Patent Document 4] Japanese Patent Publication No. 2017-515871 [Patent Document 5] Japanese Unexamined Patent Application Publication No. 2013-079220 (Patent No. 5856424) [Patent Document 6] International Publication No. 2017 / 073516 (Patent No. 6453481) [Summary of the Invention] [Problems to be Solved by the Invention]

[0006] The present invention relates to a transdermal absorption preparation containing a stabilizer. The stabilizer functions to improve the stability of the drug in the adhesive layer. However, as a result of adding the stabilizer to the adhesive base, the adhesiveness should not decrease or the skin irritation should not increase. Therefore, as the stabilizer, it is necessary to select an optimal one in consideration of the target drug, the adhesive base to be formulated, etc. In addition, since the stabilizer acts on the skin during the period when the transdermal preparation is attached to the skin, it must not have skin irritation. Many stabilizers have been used to date. Representative stabilizers are antioxidants such as BHT (dibutylhydroxytoluene), tocopherol, vitamin C and its derivatives, hydroquinone, etc. Thiosulfates and sulfites have strong reducing properties and a powerful antioxidant effect. However, these compounds are inorganic salts and have the drawback that they have poor compatibility with rubber-based adhesives and acrylic-based adhesives, which are common bases for transdermal preparations, and tend to aggregate in the form of particles in the base and are difficult to exhibit a stabilizing effect. An object of the present invention is to provide a transdermal preparation that stably holds a sufficient amount of a drug to exhibit the desired medicinal effect in a paste in view of the above circumstances.

Means for Solving the Problems

[0007] While the present inventors were intensively studying a novel stabilizer, they found that inorganic reducing substances such as thiosulfates and sulfites are excellent in stabilizing many drugs and have low skin irritation. Since these compounds are hardly 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 preparations, even when thiosulfates and sulfites are blended, they do not disperse uniformly and are difficult to exhibit an effect due to crystal precipitation. The present inventors have found that by coexisting glycerin with these inorganic salts, thiosulfates, sulfites, etc. can be uniformly microdispersed in the base, and the antioxidant effect of the reducing inorganic salts can be exhibited, and thus the present invention has been completed. Thiosulfates and sulfites are well-known as reducing agents and are substances with a lot of safety data that have been used for a long time in cosmetics, foods, and medical applications. However, even though it is assumed that adding this substance to a transdermal preparation gives the property of imparting stability to a drug, it is inconvenient to use because it is an inorganic salt. There is one report (Japanese Patent No. 5856424) on sulfites for transdermal preparation use, but the addition of thiosulfates was not known at all.

[0008] The present invention is as follows. (1) In a transdermal absorption preparation comprising a drug and a stabilizer in a base, the transdermal absorption preparation wherein the stabilizer is selected from the group consisting of thiosulfates, sulfites, bisulfites, and nitrites. (2) The transdermal absorption preparation 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 absorption preparation according to (1) or (2), wherein the content of the stabilizer in the total weight of the paste containing the drug is 0.01 to 2% by weight. (4) In a transdermal absorption preparation comprising a drug and a stabilizer in a base, the transdermal absorption preparation wherein the stabilizer is selected from the group consisting of thiosulfates, sulfites, bisulfites, and nitrites, and further comprising glycerin. (5) The transdermal absorption preparation according to (4), wherein the content of glycerin is 0.01 to 20% by weight in the total weight of the paste containing the drug. (6) The transdermal absorption preparation according to (4) or (5), wherein the drug, the stabilizer, and glycerin coexist in the base of the adhesive, and the added amount of the glycerin is 1.5 to 2000 parts by weight with respect to 1 part by weight of the stabilizer. (7) The transdermal absorption preparation according to (4) or (5), wherein the drug, the stabilizer, and glycerin coexist in the base of the adhesive, the added amount of the glycerin is 1.5 to 2000 parts by weight with respect to 1 part by weight of the stabilizer, and further comprising an absorption promoter. (8) The transdermal absorption preparation according to any one of (1) to (7), wherein the drug is rotigotine or a salt thereof. (9) The transdermal absorption preparation according to any one of (1) to (3), wherein the drug is rotigotine or a salt thereof, and further comprising an absorption promoter. (10) The transdermal absorption preparation according to (9), wherein the absorption promoter is selected from the group consisting of cetyl alcohol, lauric acid diethanolamide, isopropyl myristate (IPM), isopropyl palmitate (IPP), and stearic acid. 〔11〕The transdermal absorption preparation according to 〔9〕 or 〔10〕, wherein the drug is rotigotine or a salt thereof, and the adhesive base of a polyisobutylene (PIB) and acrylic acid mixture contains cetyl alcohol. 〔12〕The transdermal absorption preparation according to 〔9〕 or 〔10〕, wherein the drug is rotigotine or a salt thereof, and the adhesive base of a styrene-isoprene-styrene block copolymer (SIS) and acrylic acid mixture contains IPM. 〔13〕The transdermal absorption preparation according to any one of 〔1〕 to 〔7〕, wherein the drug is fentanyl or a salt thereof. 〔14〕The transdermal absorption preparation according to any one of 〔1〕 to 〔3〕, wherein the drug is fentanyl or a salt thereof, and further contains an absorption enhancer. 〔15〕The transdermal absorption preparation according to 〔14〕, wherein the absorption enhancer is selected from the group consisting of cetyl alcohol, diethanolamine laurate, isopropyl myristate (IPM), isopropyl palmitate (IPP), and stearic acid. 〔16〕The transdermal absorption preparation according to 〔14〕 or 〔15〕, wherein the drug is fentanyl or a salt thereof, and the base is an adhesive of a styrene-isoprene-styrene block copolymer (SIS). 〔17〕A method for producing a transparent or semi-transparent coating solution, comprising the step of mixing a drug, a stabilizer selected from the group consisting of thiosulfate, sulfite, bisulfite, and nitrite, and glycerin in a rubber-based or acrylic-based adhesive solution. 〔18〕A method for producing a coating solution, comprising the step of coexisting a drug, a stabilizer selected from the group consisting of thiosulfate, sulfite, bisulfite, and nitrite, and glycerin in a rubber-based or acrylic-based adhesive solution, and further mixing a sucrose fatty acid ester.

Advantages 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 distribution 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 easily penetrates the skin and is absorbed into the systemic 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 can be avoided, or the area of erythema can be reduced. And since the area of the preparation can be small, the application operation is easy and there is no discomfort due to the application.

Brief Description of Drawings

[0010]

Figure 1

Figure 2

Figure 3

Modes for Carrying Out the Invention

[0011] Examples of stabilizers in the transdermal preparation of the present invention include thiosulfates, sulfites, bisulfites, and nitrates. Examples of 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, more preferably 0.02 to 2% by weight, based on the base (total weight of the paste). 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, crystal precipitation in the base tends to cause problems. Another feature of the present invention is to add a salt dissolution aid when incorporating 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 preparation, it is stably micro-dispersed in the base and exhibits the stabilizing effect on the drug. The addition amount of glycerin is 0.01 to 20% by weight, more preferably 0.02 to 10% by weight, based on the base (total weight of the paste). 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 in 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 tend to occur. Further, 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 preparation of the present invention, an absorption enhancer can be used in combination. Examples of absorption 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 acid methanol amide, lauric acid diethanol amide, 1-methyl-2-pyrrolidone, isopropyl myristate (IPM), isopropyl palmitate (IPP), triacetin, lactic acid, polyoxyethylene alkyl ether phosphate, etc. Among them, cetyl alcohol, lauric acid diethanol amide, isopropyl myristate (IPM), isopropyl palmitate (IPP), and stearic acid are preferred. For promoting the absorption of basic drugs, triacetin, diisopropanolamine, etc. are preferred. The addition amount of these is preferably 1 to 20% by weight based on the base (total weight of the ointment). If the addition amount in the base is less than 1% by weight, the promoting effect is weak, and if it exceeds 20% by weight, there is often a problem that the action on the skin is strong and irritation occurs.

[0013] The addition amounts of the drug and the absorption enhancer contained in the above base correspond to the addition amounts to the preparation itself in the case of ointments, creams, and liniments, and in the case of tapes and patches, they correspond to the addition amounts to the part excluding the support and the release paper from the preparation, that is, the part of the pressure-sensitive adhesive base, and in the case of patches, they correspond to the addition amounts to the base contained in the reservoir layer and / or the adhesive layer.

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

[0015] The above pressure-sensitive adhesive base is not particularly limited as long as it can dissolve the drug and has a pressure-sensitive adhesiveness that can adhere to the skin or mucosa for a long time at room temperature. Preferred pressure-sensitive adhesive bases include bases composed of acrylic adhesives, bases composed of rubber adhesives, bases composed of silicone adhesives, etc. These may be used alone or in combination of two or more.

[0016] Examples of acrylic pressure-sensitive adhesives used for acrylic pressure-sensitive adhesive bases include homopolymers, copolymers of alkyl (meth) acrylates obtained from aliphatic alcohols having 1 to 18 carbon atoms, particularly preferably 4 to 18 carbon atoms, and (meth) acrylic acid, and copolymers of alkyl (meth) acrylates and other functional monomers.

[0017] Examples of functional monomers include monomers having a hydroxyl group, monomers having a carboxyl group, monomers having an amide group, monomers having an amino group, etc. Examples of copolymerizable monomers include vinyl acetate, styrene, α-methylstyrene, vinyl chloride, acrylonitrile, ethylene, propylene, butadiene, etc. It is preferable that alkyl (meth) acrylate is contained in the pressure-sensitive adhesive as a (co) polymerization component in an amount of 50% by weight or more.

[0018] To prepare an acrylic pressure-sensitive adhesive, usually, solution polymerization of the required monomers is carried out in the presence of a polymerization initiator. However, the polymerization form is not limited to this. Also, the polymerization reaction conditions are mainly appropriately selected according to the type of monomer.

[0019] Examples of rubber-based pressure-sensitive adhesives used for rubber-based pressure-sensitive adhesive bases include 100 parts by weight of a rubber elastomer such as natural rubber, styrene-isoprene-styrene block copolymer (SIS), styrene-butadiene-styrene block copolymer, styrene-olefin-styrene block copolymer, polyisoprene, polybutene, polyisobutylene (PIB), ethylene-vinyl acetate copolymer, etc., and 20 to 200 parts by weight of a tackifier such as a rosin resin, a polyterpene resin, a coumarone-indene resin, a petroleum resin, a terpene-phenol resin, etc., and, if necessary, a softening agent such as liquid polybutene, mineral oil, lanolin, liquid polyisoprene, liquid polyacrylate, etc., a filler such as titanium oxide, an antioxidant such as butylhydroxytoluene, etc. added in appropriate amounts.

[0020] Examples of silicone-based pressure-sensitive adhesives used for silicone-based pressure-sensitive adhesive bases include those having polydimethylsiloxane as a main component.

[0021] In the above-mentioned adhesive, compounding agents such as plasticizers, fillers, antioxidants, etc. may be added as necessary.

[0022] Examples of the non-adhesive base include beeswax, fats and oils, lanolin, white petrolatum, paraffin, plastic base, higher fatty acids, higher alcohols, emulsifiers, macrogol, carboxyvinyl polymer, and the like.

[0023] The drug (bioactive substance) used in the present invention may be any substance that can permeate the biological membrane transdermally.

[0024] Examples of drugs include, for example, antipyretics, anti-inflammatory and analgesic agents, steroid anti-inflammatory agents, non-steroidal anti-inflammatory agents, narcotic analgesics, anti-epileptic agents, antipsychotics, antidepressant and anti-anxiety agents, anti-Parkinson agents, anti-dementia agents, hypnotics, sedatives, antispasmodics, muscle relaxants, autonomic nervous agents, cerebral circulation and metabolism improvers, cardiotonics, anti-anginal agents, agents for hypertension and arrhythmia, vasodilators, antihypertensive agents, vasopressor agents, diuretics, respiratory stimulants, antitussives and expectorants, bronchodilators, agents for treating asthma and nasal allergies, respiratory agents, cold remedies, antiemetics, antacids, anti-ulcer agents, laxatives, antidiarrheal and intestinal agents, liver agents, pancreatic disease treatment agents, cholagogues, female hormone agents, male hormone agents, hypothalamic and pituitary hormone agents, ovulation inducers, diabetes insipidus treatment agents, thyroid hormone agents, anabolic hormone agents, antithyroid agents, calcium metabolism agents, anti-inflammatory enzyme agents, antihistamines, antirheumatic agents, gout treatment agents, hypoglycemic agents, vitamin agents, hematopoietic agents, hemostatic agents, hyperlipidemia treatment agents, antibiotics, antitumor agents, immunosuppressants, antidotes, emetics, anthelmintics, antiprotozoal agents, hemorrhoid treatment agents, urogenital agents, local anesthetics, anticoagulants, and the like.

[0025] Examples of antipyretics, anti-inflammatory and analgesic agents include indomethacin, salicylic acid, salicylic acid glycol, aspirin, acetaminophen, diclofenac sodium, ibuprofen, sulindac, naproxen, ketoprofen, and the like.

[0026] Examples of steroid anti-inflammatory agents include hydrocortisone, prednisolone, fluocinolone acetonide, fludrocortide, methylprednisolone, and the like.

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

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

[0029] Examples of agents for hypertension and arrhythmia include propranolol, atenolol, pindolol, quinidine sulfate, ajmaline, alprenolol hydrochloride, metoprolol tartrate, nadolol, timolol maleate, disopyramide, and the like.

[0030] Examples of antihypertensive agents include clonidine hydrochloride, captopril, bunitrolol hydrochloride, and the like.

[0031] Examples of antitussive and expectorant agents include procaterol hydrochloride, terbutaline sulfate, and the like.

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

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

[0034] Examples of hormonal agents include steroid hormones such as estrogen, estradiol, testosterone, progesterone, prostaglandin, and peptide hormones such as insulin.

[0035] Examples of anti-asthma and anti-nasal allergy agents include ketotifen fumarate, azelastine hydrochloride, sodium cromoglycate, etc.

[0036] Examples of antihistamines include cyproheptadine hydrochloride, diphenhydramine hydrochloride, phenbenzamine, mequitazine, etc.

[0037] Examples of anticoagulants include heparin, etc.

[0038] Examples of antispasmodics include scopolamine, clofuperol, etc.

[0039] Examples of agents for improving cerebral circulation and metabolism include vinpocetine, flunarizine hydrochloride, nifedipine hydrochloride, brovincamine fumarate, dihydroergotoxine mesylate, ifenprodil tartrate, isoxsuprine hydrochloride, etc.

[0040] Examples of antidepressant and anti-anxiety agents include maprotiline hydrochloride, etizolam, diazepam, bromazepam, amitriptyline hydrochloride, mianserin hydrochloride, etc.

[0041] Examples of anti-dementia agents include donepezil, rivastigmine.

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

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

[0044] Examples of hypoglycemic agents include glibenclamide, gliclazide, etc.

[0045] Examples of antiulcer agents include clebopride malate, famotidine, glycopyrronium bromide, and the like.

[0046] Examples of hypnotics include phenobarbital, amobarbital, and the like.

[0047] Examples of antibiotics include tetracycline, chloramphenicol, and the like.

[0048] In the present invention, the transdermal absorbability of various drugs can be promoted. Therefore, whether the drug is a basic drug or an acidic drug, a formulation excellent in transdermal absorbability can be produced by combining it with the composition of the present invention. However, from the viewpoint of using thiosulfate or the like as a stabilizer, 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 the molecule and exhibits basicity as a compound, and an acidic drug is a drug that has an acidic functional group such as a carboxy group in the molecule and exhibits acidity as a compound. Rotigotine for Parkinson's disease and its salts, and fentanyl as an analgesic and its salts are also examples of basic compounds.

[0049] The addition amounts of these drugs vary depending on the type of drug, the purpose of use of the transdermal absorption preparation, etc., but are preferably 0.1 to 30% by weight. The saturated solubility of the drug in the base varies depending on the composition of the base. By dissolving the drug in the base at a concentration as close as possible to its saturated solubility so that crystal precipitation does not occur, high drug release properties can be obtained. However, even if crystals of the drug precipitate in the base, there is no particular problem. It is also possible to encapsulate the drug or the absorption promoter, or to provide a storage layer for the drug or the absorption promoter.

[0050] The transdermal absorption preparations used in the present invention include tape agents, poultices, patches, creams, liniments, and ointments.

[0051] However, the drug, stabilizer, etc. 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 non-adhesive base with additives such as drugs, stabilizers and absorption promoters that may be added as necessary.

[0053] The tape agent is one in which the adhesive base containing drugs, stabilizers and additives such as absorption promoters that may be added as necessary is provided on one side of the support, and a preferable adhesive base has good adhesiveness to the skin.

[0054] The above-mentioned poultice is obtained by laminating the adhesive base containing drugs, stabilizers, water and additives such as absorption promoters that may be added as necessary on one side of the support in layers, and a preferable adhesive base has good affinity with water. When the adhesiveness of the adhesive base is poor, it is fixed to the skin surface with a band-aid, adhesive tape, etc.

[0055] The above-mentioned patch is configured by sequentially laminating a non-adhesive reservoir layer and an adhesive layer composed of the above-mentioned adhesive on one side of the support, and the non-adhesive base containing drugs, stabilizers and additives such as absorption promoters that may be added as necessary is retained in the reservoir layer. This reservoir layer is affixed to the skin via the adhesive layer, and the drug in the reservoir layer is transdermally absorbed through the adhesive layer.

[0056] Fat-soluble solvents, purified water, water-soluble solvents, pH adjusters, etc. may be added to the cream and ointment. Examples of the fat-soluble solvent include liquid paraffin, isopropyl myristate, diethyl sebacate, etc., and examples of the water-soluble solvent include ethanol, glycerin, propylene glycol, etc.

[0057] As the support for tapes, cataplasms, and patches, those that are flexible but impart self-supporting properties to transdermal preparations and serve to prevent the volatilization and migration of drugs in the pressure-sensitive adhesive base layer or reservoir layer are used. Examples of the support materials include cellulose acetate, ethyl cellulose, polyethylene terephthalate, plasticized vinyl acetate-vinyl chloride copolymer, nylon, ethylene-vinyl acetate copolymer, plasticized polyvinyl chloride, polyurethane, polyethylene, polyvinylidene chloride, aluminum, and the like. These materials are used, for example, as single-layer sheets or films or as laminates of two or more layers. Materials other than aluminum may be used as woven or non-woven fabrics. As the support, those made of materials having followability to the skin surface are preferably used, and particularly a laminate film of polyethylene terephthalate and ethylene-vinyl acetate copolymer is preferred. The thickness of the support is preferably 5 to 100 μm.

[0058] A pressure-sensitive adhesive base layer is formed on one side of the above support to form a tape, and a reservoir layer and a pressure-sensitive adhesive layer are sequentially laminated on one side of the above support to form a patch. In the patch, an appropriate control film may be present between the reservoir layer and the pressure-sensitive adhesive layer.

[0059] In the preparation of a tape, the manufacturing method of ordinary adhesive tapes can be applied to form the pressure-sensitive adhesive base layer. A typical example is the solvent coating method, and in addition, the hot melt coating method, electron beam curing emulsion coating method, and the like are also used. To form the pressure-sensitive adhesive base layer by the solvent coating method, for example, additives such as drugs, stabilizers, and absorption promoters added as necessary are dissolved or dispersed in an appropriate solvent, and the obtained solution or dispersion is directly applied and dried on one side of the support to form a pressure-sensitive adhesive base layer with the required thickness. Alternatively, this solution or dispersion may be applied on a release paper for protection, and the pressure-sensitive adhesive base layer obtained after drying may be adhered to the support. The thickness of the pressure-sensitive adhesive base layer varies depending on the purpose of use, but is preferably 10 to 200 μm.

[0060] The tape preparation usually has a release paper on its sticking surface to protect the surface of the adhesive base agent layer until use. The patch preparation has a release paper on the sticking surface of the adhesive layer. As the release paper, a polyethylene terephthalate film treated with silicone is often used, but the release paper is not limited to this. The thickness of the release paper is 1000 μm or less, preferably 30 to 200 μm.

[0061] To produce a poultice preparation, an adhesive base, a drug, a stabilizer, water, and additives such as an absorption enhancer that may be added as necessary are uniformly mixed, and the obtained drug-containing paste is applied in layers on one side of a support. Further, other additives such as purified water, a humectant, an inorganic filler, a viscosity modifier, a crosslinking agent, and an antioxidant may be added to the drug-containing paste. Examples of the humectant include glycerin and propylene glycol, and examples of the inorganic filler include kaolin, bentonite, zinc white, and titanium dioxide.

[0062] The obtained transdermal absorption preparations in various dosage forms are usually directly applied or coated on the surface of the skin or mucosa for the purpose of transdermally or transmucosally administering the drug to the systemic circulation system. Further, these transdermal absorption preparations may also be applied or coated on the skin or mucosa for the purpose of treating skin or mucosal diseases.

Examples

[0063] Hereinafter, examples are shown to more specifically explain the present invention. Note that the present invention is not limited to these examples, and various modifications can be made without departing from the technical idea of the present invention. Hereinafter, "parts" means "parts by weight". Also, the evaluation methods and measurement methods for the skin migration test, skin irritation test, and skin permeability test shown in the results are as follows.

[0064] Preparation of Transdermal Absorption Preparation (Rotigotine Transdermal Preparation) The manufacturing method of the transdermal absorption preparation of Example 1 is as follows. Example 0, Example 2, and the Comparative Example were manufactured according to Example 1. The compositions are shown in Table 1. Solutions of a predetermined amount of (1) and (2) in cyclohexane, (3) in ethyl acetate, (5) and (6) in toluene, and aqueous solutions of the mixture of (7), (8) and (9) were prepared. A predetermined amount of the ethyl acetate solution of (3), the ethanol solution of (11), and the toluene solution of (12) were added thereto. Further, a THF solution of (4) was added and stirred well to obtain a coating solution by mixing. The coating solution was applied to a PET film with a thickness of 40 μm and dried to obtain a tape-type transdermal preparation having an adhesive layer with a thickness of 50 μm laminated thereon.

[0065]

Table 1

[0066]

Table 2

[0067] (Fentanyl transdermal preparation) The method for producing the transdermal preparation of Example 3 is as follows. Example 4 and the comparative examples were produced according to 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 obtain a base solution. A predetermined amount of diethanolamine laurate was dissolved in methanol, and a predetermined amount of fentanyl citrate was further added to obtain a drug solution. The drug solution was added to the base solution, and an aqueous sodium sulfite solution or an aqueous sodium bisulfite solution was added thereto. Further, glycerin was added and stirred well to obtain a coating solution by mixing. The coating solution was applied to a PET film with a thickness of 40 μm and dried to obtain a tape-type transdermal preparation having an adhesive layer with a thickness of 50 μm laminated thereon.

[0068]

Table 3

[0069]

Table 4

[0070] (Rotigotine Transdermal Preparation) A transdermal absorption preparation containing rotigotine in a mixed pressure-sensitive adhesive base of styrene-isoprene-styrene block copolymer (SIS) and an acrylic pressure-sensitive adhesive, or an acrylic pressure-sensitive adhesive base, was prepared according to Example 1. The composition is shown in Table 5.

[0071]

Table 5

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

[0073] Drug percutaneous absorption test Human excised skin was sandwiched in a Franz-type diffusion cell with water at 37 °C circulated, and PBS buffer solution (pH 7.4) was supplied to the receiver (dermis) side and stirred by a magnetic stirrer. The obtained transdermal absorption preparation was applied to the donor (stratum corneum) side, and a permeation test was conducted. The mixed solution in the receiver was collected after 12 hours and 24 hours, and the drug concentration therein was measured by high performance liquid chromatography (HPLC) to determine the cumulative amount of drug permeated through the skin. The cumulative amount of drug was taken as the average of the test results with n = 3.

[0074] Drug stability test The prepared tape formulation was punched into a circle with a diameter of 2 cm, sealed in an aluminum laminate bag, and stored at 60 °C for 1 week in Examples 1, 2, Comparative Examples 1, and 2. In Examples 3, 4, Comparative Examples 1, and 2, it was stored for 3 days. In Examples 5, 6, Comparative Examples 3, and 4, it was stored at 60 °C for 4 weeks. Then, the tape formulation was immersed in ethanol, etc. for 4 hours to extract the drug, and the drug content was measured by HPLC. A peak of a related substance derived from a substance considered to be a related substance of the drug appeared due to heat storage. As a measure of stability, the expression level of the related substance peak was measured simultaneously with the drug content measurement. The situation of the expression of the related substance of rotigotine is shown in Fig. 1 as a chromatogram from the test results for the sample of Comparative Example 2, and the chromatogram of Example 1 is shown in Fig. 2. Similarly, the situation of the expression of the related substance of fentanyl is shown in Fig. 3B as a chromatogram from the test results for the sample of Comparative Example 4, and the chromatogram of Example 3 is shown in Fig. 3A.

[0075] Rotigotine HPLC conditions Detector: Ultraviolet absorption photometer (measurement wavelength: 225 nm) Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 25 cm is filled with 5 μm octadecylsilylated silica gel for liquid chromatography. (CAPCELL PAK C18 or a column having 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: 53.8 mL of acetonitrile is added to 100 mL of a buffer solution of 50 mM NaH2PO4 and 2.5 mM Na 1-octanesulfonate (pH 4.5) Flow rate: 1.0 mL per minute Sample temperature: Constant temperature around 4 °C Area measurement range: Up to 25 minutes after injection

[0076] Fentanyl HPLC conditions Detector: Ultraviolet absorption photometer (measurement wavelength: 210 nm) Column: A stainless steel tube with an inner diameter of 3.0 mm and a length of 10 cm is filled 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: A constant temperature around 25 °C Mobile phase A: 0.02 mol / L phosphate buffer with pH 2.5 Mobile phase B: Acetonitrile Liquid delivery of the mobile phase: The concentration gradient control is performed 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] Using the obtained tape-type transdermal absorption preparation, a drug transdermal absorption test was conducted, and the results are shown in Table 7.

[0080]

Table 7

[0081] It can be seen from Table 6 that the addition of thiosulfate and glycerin significantly improves the drug stability of the rotigotine transdermal absorption preparation.

Claims

1. In a transdermal absorption preparation 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 is one or more selected from the group consisting of acrylic adhesives and rubber adhesives, The percutaneous absorption preparation further comprises glycerin in the base, the amount of said glycerin being 1.5 to 2000 parts by weight per part by weight of said stabilizer.

2. 2. The percutaneous absorption preparation according to claim 1, wherein the content of said stabilizer in the total weight of the plaster containing the drug is 0.01 to 2% by weight.

3. 3. The percutaneous absorption preparation according to claim 1, wherein the content of said glycerin is 0.01 to 20% by weight based on the total weight of the plaster containing the drug.

4. 3. The percutaneous absorption preparation according to claim 1, further comprising an absorption enhancer in the adhesive base.

5. 5. The percutaneous absorption preparation 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. 6. The percutaneous absorption preparation 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 base, and contains cetyl alcohol.

7. 6. The percutaneous absorption preparation according to claim 5, wherein the drug is rotigotine or a salt thereof, and the adhesive base is a mixture of styrene-isoprene-styrene block copolymer (SIS) and an acrylic-based adhesive and contains IPM.

8. 6. The percutaneous absorption preparation according to claim 5, wherein the drug is fentanyl or a salt thereof, and the base is an adhesive of styrene-isoprene-styrene block copolymer (SIS).

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