JP2016106133A - Transdermal absorption-promoting agent and transdermal absorption formulation containing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a transdermal absorption formulation comprising a highly safe transdermal absorption-promoting agent with excellent transdermal absorption promoting effects and high usability.SOLUTION: A transdermal absorption formulation comprises a specific basic low molecular medicine, and a transdermal absorption-promoting agent that comprises (i) lactic acid, and (ii) at least one additive selected from the group consisting of α-monoisostearyl glyceryl ether, lauromacrogol, adipic acid diisopropyl, lauryl alcohol, diethyl sebacate, and oleate.SELECTED DRAWING: None

Description

  The present invention relates to a transdermal absorption enhancer. Specifically, the present invention relates to a percutaneous absorption enhancer containing lactic acid and specific additives, and a percutaneous absorption type preparation containing the same.

  Drug transdermal administration can maintain blood drug levels more sustainably than oral administration, and reduce liver metabolism and drug interactions to avoid first-pass effects. It is useful because it can be reduced. In addition, administration by transdermal preparations, particularly patch preparations, is not affected by meals, can be administered to patients who have difficulty swallowing, can be easily confirmed and interrupted, etc. There are many good points.

  However, since the skin functions as a barrier to prevent the invasion of foreign substances from the outside, even if a drug is simply applied to or applied to the skin, a necessary and sufficient amount of drug that produces a medicinal effect is sent into the body. It ’s difficult. For this reason, generally, there is a method in which a medicinal effect is expressed by adding an additive for the purpose of promoting the skin permeation of the drug, that is, a transdermal absorption enhancer, and administering the drug. It has been broken. As an example of a percutaneous absorption enhancer, for example, a method for improving the skin permeability of a drug by combining a plurality of additives is proposed, and a combination of diglycerin and a low molecular weight betaine is known (Patent Document 1). Moreover, although the improvement of the percutaneous absorption by the lactic acid with respect to a specific compound is known (patent document 2), the preferable additive combined with the lactic acid which improves skin permeability is not known specifically. Under such circumstances, there has been a demand for the development of a transdermal absorption enhancer that is safe, excellent in usability, and highly effective regardless of the type of drug.

JP-A-2005-336134 International Publication No. 2007/142295 Pamphlet

  An object of the present invention is to provide a percutaneous absorption enhancer capable of remarkably improving the skin permeation of a drug.

As a result of intensive studies on the composition that promotes skin permeation, the present inventors have found that a combination of lactic acid and a specific additive has a synergistic effect in promoting skin permeation of drugs, and the present invention has been completed. It came to do.
That is, the present invention is as follows.

[1] (i) lactic acid and (ii) at least one addition selected from the group consisting of α-monoisostearyl glyceryl ether, lauromacrogol, diisopropyl adipate, lauryl alcohol, diethyl sebacate, and oleic acid A transdermal absorption enhancer containing an agent.
[2] The transdermal absorption enhancer according to [1], wherein the additive is at least one selected from the group consisting of α-monoisostearyl glyceryl ether, lauromacrogol, and diisopropyl adipate.
[3] The percutaneous absorption enhancer according to the above [1] or [2], wherein the additive comprises α-monoisostearyl glyceryl ether or lauromacrogol.
[4] The percutaneous absorption enhancer according to any one of [1] to [3], wherein the additive contains α-monoisostearyl glyceryl ether.
[5] The transdermal absorption enhancer according to any one of [1] to [3], wherein the additive contains lauromacrogol.
[6] The percutaneous absorption enhancer according to any one of the above [1] to [5], which contains 0.1 to 30 parts by weight of the additive as a total amount with respect to 1 part by weight of lactic acid.
[7] Basic low molecular drug (however, 2- (4-ethyl-1-piperazinyl) -4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b ] Pyridine, or (3aR, 4S, 7R, 7aS) -2-{(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) piperazin-1-ylmethyl] cyclohexylmethyl} Excluding hexahydro-4,7-methano-2H-isoindole-1,3-dione, or physiologically acceptable acid addition salts thereof), and any one of [1] to [6] above. A transdermal preparation containing a transdermal absorption enhancer.
[8] The transdermal absorption preparation according to [7], wherein the transdermal absorption enhancer comprises (i) lactic acid, (ii) α-monoisostearyl glyceryl ether, and (iii) lauromacrogol.
[9] The transdermal absorption preparation according to [7], wherein the transdermal absorption enhancer comprises (i) lactic acid and (ii) α-monoisostearyl glyceryl ether.
[10] The transdermal absorption preparation according to [7], wherein the transdermal absorption enhancer comprises (i) lactic acid and (ii) lauromacrogol.
[11] The transdermal absorption preparation according to [7], wherein the transdermal absorption enhancer comprises (i) lactic acid and (ii) diisopropyl adipate.
[12] The transdermal absorption preparation according to any of [7] to [11], wherein the dosage form is a patch preparation, an ointment, a gel, a cream, or a lotion.
[13] The transdermal absorption preparation according to [12], wherein the dosage form is a patch preparation.
[14] A patch preparation comprising an adhesive layer formed on one side of a support, wherein the adhesive layer is (1) a transdermal absorption enhancer according to any one of [1] to [6] above (2) The percutaneously absorbable preparation according to [13] above, which contains a basic low molecular weight drug and (3) an adhesive.
[15] The transdermal absorption preparation according to [14], wherein the pressure-sensitive adhesive is at least one selected from an acrylic pressure-sensitive adhesive, a rubber-based pressure-sensitive adhesive, and a silicone pressure-sensitive adhesive.
[16] The percutaneous absorption preparation according to [15], wherein the adhesive comprises an acrylic adhesive.
[17] The acrylic pressure-sensitive adhesive is selected from the group consisting of (co) polymers mainly composed of (meth) acrylic acid alkyl esters, and copolymers of (meth) acrylic acid alkyl esters and functional monomers. The percutaneous absorption preparation according to [15] or [16], which is at least one kind.
[18] The percutaneous absorption preparation according to [15] or [16], wherein the adhesive comprises a rubber-based adhesive.
[19] The transdermal preparation according to [15] or [18], wherein the rubber-based adhesive is at least one selected from the group consisting of a styrene-isoprene-styrene block copolymer and polyisobutylene. .
[20] A basic low molecular weight drug is perospirone, 5- (3-methoxyphenyl) -3- (5-methyl-1,2,4-oxadiazol-3-yl) -2-oxo-1,2 -The percutaneously absorbable preparation according to any one of [7] to [19], which is dihydro-1,6-naphthyridine or zonisamide.
[21] The transdermally absorbable preparation according to any one of [7] to [20], wherein the additive is contained in a proportion of 0.1 to 30 parts by weight as a total amount with respect to 1 part by weight of lactic acid.
[22] A transdermal preparation containing at least one additive selected from the group consisting of zonisamide, lactic acid, and α-monoisostearyl glyceryl ether and lauromacrogol.
[23] A transdermal preparation containing zonisamide, lactic acid and α-monoisostearyl glyceryl ether.
[24] A transdermal preparation containing zonisamide, lactic acid and lauromacrogol.
[25] The percutaneous absorption preparation according to any one of [22] to [24], wherein the additive is contained in a proportion of 0.1 to 30 parts by weight with respect to 1 part by weight of lactic acid.

  The transdermal absorption enhancer of the present invention promotes skin permeation of a drug, thereby providing a transdermal absorption preparation containing a basic low molecular weight drug required as a medical site as a drug. It is possible to contribute to improvement in medical use, safety, and economy, such as downsizing of the preparation, reduction of application area and required amount, and reduction of drug remaining in the preparation after administration.

  Hereinafter, preferred embodiments of the present invention will be described in detail.

(1) Percutaneous absorption enhancer The transdermal absorption enhancer of the present invention comprises a combination of (i) lactic acid and (ii) a specific additive, and the ratio of both in the agent is 1 part by weight of lactic acid. The specific additive is usually 0.1 to 30 parts by weight, preferably 0.5 to 12 parts by weight. The transdermal absorption enhancer can be produced, for example, by mixing both.

(I) Lactic acid lactic acid may be a racemic DL-lactic acid, or an optically active L-lactic acid or D-lactic acid. Any of these may be sufficient as lactic acid as used in this specification.

(Ii) Specific Additives In the present invention, a synergistic effect on skin permeation promotion by a combination of lactic acid and specific additives was found.

  Suitable specific additives used in the present invention include at least one selected from the group consisting of α-monoisostearyl glyceryl ether, lauromacrogol, diisopropyl adipate, lauryl alcohol, oleic acid, and diethyl sebacate. In particular, α-monoisostearyl glyceryl ether, lauromacrogol or diisopropyl adipate is preferable.

  The specific additives may be used alone or in combination of two or more, and may contain α-monoisostearyl glyceryl ether, lauromacrogol, or both.

(2) Percutaneous absorption preparation As a dosage form of the percutaneous absorption preparation in the present invention, a dosage form conventionally used as an external preparation, for example, a patch preparation, an ointment, a cream, a gel, a gel cream It can be used as an external preparation of any dosage form such as an agent, lotion, spray, aerosol, liniment and the like. Of these, a patch is preferred. A patch (hereinafter also referred to as a patch preparation) means any preparation that is attached to the skin, and includes, for example, a tape preparation, a patch preparation, a poultice preparation, a plaster preparation, and the like. Among these, a tape preparation or a patch preparation is particularly preferable.
The percutaneous absorption-type preparation of the present invention can be produced by a usual method by blending appropriate amounts of the above (i) lactic acid and (ii) specific additives as percutaneous absorption enhancers in the preparation. In addition, when the solubility of lactic acid and a specific additive and base is not expected, a solvent can be appropriately used to improve the solubility. Next, the patch preparation will be described in more detail as the transdermal preparation of the present invention.

  In the case of a patch preparation, the percutaneous absorption enhancer comprising (i) lactic acid and (ii) a specific additive can be blended with the drug and the adhesive in the adhesive layer of the preparation. Furthermore, you may mix | blend the following pharmacologically acceptable formulation component used for manufacture of a patch preparation as needed.

  The blending amount of the transdermal absorption promoter blended in the patch preparation of the present invention is usually about 0.01 to 50% by weight, preferably 0.1 to 40% by weight, based on the total amount of the pressure-sensitive adhesive layer. Preferably, it is 0.3 to 40% by weight, and more preferably 1 to 40% by weight.

  In the present claims and the present specification, the pressure-sensitive adhesive layer is a layer containing a drug formed on a support, and includes at least (i) a drug, (ii) a pressure-sensitive adhesive, and (iii) It contains lactic acid and (iv) specific additives, and may further contain other formulation ingredients.

  In the present claims and in the present specification, what is simply indicated by “% by weight” is the weight% when the total weight of the pressure-sensitive adhesive layer substantially free of solvent or the like is 100% by weight due to drying or the like. means.

  The pressure-sensitive adhesive used in the patch preparation of the present invention can be appropriately selected from known ones in consideration of skin safety, drug release properties, adhesion to the skin, and the like. Examples of preferable adhesives include silicone adhesives, rubber adhesives, acrylic adhesives, and the like.

  Examples of the silicone-based pressure-sensitive adhesive include those mainly composed of silicone rubber such as polydimethylsiloxane and diphenylsiloxane. Examples of the rubber-based pressure-sensitive adhesive include natural rubber, polyisopropylene rubber, polyisobutylene, styrene- Examples thereof include a butadiene copolymer, a styrene-isopropylene copolymer, and a styrene-isoprene-styrene block copolymer.

As the acrylic pressure-sensitive adhesive, for example, a (co) polymer mainly composed of (meth) acrylic acid alkyl ester, specifically, a polymer mainly composed of alkyl acrylate ester, mainly composed of methacrylic acid alkyl ester. And a copolymer mainly composed of alkyl acrylate, a copolymer mainly composed of alkyl methacrylate, and a copolymer mainly composed of alkyl acrylate and alkyl methacrylate. The (co) polymer may be a copolymer of two or more kinds of (meth) acrylic acid alkyl esters as described above, and a functional monomer that can be copolymerized with the (meth) acrylic acid alkyl ester; A copolymer with (meth) acrylic acid alkyl ester may be used.
Here, “(meth) acrylic acid” means “acrylic acid or methacrylic acid” or “acrylic acid and / or methacrylic acid”, and “(co) polymer” Means “polymer or copolymer” or “polymer and / or copolymer”.

  Examples of (meth) acrylic acid alkyl ester include (meth) acrylic acid alkyl ester esterified with linear or branched alkyl having 1 to 18 carbon atoms, specifically (meth) Examples include acrylic acid methyl ester, (meth) acrylic acid butyl ester, (meth) acrylic acid hexyl ester, (meth) acrylic acid octyl ester, (meth) acrylic acid nonyl ester, (meth) acrylic acid decyl ester, and the like. Examples of the functional monomer include a monomer having a hydroxyl group (such as (meth) acrylic acid hydroxyethyl ester), a monomer having a carboxyl group (such as butyl maleate and crotonic acid), and a monomer having an amide group (such as (meth) acrylamide) ), A monomer having an amino group (such as dimethylaminoacrylate), a monomer having a pyrrolidone ring (such as N-vinyl-2-pyrrolidone), and the like.

  You may use the acrylic adhesive of this invention individually or in combination of 2 or more types. Moreover, the mixture with another adhesive may be sufficient. Examples of other pressure-sensitive adhesives include silicone pressure-sensitive adhesives and rubber-based pressure-sensitive adhesives.

  Specific preferred acrylic pressure-sensitive adhesives include, but are not limited to, for example, acrylic acid / octyl acrylate ester copolymer, acrylic ester / vinyl acetate copolymer, 2-ethylhexyl acrylate / vinyl pyrrolidone copolymer Copolymer, 2-ethylhexyl acrylate / 2-ethylhexyl methacrylate / dodecyl methacrylate copolymer, ethyl acrylate / methyl methacrylate copolymer, silk fibroin acrylate copolymer, methyl acrylate / -2-ethylhexyl acrylate For example, commercially available products such as “Polychic 410-SA” manufactured by Sanyo Chemical Industries, Ltd., “Olivein BPS-4849-40” manufactured by Toyo Ink Manufacturing Co., Ltd., “DURO-TAK” manufactured by National Starch & Chemical Co., Ltd. 87-2194 (registered trademark) "," DURO-TAK 387-2516 (registered trademark) ”,“ MAS811 ”,“ MAS683 ”,“ MAS955 ”manufactured by Kosmedy Pharmaceutical Co., Ltd. and the like.

  Moreover, in order to give moderate adhesiveness with respect to skin, you may add a hardening | curing agent as needed. Examples of the curing agent include commercially available “Polysic SC-75” manufactured by Sanyo Chemical Industries, Ltd., “BHS8515” manufactured by Toyo Ink Manufacturing Co., Ltd., and the like. What is necessary is just to select suitably according to the characteristic of an adhesive as the compounding quantity, for example, it is about 0.001-0.05 weight part with respect to 1 weight part of adhesives.

  As the compounding amount of the adhesive in the patch preparation of the present invention, the percutaneous absorption enhancer consisting of a drug, lactic acid and specific additives in the adhesive layer, and various formulation ingredients to be added as necessary are described below. The remaining amount is the amount necessary to complete the pressure-sensitive adhesive layer. Therefore, for example, when the pressure-sensitive adhesive layer contains 10% by weight of the drug and 20% by weight of the transdermal absorption enhancer, the pressure-sensitive adhesive is about 70% by weight.

  The tackiness of the pressure-sensitive adhesive used here is such that it can be used as a medical patch preparation, and is intended to be tacky to the extent that it can be easily applied to the skin and does not cause any particular problems.

  The drug in the patch preparation of the present invention is not particularly limited as long as it is a basic low molecular weight drug. Here, the low molecule means a molecule having a molecular weight of less than 700.

  Specifically, for example, antihistamines (diphenhydramine, chlorpheniramine, etc.), antihypertensives (diltiazem, nicardipine, metoprolol, bisoprolol, propranolol, penbutolol, etc.), antiarrhythmic drugs (mexiletine, etc.), antiparkinson drugs (pergolide, bromocriptine, Ropinirole, selegiline, amantadine, rotigotine, zonisamide, etc.), bronchodilators (tulobuterol, fenoterol, procaterol, salbutamol, etc.), antiallergic agents (ketotifen, azelastine, etc.), local anesthetics (lidocaine, dibucaine, etc.), narcotic analgesics (Fentanyl, morphine, etc.), urinary agents (oxybutynin, tamsulosin, tolterodine, etc.), neuropsychiatric agents (chlorpromazine, bupropion, etc.), antidepressants ( Luoxetine, paroxetine, citalopram, duloxetine, escitalopram, etc.), anti-dementia drugs (donepezil, rivastigmine, etc.), expectorants (ambroxol, etc.), anti-anxiety drugs (tandospirone, etc.), antipsychotic drugs (quetiapine, aripiprazole, perospirone, etc.) , ADHD treatments (methylphenidate, atomoxetine, etc.), osteoporosis treatments (raloxifene, etc.), breast cancer prevention drugs (tamoxifen, etc.), anticancer agents (irinotecan, paclitaxel, etc.), anti-obesity drugs (sibutramine, etc.), insomnia Examples thereof include improvers (such as zolpidem) and antiemetics (ondansetron, palonosetron, ramosetron, etc.), and these may be free bases or physiologically acceptable acid addition salts thereof. . For example, organic acid addition salts include, for example, formate, acetate, lactate, adipate, citrate, tartrate, methanesulfonate, fumarate, maleate, and the like. Examples of the addition salt of inorganic acid include hydrochloride, sulfate, nitrate, phosphate and the like. Furthermore, the free base, or a physiologically acceptable acid addition salt thereof, may be a solvate, a hydrate and a non-hydrate.

  The drug blended in the patch preparation of the present invention is usually about 0.1 to 40% by weight in 100% by weight of the pressure-sensitive adhesive layer in terms of free base when the drug is in the form of a salt. Depending on the area of the patch preparation, preferably, it is about 0.1 to 30% by weight, more preferably about 0.1 to 20% by weight, and preferably about 0.5 to 40% by weight, Preferably it is about 0.5-30 weight%, More preferably, it is about 0.5-20 weight%. Here, in terms of conversion to a free base or the like, when the drug is in the form of a salt, or when the drug has crystal water, the equivalent amount of the salt or crystal water is not included in the weight of the drug. It is meant to be.

  The pharmaceutically acceptable conventional formulation component to be blended as necessary in the patch preparation of the present invention is not inconvenient even if it is blended, and may be any as long as it is necessary to blend. Examples thereof include a stabilizer, a tackifier, a plasticizer, a fragrance, a filler, a thickener, and a curing agent.

  Stabilizers include but are not limited to, for example, ascorbic acid, sodium alginate, propylene glycol alginate, dibutylhydroxytoluene, butylhydroxyanisole, tocopherol acetate, tocopherol, propyl gallate, ethyl paraoxybenzoate, paraoxybenzoic acid Examples include butyl, propyl paraoxybenzoate, methyl paraoxybenzoate, and 2-mercaptobenzimidazole.

  Examples of the tackifier include, but are not limited to, ester gum, glycerin, hydrogenated rosin glycerin ester, petroleum resin, rosin, polybutene, and the like. Examples of the plasticizer include, but are not limited to, polybutene, glycerin, glycerin fatty acid ester, and the like. Examples of the fragrance include, but are not limited to, dl-menthol, orange oil, mint oil, lemon oil, rose oil, and the like. Examples of the filler include, but are not limited to, titanium oxide, zinc oxide, starch acrylate 100, and the like.

  Examples of the thickener include, but are not limited to, carboxymethylcellulose, carrageenan, pectin, poly (N-vinylacetamide), N-vinylacetamide / sodium acrylate copolymer, and the like.

  In the patch preparation of the present invention, the above-mentioned pressure-sensitive adhesive layer is formed on one surface (one surface) of the support, and a release liner is appropriately provided on the other surface that does not contact the support of the pressure-sensitive adhesive layer. In use, the release liner is peeled off, and the adhesive layer of the patch preparation is applied to the skin for transdermal administration.

  The support is not particularly limited as long as it is made of a material that does not permeate or hardly permeates the drug, and does not affect or hardly affects the drug release. It may be. For example, but not limited to these, resin films such as ethyl cellulose, nylon, polyethylene terephthalate (PET), polyester, polypropylene, and combinations thereof can be exemplified. Moreover, the nonwoven fabric made from PET etc. may be formed in one surface of the support body in which an adhesive layer is not formed. Moreover, even if it is a support body of a single layer structure, the support body of the structure where the some raw material was laminated | stacked may be sufficient. Even if the support is colorless and transparent, it may be colored white or skin color, etc., and the one colored white or skin color is the one where the surface of the support is coated with a pigment, It may be one in which a dye or a pigment is uniformly kneaded in the support.

  The support surface on which the pressure-sensitive adhesive layer is formed is preferably subjected to surface treatment such as corona discharge treatment, plasma treatment, oxidation treatment, hairline processing, and sand mat processing.

  The patch preparation of the present invention can be produced by a usual method. For example, it can be produced according to the section concerning the production of a plaster described in “Transdermal Formulation Development Manual” supervised by Mitsuo Matsumoto (1985). Further, for example, it can be produced by the apparatus and method described in “Development of device for producing a patch for a transdermal therapeutic system (Membrane, 32 (2), 116-119 (2007))”.

  Specifically, in the preparation of a patch preparation of the present invention, particularly a tape preparation, a general method for producing an adhesive tape can be applied to form an adhesive layer. A typical example is a solvent coating method, and a hot melt coating method, an electron beam curable emulsion coating method, and the like are also used.

  In order to form the pressure-sensitive adhesive layer by a solvent coating method, for example, a drug, a mixed solution containing a pressure-sensitive adhesive, and a formulation component such as a transdermal absorption accelerator or a curing agent, and an organic solvent are mixed with the pressure-sensitive adhesive layer. Produced by preparing a mixed solution, applying the mixed solution to one side of a support or release liner, drying to remove the organic solvent, and bonding the release liner or support together at any timing before and after drying can do. The thickness of the resulting pressure-sensitive adhesive layer is about 10 to about 400 μm, preferably about 20 to about 200 μm. However, the thickness of the adhesive layer is not limited to these ranges, and it is within the scope of the present invention whether it is thicker or thinner than these ranges.

  The release liner for covering the surface of the pressure-sensitive adhesive layer is appropriately selected. However, the release liner having a release performance on the surface thereof is not limited to this. For example, a paper binder treated with a silicon resin, A plastic film etc. are mentioned.

  The patch preparation of the present invention thus obtained is produced in an appropriate size according to factors such as the dose, or cut into such a form. Note that the patch preparation of that size may be a tape larger than the size to be actually applied, or conversely, it may be a small tape. May be. The body part to be affixed is not particularly limited, and examples thereof include an arm, a shoulder, a neck, a back, a waist, an abdomen, a chest, a buttock, and a foot. The patch preparation of the present invention is packaged and distributed together with a description describing information on the patch preparation. The description may be on the package or may be included as an instruction in the package.

  Next, the formulation of other ointments, gels, creams, and lotions, which are other transdermal absorption agents, will be briefly described.

  Ointments are not only percutaneous absorption enhancers consisting of a combination of a drug, lactic acid and specific additives, but also higher fatty acids such as myristic acid, lauric acid, palmitic acid, stearic acid, linoleic acid or esters thereof, whale At least a wax such as wax, a surfactant such as polyoxyethylene alkyl ether and sucrose fatty acid ester, and a hydrocarbon such as hydrophilic petrolatum and plastibase are blended. The formulation of the ointment is, for example, 5 to 15% by weight of a higher fatty acid or ester thereof, 1 to 10% by weight of a surfactant, 0.5 to 10% by weight of a drug, and 0.1 to 20 of the transdermal absorption enhancer. Mix the weight% at room temperature or under heating, add 4-10% by weight waxes, 50-80% by weight hydrocarbon, heat or heat melt, keep at 50-100 ° C., all components are transparent solution After mixing, mix evenly with a homomixer. Then, it is made into an ointment by lowering to room temperature while stirring.

  In addition to a percutaneous absorption enhancer comprising a combination of a drug and lactic acid and a specific additive, the gel is a lower alcohol such as ethanol, water, a gelling agent such as carboxyvinyl polymer, triethanolamine or the like. It comprises at least a neutralizing agent. For example, the gel formulation is expanded by adding 0.5 to 5% by weight of a gelling agent to 55% by weight or less of water. On the other hand, 0.5 to 10% by weight of the drug and 0.1 to 20% by weight of the transdermal absorption enhancer are dissolved in a mixture of 40% by weight or less of glycols and 60% by weight or less of the lower alcohol. Both of these are mixed and further neutralized to adjust to pH 4-7 to obtain a gelling agent.

  In addition to the percutaneous absorption enhancer consisting of a combination of a drug and lactic acid and specific additives, the cream is a higher fatty acid ester such as myristic acid ester and oleic acid ester, water, hydrocarbons such as liquid paraffin, It comprises at least an emulsifier such as polyoxyethylene alkyl ethers. This cream formulation can be obtained by adding an appropriate amount of the aforementioned drug, the transdermal absorption accelerator, higher fatty acid ester, water, hydrocarbons, and emulsifier, and mixing and stirring.

  The lotion preparation contains, as a base material, at least a lower alcohol such as ethanol, water, glycerin, and / or glycols in addition to a percutaneous absorption enhancer comprising a combination of a drug, lactic acid and a specific additive. The formulation of this lotion can be obtained by adding an appropriate amount of the aforementioned drug, the transdermal absorption enhancer, lower alcohol, water and / or glycols, and mixing and stirring.

  The other percutaneously absorbable preparations of the present invention, as long as they do not impair the purpose of the present invention, are pharmaceutically acceptable conventional formulation ingredients such as a stabilizer, A fragrance | flavor, a filler, a thickener, etc. can be added.

  As one aspect of the transdermally absorbable preparation of the present invention, transdermally absorbable containing zonisamide, lactic acid, and at least one additive selected from the group consisting of α-monoisostearyl glyceryl ether and lauromacrogol. A formulation is mentioned. Furthermore, a percutaneous absorption preparation containing zonisamide, lactic acid and α-monoisostearyl glyceryl ether, and a percutaneous absorption preparation containing zonisamide, lactic acid and lauromacrogol can be mentioned. Further, examples of the transdermally absorbable preparation include a patch preparation, and a tape preparation or a patch preparation is preferable.

  Hereinafter, the present invention will be described in more detail with reference to Examples, Reference Examples, Test Examples, and the like, but the present invention is not limited thereto. In the following examples and the like, “%” means “% by weight”.

  For Examples 1-11 and Reference Examples 1-14, the support was a 25 μm polyethylene terephthalate film manufactured by Fujimori Kogyo Co., Ltd., and for Examples 12-14 and Reference Examples 15-19, 3M Healthcare Corporation A company-made 50.8 μm polyethylene terephthalate / ethylene vinyl acetate copolymer laminate film (Scotchpak # 9732) was used. As the release liner, a binder sheet 64S-018B manufactured by Fujimori Industry Co., Ltd. was used.

Example 1
Acrylic adhesive (Policic 410-SA, manufactured by Sanyo Chemical Industries, Ltd., solid content 38 wt%) 4.63 g, curing agent (Policic SC-75, manufactured by Sanyo Chemical Industries, Ltd., solid content 75 wt%) 28. 0 mg, 1.2 ml of ethyl acetate, and lactic acid and α-monoisostearyl glyceryl ether were mixed so that the content in the pressure-sensitive adhesive layer was 5% each. In this mixed solution, 5- (3-methoxyphenyl) -3- (5-methyl-1,2,4-oxadiazol-3-yl)-was added so that the content in the pressure-sensitive adhesive layer was 1%. 2-Oxo-1,2-dihydro-1,6-naphthyridine (hereinafter referred to as “Compound 1”) was added and stirred sufficiently. The obtained mixed liquid was spread on a support so that the thickness of the pressure-sensitive adhesive layer after drying was about 60 μm, and dried at room temperature for 1 day. Thereafter, a release liner was bonded to produce a tape preparation.

Examples 2-4
Each tape formulation was manufactured using the additive shown in the following Table 1 instead of the alpha-monoisostearyl glyceryl ether of Example 1.

Reference example 1
4.89 g of acrylic pressure-sensitive adhesive (Polysic 410-SA, manufactured by Sanyo Chemical Industries, solid content 38% by weight), 30 mg of curing agent (Polysic SC-75, manufactured by Sanyo Chemical Industries, Ltd., solid content 75% by weight), Lactic acid was added and mixed so that 1.2 ml of ethyl acetate and the content in the pressure-sensitive adhesive layer were 5%. Compound 1 was added to the mixed solution so that the content in the pressure-sensitive adhesive layer was 1%, and the mixture was sufficiently stirred. The obtained mixed liquid was spread on a support so that the thickness of the pressure-sensitive adhesive layer after drying was about 60 μm, and dried at room temperature for 1 day. Thereafter, a release liner was bonded to produce a tape preparation.

Reference Examples 2-5
Each tape formulation was manufactured using the additive shown in the following Table 2 instead of the lactic acid of Reference Example 1.

Test example 1
Hairless rat skin permeation experiment
Using an in vitro diffusion cell, the skin permeability of Compound 1 for the tape preparations obtained in Examples 1 to 4 and Reference Examples 1 to 5 on the skin of the abdomen of 5 to 6 weeks old hairless rats Examined. That is, hairless rat skin was set in an in vitro diffusion cell with a permeation area of 1.13 cm ² and 0.75 ml of a 2: 1 mixture of polyethylene glycol 200 (Macrogol 200) and phosphate buffer was used as the receiver solution. Then, each preparation was affixed to the skin on the donor side (n = 4). After stirring the receiver liquid for 24 hours at 37 ° C., the concentration of Compound 1 in the receiver liquid was determined by high performance liquid chromatography (column: YMC AM312 ODS 5 μm (6 mmφ × 150 mm; YMC), mobile phase: 0.05 mol / l. Sodium dihydrogen phosphate (adjusted with phosphoric acid to pH 3.0): acetonitrile (3: 1), column temperature: 40 ° C., flow rate: 1.5 ml / min), and the permeation amount of Compound 1 in each preparation was determined. Asked. The results are shown in Table 3.

Example 5
Acrylic adhesive (Policic 410-SA, manufactured by Sanyo Chemical Industries, Ltd., solid content 38 wt%) 4.63 g, curing agent (Policic SC-75, manufactured by Sanyo Chemical Industries, Ltd., solid content 75 wt%) 28. 0 mg, 1.2 ml of ethyl acetate, and lactic acid and α-monoisostearyl glyceryl ether as an additive were mixed so that the content in the adhesive layer was 5% each. In this mixed solution, cis-N- [4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl] cyclohexane- is used so that the content in the pressure-sensitive adhesive layer is 1%. 1,2-dicarboximide (perospirone, hereinafter referred to as “compound 2”) was added and sufficiently stirred. The obtained mixed liquid was spread on a support so that the thickness of the pressure-sensitive adhesive layer after drying was about 60 μm, and dried at room temperature for 1 day. Thereafter, a release liner was bonded to produce a tape preparation.

Examples 6-9
Each tape formulation was manufactured using the additive shown in the following Table 4 instead of the alpha-monoisostearyl glyceryl ether of Example 5.

Reference Example 6
4.89 g of acrylic pressure-sensitive adhesive (Polysic 410-SA, manufactured by Sanyo Chemical Industries, solid content 38% by weight), 30 mg of curing agent (Polysic SC-75, manufactured by Sanyo Chemical Industries, Ltd., solid content 75% by weight), Lactic acid was added and mixed so that 1.2 ml of ethyl acetate and the content in the pressure-sensitive adhesive layer were 5%. Compound 2 was added to this mixed solution so that the content in the pressure-sensitive adhesive layer was 1%, and the mixture was sufficiently stirred. The obtained mixed liquid was spread on a support so that the thickness of the pressure-sensitive adhesive layer after drying was about 60 μm, and dried at room temperature for 1 day. Thereafter, a release liner was bonded to produce a tape preparation.

Reference Examples 7-11
Each tape formulation was manufactured using the additive shown in the following table instead of lactic acid in Reference Example 6.

Test example 2
Hairless rat skin permeation experiment
Using an in vitro diffusion cell, the skin permeability of Compound 2 for the tape preparations obtained in Examples 5-9 and Reference Examples 6-11 to the skin of the abdomen of 5-6 week old hairless rats Examined. That is, hairless rat skin was set in an in vitro diffusion cell with a permeation area of 1.13 cm ² and 0.75 ml of a 2: 1 mixture of polyethylene glycol 200 (Macrogol 200) and phosphate buffer was used as the receiver solution. Then, each preparation was affixed to the skin on the donor side (n = 4). The receiver solution was stirred for 24 hours while maintaining at 37 ° C., and then the concentration of Compound 2 in the receiver solution was measured by high performance liquid chromatography (column: YMC AM312 ODS 5 μm (6 mmφ × 150 mm; YMC), mobile phase: 0.05 mol / l 1. -Sodium heptanesulfonate aqueous solution (adjusted to pH 2.5 with phosphoric acid): acetonitrile: methanol (15: 8: 2), column temperature: 40 ° C., flow rate: 1.3 ml / min), compound in each formulation The transmission amount of 2 was determined. The results are shown in Table 6.

Example 10
Acrylic adhesive (Polysic 410-SA, manufactured by Sanyo Chemical Industries, Ltd., solid content 38 wt%) 4.42 g, curing agent (Policic SC-75, manufactured by Sanyo Chemical Industries, Ltd., solid content 75 wt%) 27 mg, Lactic acid and oleic acid as an additive were mixed so that 1.2 ml of ethyl acetate and the content in the pressure-sensitive adhesive layer were 5% each. Compound 1 was added to the mixture so that the content in the pressure-sensitive adhesive layer was 5%, and the mixture was sufficiently stirred. The obtained mixed liquid was spread on a support so that the thickness of the pressure-sensitive adhesive layer after drying was about 60 μm, and dried at room temperature for 1 day. Thereafter, a release liner was bonded to produce a tape preparation.

Example 11
A tape formulation was prepared using diethyl sebacate instead of the oleic acid of Example 10.

Reference Example 12
4.68 g of acrylic pressure-sensitive adhesive (Polysic 410-SA, manufactured by Sanyo Chemical Industries, Ltd., solid content 38% by weight), 28 mg of curing agent (Polysic SC-75, manufactured by Sanyo Chemical Industries, Ltd., solid content 75% by weight), Lactic acid was added and mixed so that 1.2 ml of ethyl acetate and the content in the pressure-sensitive adhesive layer were 5%. Compound 1 was added to the mixture so that the content in the pressure-sensitive adhesive layer was 5%, and the mixture was sufficiently stirred. The obtained mixed liquid was spread on a support so that the thickness of the pressure-sensitive adhesive layer after drying was about 60 μm, and dried at room temperature for 1 day. Thereafter, a release liner was bonded to produce a tape preparation.

Reference Examples 13 and 14
Each tape formulation was manufactured using the additive shown in the following Table 7 instead of the lactic acid of Reference Example 12.

Test example 3
Hairless Rat Skin Permeation Experiment In the same manner as in Test Example 1, the skin permeability of Compound 1 for the tape preparations obtained in Examples 10 and 11 and Reference Examples 12 to 14 to the skin of the abdomen of hairless rats was measured. Examined. The results are shown in Table 8.

Example 12
Acrylic pressure-sensitive adhesive (Polysic 410-SA, manufactured by Sanyo Chemical Industries, Ltd., solid content 38 wt%) 2.21 g, curing agent (Policic SC-75, manufactured by Sanyo Chemical Industries, Ltd., solid content 75 wt%) 13. Lactic acid and α-monoisostearyl glyceryl ether were mixed so that the content in the pressure-sensitive adhesive layer was 0% and 0 mg. 1,2-benzisoxazole-3-methanesulfonamide (zonisamide, hereinafter referred to as “compound 3”) dissolved in 0.8 ml of acetone so that the content of the pressure-sensitive adhesive layer in the mixed solution is 5%. Was added and stirred thoroughly. The obtained mixed solution was spread on a support so that the thickness of the pressure-sensitive adhesive layer after drying was about 60 μm, and dried at room temperature for 2 days. Thereafter, a release liner was bonded to produce a tape preparation.

Example 13
A tape formulation was prepared using lauromacrogol in place of the α-monoisostearyl glyceryl ether of Example 12.

Reference Example 15
Acrylic adhesive (Polysic 410-SA, manufactured by Sanyo Chemical Industries, Ltd., solid content 38 wt%) 2.34 g, curing agent (Policic SC-75, manufactured by Sanyo Chemical Industries, Ltd., solid content 75 wt%) 14. Lactic acid was mixed so that 0 mg and the content in the pressure-sensitive adhesive layer were 5%. Compound 3 dissolved in 0.8 ml of acetone was added to this mixed solution so that the content in the pressure-sensitive adhesive layer was 5%, and the mixture was sufficiently stirred. The obtained mixed solution was spread on a support so that the thickness of the pressure-sensitive adhesive layer after drying was about 60 μm, and dried at room temperature for 2 days. Thereafter, a release liner was bonded to produce a tape preparation.

Reference Examples 16 and 17
A tape preparation was produced using the additives shown in Table 9 below instead of lactic acid in Reference Example 15.

Test example 4
Hairless rat skin permeation experiment
Using an in vitro diffusion cell, the skin permeability of Compound 3 was examined for the tape preparations obtained in Examples 12 and 13 and Reference Examples 15 to 17 on the skin of the abdomen of 6-week-old hairless rats. . That is, hairless rat skin was set in an in vitro diffusion cell with a permeation area of 1.13 cm ² and 0.75 ml of a 2: 3 mixture of polyethylene glycol 400 (Macrogol 400) and phosphate buffer was used as the receiver solution. Then, each preparation was affixed to the skin on the donor side (n = 4). After stirring the receiver solution for 16 hours at 37 ° C., the concentration of Compound 3 in the receiver solution was determined by high performance liquid chromatography (column: YMC AM312 ODS 5 μm (6 mmφ × 150 mm; YMC), mobile phase: 1% -acetic acid: Measurement was performed with methanol (3: 2), column temperature: 40 ° C., flow rate: 1.5 ml / min), and the permeation amount of Compound 3 in each preparation was determined. The results are shown in Table 10.

Example 14
Acrylic adhesive (Polysic 410-SA, manufactured by Sanyo Chemical Industries, Ltd., solid content 38 wt%) 1.95 g, curing agent (Policic SC-75, manufactured by Sanyo Chemical Industries, Ltd., solid content 75 wt%) 12. Lactic acid and lauromacrogol were mixed so that 0 mg and the content in the pressure-sensitive adhesive layer were 10% each. Compound 3 dissolved in 0.8 ml of acetone was added to this mixed solution so that the content in the pressure-sensitive adhesive layer was 5%, and the mixture was sufficiently stirred. The obtained mixed liquid was spread on a support so that the thickness of the pressure-sensitive adhesive layer after drying was about 60 μm, and dried at room temperature for 3 days. Thereafter, a release liner was bonded to produce a tape preparation.

Reference Example 18
Acrylic pressure-sensitive adhesive (Polysic 410-SA, manufactured by Sanyo Chemical Industries, Ltd., solid content 38 wt%) 2.21 g, curing agent (Policic SC-75, manufactured by Sanyo Chemical Industries, Ltd., solid content 75 wt%) 13. Lactic acid was mixed so that 0 mg and the content in the pressure-sensitive adhesive layer were 10%. Compound 3 dissolved in 0.8 ml of acetone was added to this mixed solution so that the content in the pressure-sensitive adhesive layer was 5%, and the mixture was sufficiently stirred. The obtained mixed liquid was spread on a support so that the thickness of the pressure-sensitive adhesive layer after drying was about 60 μm, and dried at room temperature for 3 days. Thereafter, a release liner was bonded to produce a tape preparation.

Reference Example 19
A tape preparation was produced using lauromacrogol instead of lactic acid in Reference Example 15.

Test Example 5
Hairless Rat Skin Permeation Experiment In the same manner as in Test Example 4, the skin permeability of Compound 3 was examined for the tape preparations obtained in Example 14 and Reference Examples 18 and 19 on the skin of the abdomen of hairless rats. . The results are shown in Table 11.

  The transdermal absorption enhancer of the present invention significantly increases the transdermal absorption of drugs, for example, basic low molecular weight drugs. The percutaneous absorption-type preparation comprising the percutaneous absorption enhancer of the present invention is excellent in usability and can rapidly deliver a desired drug to the whole body through a local site or circulatory system. It is extremely useful for the treatment of diseases.

  Although several specific embodiments of the present invention have been described in detail, those skilled in the art will recognize that various modifications may be made to the specific embodiments shown without departing from the teachings and advantages of the invention. It is possible to make changes. Accordingly, all such modifications and changes are intended to be included within the spirit and scope of the invention as claimed in the following claims.

  This application is based on patent application No. 2011-021196, the contents of which are incorporated in full herein.

Claims (22)

A percutaneous absorption-type preparation comprising a basic low molecular weight drug and a percutaneous absorption enhancer,
Basic low-molecular-weight drugs are diphenhydramine, chlorpheniramine, diltiazem, nicardipine, metoprolol, bisoprolol, propranolol, penbutolol, mexiletine, pergolide, ropinirole, selegiline, amantadine, rotigotine, tulobuterol, fenoteroltin, procateroltin dibutamol , Fentanyl, morphine, oxybutynin, tamsulosin, tolterodine, chlorpromazine, bupropion, fluoxetine, paroxetine, citalopram, duloxetine, escitalopram, rivastigmine, ambroxol, tandospirone, quetiapine, aripiprazole, methylphenidazole, methylphenidazole Notekan, paclitaxel, sibutramine, zolpidem, ondansetron, a palonosetron or ramosetron,,
The transdermal absorption enhancer is selected from the group consisting of (i) lactic acid and (ii) α-monoisostearyl glyceryl ether, lauromacrogol, diisopropyl adipate, lauryl alcohol, diethyl sebacate, and oleic acid. A percutaneous absorption preparation containing a seed additive.   The transdermal preparation according to claim 1, wherein the additive is at least one selected from the group consisting of α-monoisostearyl glyceryl ether, lauromacrogol, and diisopropyl adipate.   The transdermal preparation according to claim 1 or 2, wherein the additive comprises α-monoisostearyl glyceryl ether or lauromacrogol.   The transdermally absorbable preparation according to any one of claims 1 to 3, wherein the additive comprises α-monoisostearyl glyceryl ether.   The transdermal absorption preparation according to any one of claims 1 to 3, wherein the additive comprises lauromacrogol.   The transdermally absorbable preparation according to any one of claims 1 to 5, comprising an additive in a proportion of 0.1 to 30 parts by weight as a total amount with respect to 1 part by weight of lactic acid.   The transdermal absorption preparation according to any one of claims 1 to 6, wherein the dosage form is a patch preparation, an ointment, a gel, a cream, or a lotion.   The transdermal preparation according to claim 7, wherein the dosage form is a patch preparation.   A patch preparation comprising an adhesive layer formed on one side of a support, wherein the adhesive layer comprises (1) a transdermal absorption enhancer, (2) a basic low molecular weight drug, and (3) an adhesive. The percutaneous absorption type preparation according to claim 8, which is contained.   The transdermal preparation according to claim 9, wherein the adhesive is at least one selected from an acrylic adhesive, a rubber adhesive, and a silicone adhesive.   The transdermal preparation according to claim 10, wherein the adhesive comprises an acrylic adhesive.   The acrylic pressure-sensitive adhesive is at least one selected from the group consisting of (co) polymers mainly composed of (meth) acrylic acid alkyl esters, and copolymers of (meth) acrylic acid alkyl esters and functional monomers. The transdermally absorbable preparation according to claim 10 or 11, wherein   The transdermal preparation according to claim 10 or 11, wherein the adhesive comprises a rubber-based adhesive.   The transdermal preparation according to claim 10 or 13, wherein the rubber-based adhesive is at least one selected from the group consisting of a styrene-isoprene-styrene block copolymer and polyisobutylene.   Basic low molecular weight drugs are chlorpheniramine, diltiazem, nicardipine, metoprolol, bisoprolol, propranolol, penbutolol, ropinirole, selegiline, rotigotine, tubuterol, fenoterol, procaterol, salbutamol, ketotifen, azelastine, fentanyl, morphantine, morphinecine, , Chlorpromazine, bupropion, fluoxetine, citalopram, duloxetine, rivastigmine, ambroxol, tandospirone, quetiapine, aripiprazole, methylphenidate, raloxifene, tamoxifen, irinotecan, sibutramine, zolpidem, ondansetron, or claim ramosetron 14. The process according to any one of 14 Absorption type preparation.   Basic small molecule drugs are chlorpheniramine, diltiazem, nicardipine, ropinirole, selegiline, rotigotine, ketotifen, azelastine, fentanyl, morphine, oxybutynin, tolterodine, chlorpromazine, citalopram, rivastigmine, tandospirone, quetiapineol, Or percutaneously absorbable preparation according to any one of claims 1 to 14, which is sibutramine.   The transdermal absorption type according to any one of claims 1 to 14, wherein the basic small molecule drug is selegiline, rotigotine, tulobuterol, fentanyl, morphine, oxybutynin, rivastigmine, tandospirone, quetiapine, aripiprazole or methylphenidate. Formulation.   The transdermally absorbable preparation according to any one of claims 1 to 14, wherein the basic low-molecular-weight drug is tandospirone, quetiapine, or aripiprazole.   The transdermal preparation according to any one of claims 1 to 14, wherein the basic low-molecular-weight drug is tandospirone.   The transdermal preparation according to any one of claims 1 to 14, wherein the basic low molecular weight drug is morphine.   The transdermal absorption preparation according to any one of claims 9 to 20, wherein the amount of the transdermal absorption enhancer is 0.01 to 50% by weight relative to the total amount of the pressure-sensitive adhesive layer.   The transdermally absorbable preparation according to any one of claims 9 to 21, wherein the compounding amount of the basic low molecular weight drug is 0.1 to 40% by weight based on the total amount of the pressure-sensitive adhesive layer.