JP5301190B2 - Patch - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a transdermal patch excellent in the transdermal absorption and preservation stability of a free basic medicine. <P>SOLUTION: The transdermal patch includes a prescribed amount of a fatty acid having an 8-22C aliphatic hydrocarbon group in the inside of an oily layer, thereby improves the solubility and diffusion of the free basic medicine and raises the transdermal absorption without spoiling the preservation stability of the free basic medicine in the oily layer, and includes the free basic medicine in a sufficient amount which is diffused in the oily layer, and thereby the continuous transdermal administration of the free basic medicine is possible. <P>COPYRIGHT: (C)2010,JPO&amp;INPIT

Description

  The present invention relates to a patch containing a free base drug, and in particular, to a transdermal application formulation of a free base drug having good skin permeability and excellent storage stability of the preparation.

  Antihistaminergic drugs such as chlorpheniramine, ketotifen, azelastine or their salts are known as therapeutic agents for bronchial asthma, allergic rhinitis, allergic conjunctivitis, etc. ing. Oral preparations are widely used because they are effective for allergic reactions such as nasal mucosa, ocular mucosa, skin, and bronchi, but they may be degraded by the first-pass effect in the liver or cause gastrointestinal problems. In addition, since the blood concentration varies greatly, the blood concentration may increase excessively, resulting in side effects such as sleepiness, or conversely, the blood concentration may decrease and the effect may not be obtained when necessary.

  On the other hand, in the case of transdermal administration, the initial passage effect in the liver can be avoided, and gastrointestinal disorders can be avoided. In addition, since absorption is performed continuously, for example, if administration is started before going to bed, it is possible to effectively suppress the allergic reaction to get up. Furthermore, it can be effectively applied to local symptoms of skin pruritus. Among the transdermally absorbable preparations, the patch can be continuously absorbed, and therefore a stable effect is expected for allergic reactions that occur suddenly.

  So far, the possibility of a transdermal absorption-type preparation for basic active substances having an antihistamine action such as azelastine, ketotifen, azelastine hydrochloride or ketotifen fumarate and salts thereof has been studied.

  In Patent Document 1, when azelastine hydrochloride and a monoglyceride of a fatty acid having 8 to 12 carbon atoms and / or a lactic acid ester of an aliphatic alcohol having 12 to 18 carbon atoms are blended, the solubility of azelastine or a salt thereof is moderate. Moreover, it is disclosed that the skin permeability of azelastine or its salts is remarkably improved.

Patent Document 2 discloses a tape preparation in which a drug-containing pressure-sensitive adhesive layer containing a free basic drug in a pressure-sensitive adhesive is laminated on a support, and Patent Document 3 discloses a basic drug and When dissolved in a transdermal preparation containing a liquid component with an organic acid salt such as sodium acetate, or a combination of a basic drug (free form) and an organic acid (free form) such as acetic acid, an ion pair is formed. It is disclosed that the solubility of the drug in the liquid component as the base component and the partition ratio to the skin are increased, and the skin permeability of the drug is significantly improved, and the solubility parameter of the liquid component is 7 to It is disclosed that the solubility of the drug increases and the transdermal absorbability of the drug improves within the range of 13 (cal / cm ³ ) ^1/2 .

  Patent Document 4 discloses a medical patch in which the pH of the exposed surface of a pressure-sensitive adhesive layer comprising a (meth) acrylic acid alkyl ester having an alkyl group having 4 to 13 carbon atoms is 7 or more, and a basic drug In addition, by containing an acidic substance in the pressure-sensitive adhesive layer, a preparation excellent in drug stability and transdermal absorbability is realized. Here, a suitable acidic substance is an organic acid, and citric acid, succinic acid, tartaric acid, maleic acid, fumaric acid, benzoic acid, salicylic acid, and lactic acid are listed.

  Furthermore, Patent Document 5 proposes a preparation that contains azelastine hydrochloride and a fatty acid having 8 or more carbon atoms to prevent the formation of crystalline hydrate and is excellent in transdermal and transmucosal absorbability.

  However, in a prescription that prioritizes absorbability, the drug solubility may be too high and the drug stability in the preparation may be reduced. In addition, the compounds for improving skin permeability in the above-mentioned document are not necessarily suitable for patches, and the necessary amount of the above-mentioned compounds cannot be contained in the preparation, or the patchability is insufficient. There was a problem that it could not withstand continuous use. Furthermore, in the above document, the effect of the compound due to the difference in characteristics between the free base type drug and the acid addition salt type drug is not examined in detail, and the optimum compound when the free base type drug is contained in the patch is not described. No investigation was made.

  Furthermore, in general, the free base type (free form) drug has a lower melting point, lower molecular weight, and polarity changes to fat-soluble compared to acid addition salt type drugs. The solubility in the stratum corneum is increased, which is advantageous for passing through the stratum corneum in transdermal administration.

  However, due to high physicochemical activity, formulation stability such as drug degradation during storage and crystallization from a supersaturated state is an issue, and in many cases, it cannot be realized, and sufficient stability is ensured while ensuring stability. Realizing skin absorbability has been a challenge for free base drugs.

  For example, in Patent Document 6, in order to ensure the stability of a basic drug in a preparation, a non-crosslinked adhesive layer containing a drug and a liquid component, and a drug-free layer on the surface thereof are disclosed. By laminating and integrating the cross-linked pressure-sensitive adhesive layers, stability and absorbability are improved while maintaining the cohesive force required for sticking.

  Although the above technique has an effect of suppressing the degradation of the drug during storage, it has not been sufficient for the problem of preventing the drug from crystallizing from a supersaturated state.

Japanese Patent Laid-Open No. 2-124824 JP-A-2-255611 WO00 / 61120 JP-A-2-255612 Japanese Patent Laid-Open No. 7-40949 JP 2004-10525 A

  The present invention provides a patch excellent in transdermal absorbability and storage stability of a free basic drug.

The patch of the present invention is a patch comprising a support and a paste layer laminated and integrated on one surface of the support, and the paste layer is composed of 1 to 30% by weight of a free basic drug. When a fatty acid 1 to 30 wt% of carbon atoms have from 8 to 22 aliphatic hydrocarbon group, the pressure-sensitive adhesive containing a 50 to 98 wt%, the free base drug is azelastine, the adhesive An acrylic pressure-sensitive adhesive comprising an acrylic copolymer, wherein the acrylic copolymer comprises 2-ethylhexyl methacrylate and an alkyl (meth) acrylate having 6 to 16 carbon atoms in the alkyl group other than the 2-ethylhexyl methacrylate. as component, or an acrylic copolymer in the monomer components constituting the acrylic copolymer of 2-ethylhexyl methacrylate containing 40 to 90 wt%, or, the number of carbon atoms in the alkyl group 4 18 Archi It is an acrylic copolymer containing 25 to 70% by weight of ru (meth) acrylate and 30 to 75% by weight of alkyl (meth) acrylate having an alkyl group with 3 or less carbon atoms.

As the free basic drug, azelastine is used.

  The content of the free basic drug in the plaster layer is limited to 1 to 30% by weight, preferably 2 to 20% by weight, and particularly preferably 5 to 15% by weight. This is because if the content of the free basic drug in the plaster layer is small, the amount of the drug percutaneously absorbed decreases, and the blood concentration of the drug may not be increased to a desired range, or the free base However, if the amount is too high, crystals of the free basic drug will be excessively deposited on the plaster layer, reducing the adhesive strength of the patch and the diffusibility of the drug. This is because the utilization rate of the free basic drug is lowered and the preparation may become inefficient.

  The patch of the present invention is required to increase the blood concentration of a free basic drug to a desired range as a therapeutic agent. In order to obtain such an effect, A sufficient amount of free basic drug is stably contained, and the free basic drug diffuses well in the plaster layer so that the drug is continuously supplied to the surface to be adhered to the skin. Therefore, it is required that the performance does not change even when stored for a long period of time.

  However, depending on the combination of the free basic drug and the additive, the solubility and diffusibility of the free basic drug may change over time, and the transdermal absorbability of the free basic drug may decrease. It was difficult to make a patch. In the patch of the present invention, in order to realize a patch excellent in transdermal absorbability and storage stability of a free basic drug, an aliphatic hydrocarbon group having 8 to 22 carbon atoms is contained in the plaster layer. The presence of this fatty acid ensures the transdermal absorbability and storage stability of the free basic drug.

  Fatty acids having an aliphatic hydrocarbon group having 8 to 22 carbon atoms (hereinafter sometimes simply referred to as “fatty acids”) are sufficient to dissolve a free basic drug well and to obtain a desired drug blood concentration. Any amount of free basic drug can be dissolved in the plaster layer.

  Furthermore, the solubility of the free basic drug in the plaster does not change with time, and a good percutaneous absorption performance can be exhibited even after long-term storage. Furthermore, the above fatty acids act to soften the stratum corneum of the skin or increase the hydration property, thereby improving the skin permeability of the free basic drug and as a carrier for carrying the free basic drug into the skin. It has the effect of doing. Therefore, the transdermal absorbability of the free basic drug can be greatly improved by including the fatty acid in the plaster layer.

  The fatty acid is represented by R—COOH, and R is an aliphatic hydrocarbon group having 8 to 22 carbon atoms, and preferably an aliphatic hydrocarbon group having 10 to 20 carbon atoms. This is because if the aliphatic hydrocarbon group has 7 or less carbon atoms, the compatibility with the pressure-sensitive adhesive may be reduced, and the plaster layer may become non-uniform, or This is because the reactivity increases, it becomes easier to form a salt with the drug in the plaster layer, and the transdermal absorbability of the free basic drug may decrease. On the other hand, when the number of carbon atoms of the fatty acid is 23 or more, the solubility of the free basic drug decreases, and a sufficient amount of the free basic drug is dissolved in the plaster layer to obtain a desired blood concentration of the drug. This is because it becomes impossible to reduce the flexibility of the plaster layer and the adhesive strength as a patch tends to decrease.

  The fatty acid having an aliphatic hydrocarbon group having 8 to 22 carbon atoms is not particularly limited. For example, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, behenic acid, oleic acid, Examples include undecylenic acid, and lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, and oleic acid are preferable. In addition, a fatty acid may be used independently or 2 or more types may be used together.

  If the fatty acid content in the plaster layer is small, the solubility and diffusibility of the drug in the plaster layer will be reduced, and the percutaneous absorption and storage stability of the drug will be insufficient. Since the acrylic pressure-sensitive adhesive in the body layer is excessively plasticized or the adhesiveness is lowered, it is limited to 1 to 30% by weight, preferably 3 to 20% by weight, and more preferably 5 to 15% by weight.

  The pressure-sensitive adhesive constituting the plaster layer is not particularly limited as long as it is a pressure-sensitive adhesive capable of stably blending a free basic drug and a fatty acid and realizing good sticking properties. For example, a rubber-based pressure-sensitive adhesive, acrylic An acrylic pressure-sensitive adhesive is preferable because a fatty acid can be blended well.

  The acrylic pressure-sensitive adhesive is made of an acrylic copolymer containing at least 50% by weight of an alkyl (meth) acrylate having 2 or more, preferably 2 to 18 carbon atoms of an alkyl group as a raw material monomer. Those are preferred. In the present invention, (meth) acryl means “acryl” or “methacryl”.

  The acrylic copolymer has good adhesion to the skin and solubility in the drug, and is less likely to irritate the skin, and can hold the drug stably. The acrylic copolymer includes a copolymer of an alkyl (meth) acrylate and another copolymerizable monomer, and this copolymerizable monomer (hereinafter referred to as “copolymerizable monomer”). ") Is copolymerized in an amount of 40% by weight or less, preferably in the range of 0.5 to 30% by weight.

As the acrylic copolymer, (i) 2-ethylhexyl methacrylate and an alkyl (meth) acrylate having 6 to 16 carbon atoms in the alkyl group excluding this component as a constituent component, a single monomer constituting the acrylic copolymer The body component contains 40 to 90% by weight of 2-ethylhexyl methacrylate, or (ii) 25 to 70% by weight of alkyl (meth) acrylate having 4 to 18 carbon atoms in the alkyl group and carbon number in the alkyl group There are used those containing 3 or less alkyl (meth) acrylate 30-75% by weight.

  By adjusting the kind and copolymerization ratio of the copolymerizable monomer, the sticking property, drug solubility and drug release property of the acrylic copolymer can be adjusted. Therefore, the acrylic copolymer or a mixture thereof is suitable as an adhesive for carrying the drug and additive.

  Examples of the alkyl (meth) acrylate used for constituting the acrylic copolymer include ethyl (meth) acrylate, n-butyl acrylate, n-butyl methacrylate, hexyl acrylate, 2-ethylbutyl acrylate, isooctyl acrylate, 2 -Ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate, tridecyl methacrylate and the like.

  Examples of the copolymerizable monomer include (meth) acrylic acid, itaconic acid, maleic acid, maleic anhydride, hydroxyethyl acrylate, hydroxypropyl acrylate, acrylamide, dimethylacrylamide, acrylonitrile, dimethylaminoethyl (meth) acrylate, Examples thereof include t-butylaminoethyl (meth) acrylate, vinyl acetate, vinyl propionate, vinyl pyrrolidone and the like.

Furthermore, the monomer used as the raw material for the acrylic pressure-sensitive adhesive may be an epoxy compound, a polyisocyanate compound, a metal chelate other than the polyfunctional monomer as long as it does not impair the storage stability of azelastine. You may add crosslinking agents, such as a compound and a metal alkoxide compound. By adding a crosslinking agent to the monomer used as the raw material for the acrylic adhesive, the internal cohesive strength of the acrylic adhesive is increased, so that adhesive residue is left on the skin when the patch is peeled from the skin. Can be difficult.

  The acrylic pressure-sensitive adhesive may be polymerized by a conventionally known method. For example, in the presence of a polymerization initiator, the above-mentioned monomer is blended and solution polymerization is performed. To polymerize. Specifically, a predetermined amount of alkyl group having 4 to 22 carbon atoms in the alkyl group, alkyl ester having 2 to 20 carbon atoms in the alkyl group, a polymerization initiator, and a crosslinking agent to be added as necessary Together with the polymerization solvent is supplied to a reactor equipped with a stirring device and a cooling / refluxing device for the vaporized solvent, and heated at a temperature of 60 to 80 ° C. for 4 to 48 hours to cause radical polymerization reaction of the monomer. .

  Examples of the polymerization initiator include 2,2′-azobisisobutyronitrile (AIBN), 1,1′-azobis (cyclohexane-1-carbonitrile), 2,2′-azobis- (2 Azobis-based polymerization initiators such as, 4'-dimethylvaleronitrile), peroxide-based polymerization initiators such as benzoyl peroxide (BPO), lauroyl peroxide (LPO), and di-tert-butyl peroxide. Examples of the polymerization solvent include ethyl acetate and toluene. Furthermore, the polymerization reaction is preferably performed in a nitrogen gas atmosphere.

  When the content of the acrylic adhesive in the plaster layer is small, the adhesive strength to the skin is reduced, while when it is large, the amount of free basic drug and fatty acid necessary for obtaining a desired blood concentration of the drug is obtained. Therefore, it is limited to 50 to 98% by weight, preferably 60 to 95% by weight, and more preferably 70 to 90% by weight.

  Additives such as a plasticizer, a solubilizer, an absorption promoter, a stabilizer, and a filler may be added to the plaster layer within a range that does not impair the effects of the present invention.

  The plasticizer is added for the purpose of improving the adhesive strength of the patch and the diffusibility of the free basic drug in the plaster layer. Such plasticizers include, for example, hydrocarbons such as liquid paraffin; esters of aliphatic carboxylic acids such as isopropyl myristate and diethyl sebacate and monohydric or polyhydric alcohols; derived from natural products such as lanolin and olive oil And may be added in an amount of 1 to 10% by weight in the plaster layer.

  The solubilizer is added for the purpose of further increasing the amount of drug dissolved in the plaster layer. Examples of such a solubilizer include polyhydric alcohols such as polyethylene glycol, propylene glycol, butylene glycol, and glycerin, and it may be added in an amount of 1 to 10% by weight in the plaster layer.

  The absorption enhancer is used to act on the skin to increase the skin permeability of azelastine, and a softening agent for the stratum corneum and a hydration property for the stratum corneum are used. Examples of such absorption promoters include surfactants such as polysorbate, lauric acid diethanolamide, lauroyl sarcosine, polyoxyethylene alkyl ether, polyoxyethylene alkylamine, and the like. What is necessary is just to add weight%.

  The stabilizer is added for the purpose of suppressing the oxidation and decomposition of the drug. Examples of such a stabilizer include antioxidants such as butylhydroxytoluene and tocopherol acetate, cyclodextrin, ethylenediaminetetraacetic acid, and the like, and 0.05 to 10% by weight is added to the plaster layer. Good.

  Further, the filler is added to adjust the adhesive strength of the patch and the transdermal absorbability of the free basic drug. Examples of such fillers include inorganic fillers such as silicic anhydride and titanium oxide, organometallic salts such as calcium carbonate and magnesium stearate, lactose, crystalline cellulose, ethyl cellulose, and low-substituted hydroxypropyl cellulose. Examples thereof include cellulose derivatives, vinyl pyrrolidone, and polymers having (meth) acrylic acid and (meth) acrylic acid derivatives as monomers. These fillers may be added in an amount of 1 to 15% by weight in the plaster layer.

  10-250 micrometers is preferable and, as for the thickness of a paste layer, 20-200 micrometers is more preferable. This is because if the thickness of the plaster layer is less than 10 μm, the plaster layer may not contain the amount of free basic drug necessary to obtain the desired blood concentration of the drug, whereas If it is too thick, the plaster layer tends to protrude from the patch when the patch is stored or applied, the feeling of sticking when the patch is applied is worsened, and the patch is applied by solvent coating described later. This is because it may take a long time to remove the solvent at the time of production, which may cause problems such as reduced production efficiency.

  The support that is laminated and integrated with the plaster layer to constitute the patch of the present invention prevents the loss of the drug in the plaster layer, protects the plaster layer, and is self-adhesive to the patch. It is required to have flexibility for imparting a good patch feeling of the patch while having strength for imparting support.

  Such a support is not particularly limited, and examples thereof include a resin sheet, a foamed resin sheet, a nonwoven fabric, a woven fabric, a knitted fabric, an aluminum sheet, and the like. It may be made.

  Examples of the resin constituting the resin sheet include cellulose acetate, ethyl cellulose, rayon, polyethylene terephthalate, plasticized vinyl acetate-vinyl chloride copolymer, nylon, ethylene-vinyl acetate copolymer, plasticized polyvinyl chloride. , Polyurethane, polyethylene, polypropylene, polyvinylidene chloride and the like, and polyethylene terephthalate is preferable.

  As the support, a polyethylene terephthalate sheet and a nonwoven fabric or a flexible resin sheet are preferably laminated and integrated from the viewpoint of flexibility and drug loss prevention effect, and a polyethylene terephthalate sheet and a nonwoven fabric are laminated. What is integrated is more preferable. Examples of the material constituting the nonwoven fabric include polyethylene, polypropylene, ethylene-vinyl acetate copolymer, ethylene- (meth) methyl acrylate copolymer, nylon, polyester, vinylon, SIS copolymer, SEBS copolymer. , Rayon, cotton and the like, and polyester is preferable. In addition, these materials may be used independently or 2 or more types may be used together.

  In order to prevent the loss of the drug in the plaster layer of the patch of the present invention and to protect the plaster layer, it is preferable that release paper is laminated and integrated on the surface of the plaster layer of the patch in a peelable manner.

  Examples of the release paper include resin films and paper made of polyethylene terephthalate, polyethylene, polypropylene, polyvinyl chloride, polyvinylidene chloride, and the like, and a release treatment is performed on the surface facing the plaster layer. It is preferable. The release paper may be a single layer or a plurality of layers.

  Further, for the purpose of improving the barrier property of the release paper, the release paper may be provided with an aluminum foil or an aluminum vapor deposition layer. Furthermore, when the release paper is made of paper, the release paper may be impregnated with a resin such as polyvinyl alcohol for the purpose of improving the barrier property of the release paper.

  Next, the manufacturing method of the patch of this invention is demonstrated. The method for producing the patch is not particularly limited. For example, a free basic drug, a pressure-sensitive adhesive, a fatty acid, and an additive that is added as necessary are added to a solvent such as ethyl acetate and stirred until uniform. The plaster layer solution obtained in this way is applied to one side of the support and then dried, so that the plaster layer is laminated and integrated on one side of the support. If necessary, the release paper is peeled off from the plaster layer. On the surface of the release paper that has been subjected to the release treatment by the method of laminating and integrating so that the surface that has undergone the release treatment of the paper faces the plaster layer, or by the coating method as described above Examples include a method in which a paste layer is formed on a release paper by applying and drying a paste layer solution, and a support is laminated and integrated on the paste layer.

  Since the patch of the present invention contains a predetermined amount of fatty acid having an aliphatic hydrocarbon group having 8 to 22 carbon atoms in the paste layer, it has an antihistamine action in the paste layer. Without sacrificing the storage stability of the basic drug, it improves the solubility and diffusibility of the free basic drug having antihistamine action to enhance the transdermal absorbability, and a sufficient amount of antibacterial agent is contained in the plaster layer. Since the free basic drug having histamine action is contained in a diffused state, transdermal administration of the free basic drug having sustained antihistamine action is possible.

  Furthermore, the patch of the present invention is suitable for use as a patch that not only does not unexpectedly peel off from the skin at the time of application, but also hardly causes adhesive residue on the skin at the time of peeling. Have power.

  The acrylic adhesives A and B used as adhesives for the patches of the present invention were prepared in the following manner to produce the patches of Examples 1 to 8 and Comparative Examples 1 to 8.

(Preparation of acrylic adhesive A)
A reaction solution consisting of 13 parts by weight of dodecyl methacrylate, 78 parts by weight of 2-ethylhexyl methacrylate, 9 parts by weight of 2-ethylhexyl acrylate, and 50 parts by weight of ethyl acetate was put into a 40 liter polymerization machine, and the inside of the polymerization machine was nitrogen at 80 ° C. The atmosphere. Then, polymerization is carried out while adding a polymerization initiator solution obtained by dissolving 0.5 parts by weight of benzoyl peroxide in 50 parts by weight of cyclohexane to the reaction solution over 24 hours, and after the polymerization, ethyl acetate is further added to the acrylic adhesive. An acrylic pressure-sensitive adhesive A solution having an agent A content of 35% by weight was obtained.

(Preparation of acrylic adhesive B)
A reaction solution consisting of 100 parts by weight of 2-ethylhexyl acrylate, 80 parts by weight of ethyl acrylate, 20 parts by weight of vinyl pyrrolidone and 200 parts by weight of ethyl acetate was put into a separable flask, and then the inside of the separable flask was filled with nitrogen at 80 ° C. The atmosphere. Then, a polymerization initiator solution prepared by dissolving 1 part by weight of benzoyl peroxide in 100 parts by weight of ethyl acetate was added to this reaction solution over 27 hours to polymerize, and after polymerization, ethyl acetate was further added to obtain an acrylic adhesive. An acrylic pressure-sensitive adhesive B solution having a B content of 32% by weight was obtained.

(Examples 1-8, Comparative Examples 1-8)
Azelastine, azelastine hydrochloride, fatty acid, fatty acid ester and azelastine, azelastine hydrochloride, fatty acid, fatty acid ester, and acrylic pressure-sensitive adhesives A and B so that the weight composition is in the ratio shown in Tables 1 and 2. Acrylic pressure-sensitive adhesives A and B solutions were blended, ethyl acetate was added so that the solid content was 22% by weight, and then mixed until uniform to prepare a paste layer solution. In the column of fatty acids in Tables 1 and 2, the number of carbon atoms of the aliphatic hydrocarbon group is described in parentheses on the right side of the compound.

  Next, a 38 μm-thick polyethylene terephthalate film that has been subjected to silicon release treatment is prepared, and the plaster layer solution is applied to the silicon release treatment surface of the polyethylene terephthalate film and dried at 60 ° C. for 30 minutes. Thereby, the laminated body by which the paste body layer of the thickness shown to Table 1, 2 was formed in the silicon mold release process surface of a polyethylene terephthalate film was produced.

  Then, a polyethylene terephthalate film having a thickness of 25 μm is prepared as a support, and is laminated so that one surface of the support and the paste layer of the laminate face each other, and the paste layer of the laminate is used as a support. A patch was produced by laminating and integrating.

  The storage stability of the patches obtained in Examples and Comparative Examples was measured in the following manner, and the results are shown in Tables 1 and 2. The patches obtained in Examples 1 and 5 and Comparative Examples 1 and 4 to 6 were subjected to a permeability test in the following manner to measure the cumulative skin permeation amount of azelastine, and the results are shown in Table 3 and FIGS. It was shown to. The patches obtained in Examples 2 to 4 and Comparative Examples 2 and 3 were subjected to a permeability test in the same manner to measure the cumulative amount of azelastine permeated through the skin. The results are shown in Table 4 and FIG. For Examples 6 to 8 and Comparative Examples 7 and 8, the amount of azelastine transferred was measured in the following manner, and the results are shown in Table 5.

(Storage stability)
Immediately after the manufacture of the patch, the surface of the plaster layer was observed visually and with a microscope to observe the crystal deposition state. Further, a test piece having a side of 10 cm was cut out from the patch, and the test piece was sealed in a light-shielding packaging material and stored at room temperature for 6 months. After 6 months, the surface of the plaster layer was again observed, and the crystal deposition state was observed visually and with a microscope. The case where no crystal was precipitated on the surface of the plaster layer was “◯”, and the case where crystal was precipitated was “x”.

(Permeability test)
A planar circular test piece (applied area: 3.14 cm ² ) having a diameter of 2 cm was cut out from the patches immediately after production obtained in Examples 1 and 5 and Comparative Examples 1 and 4 to 6, while being maintained at 37 ° C. In addition, the dorsal skin of a hairless mouse (male, 8 to 10 weeks old) was fixed to a diffusion cell of Franz, and a test piece was attached to the upper end of the skin with the paste layer. In addition, the physiological saline adjusted to pH 7.2 was used as a receptor solution, and the lower end of the skin was immersed in the receptor solution.

  6, 21, and 24 hours after the test piece was affixed to the skin, the receptor solution under the skin was collected, and the azelastine concentration was measured using HPLC. Three test pieces were prepared, and the azelastine concentration after 6, 21, and 24 hours was measured for each test piece as described above. Then, for each elapsed time, the azelastine permeation amount calculated from the azelastine concentration and the amount of the receptor liquid is calculated, the azelastine permeation amount calculated for each test piece is arithmetically averaged for each elapsed time, and the value is accumulated in the cumulative skin of azelastine The amount of transmission was used. In calculating the amount of azelastine permeation after 21 and 24 hours, since the receptor solution was collected before that, the amount of collected receptor solution was corrected.

  Furthermore, after the patch was sealed in a light-shielding packaging and stored at room temperature for 6 months, the cumulative amount of azelastine permeated through the skin was measured in the same manner as described above.

  The patches immediately after production obtained in Examples 2 to 4 and Comparative Examples 2 and 3 were subjected to a permeability test in the same manner as described above, and the cumulative skin permeation amount of azelastine was measured.

(Evaluation of transdermal absorbability by rat patch test)
For Examples 6 to 8 and Comparative Examples 7 and 8, the amount of azelastine transferred in the rat patch test was evaluated by the following method for the purpose of evaluating drug absorbability to the skin.

First, 5 pieces of a test piece having an area of 3 cm ² were cut out from each patch, and the components in the paste layer were extracted from 3 pieces, and the obtained extract was subjected to HPLC measurement to contain azelastine in the extract. The amount was quantified, and the arithmetic average value was defined as the azelastine content W ₁ (μg).

Next, the remaining two test pieces were affixed to the skin of the back of a rat (wistar male, 7 weeks old) from which the hair on the back had been removed in advance, and peeled off after 24 hours. Then, to extract the components of the plaster layer of the test piece after the sticking, by HPLC measurements, to quantify the azelastine content W ₂ ([mu] g) in the extract solution, the test pieces each with a following formula (1) It was calculated azelastine migration amount (μg / cm ² / 24h) to. The value calculated for each test piece was arithmetically averaged to obtain the amount of azelastine transferred to the patch. In Table 5, “Azelastine transfer amount” is simply expressed as “Transfer amount”.
Azelastine migration amount ^{(μg / cm 2 / 24h)} = (W 1 -W 2) / 3 ··· Equation (1)

It is the graph which showed the cumulative amount of skin permeation of azelastine obtained by conducting a permeability test about patches just after manufacture obtained in Examples 1 and 5 and Comparative Examples 1 and 4-6. It is the graph which showed the cumulative skin permeation | transmission amount of the azelastine obtained by performing the permeability test about a patch, after preserve | saving the patch obtained in Example 1, 5 and Comparative Example 1, 4-6 for 6 months. . It is the graph which showed the cumulative skin permeation amount of the azelastine obtained by conducting a permeability test about the patch immediately after manufacture obtained in Examples 2-4 and Comparative Examples 2 and 3.

Claims (4)

A patch comprising a support and a paste layer laminated and integrated on one surface of the support, wherein the paste layer has 1 to 30% by weight of a free basic drug and 8 to 8 carbon atoms. It contains 1 to 30% by weight of a fatty acid having 22 aliphatic hydrocarbon groups and 50 to 98% by weight of an adhesive, the free basic drug is azelastine, and the adhesive is made of an acrylic copolymer. An acrylic pressure-sensitive adhesive, wherein the acrylic copolymer comprises 2-ethylhexyl methacrylate and an alkyl (meth) acrylate having 6 to 16 carbon atoms in the alkyl group excluding the acrylic copolymer, It is an acrylic copolymer containing 2-90% by weight of 2-ethylhexyl methacrylate in the monomer component constituting the coalescence, or an alkyl (meth) acrylate having 4 to 18 carbon atoms in the alkyl group A patch comprising an acrylic copolymer containing 25 to 70% by weight of a polymer and 30 to 75% by weight of an alkyl (meth) acrylate having an alkyl group having 3 or less carbon atoms. The patch according to claim 1, wherein the fatty acid has an aliphatic hydrocarbon group having 10 to 20 carbon atoms. The patch according to claim 1, wherein the fatty acid has a linear or branched aliphatic hydrocarbon group. The fatty acid contains at least one fatty acid selected from the group consisting of lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, behenic acid, oleic acid and undecylenic acid. The patch described in 1.

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