JP4311728B2 - Transdermal patch - Google Patents

Description

The present invention relates to a transdermal absorption-type patch capable of transdermally administering a 5-HT ₃ receptor antagonist excellent in emetic suppression effect and the like at the time of cancer chemotherapy into the body.

The serotonin receptor is a receptor that binds to serotonin (5-hydroxytryptamine, abbreviated as “5-HT”) and brings physiological activity into cells. Serotonin receptor (receptor), the presence of 5-HT ₃ like 10 or more subtypes are known. 5-HT ₃ receptor antagonists (antagonists) are orally administered as antiemetics (also referred to as “antiemetics”) and irritable bowel syndrome therapeutics when cancer chemotherapeutic agents are administered.

However, when a 5-HT ₃ receptor antagonist is orally administered, in addition to causing the first-pass effect of the drug and side effects of the extrapituitary system, it is difficult to control the blood concentration of the drug. If the blood concentration of the drug becomes too high temporarily or continuously, side effects are likely to occur. If the blood concentration of the drug becomes too low, the drug effect cannot be stably maintained.

Conventionally, in order to overcome the various problems associated with oral administration of 5-HT ₃ receptor antagonists, a method of the percutaneous absorption type preparation which uses the 5-HT ₃ receptor antagonists are applied to the skin Proposed. For example, at least three layers comprising a drug impermeable backing layer, a drug reservoir layer containing a serotonin receptor antagonist, and a pressure sensitive adhesive layer that controls drug release (ie, a “drug release layer”). Has been proposed (see, for example, Patent Document 1).

  In the above transdermal therapeutic device, a therapeutically effective amount of a serotonin receptor antagonist is supplied from the drug solution storage layer to the skin surface through the drug release layer, and further penetrates the skin and is absorbed into the body. . When this transdermal therapeutic device is used, a therapeutically effective amount of a serotonin receptor antagonist can be continuously percutaneously absorbed, the first-pass effect of the drug can be avoided, and side effects can be reduced. However, this transdermal therapeutic device needs to be formed from at least three layers including a backing material layer, a drug storage layer, a pressure-sensitive adhesive layer, etc., so that the manufacturing process is complicated and the cost increases. There's a problem.

  On the other hand, a percutaneous absorption preparation containing a styrene-isoprene-styrene block copolymer, a softener, a tackifier resin, a drug, and hexylene glycol has been proposed (see, for example, Patent Document 2). This document discloses a wide range of drugs including follicular hormones and luteinizing hormones as effective drugs for transdermally absorbable preparations, and antiemetics are also exemplified. However, hexylene glycol does not have a sufficient action as an absorption accelerator, and when it is added in a large amount to enhance transdermal absorbability, the tendency to bleed becomes remarkable.

Japanese Patent Laid-Open No. 10-167756 Japanese Patent Laid-Open No. 11-1441

An object of the present invention is to provide a 5-HT ₃ receptor antagonist transdermal absorption patch that is excellent in skin adhesiveness, storage stability and skin permeability and has little skin irritation. Another object of the present invention is to provide a 5-HT ₃ receptor antagonist transdermal absorption patch with a simple formulation and a simple manufacturing process.

  As a result of diligent research to achieve the above object, the inventors have found that in a transdermal absorption patch in which an adhesive composition layer containing an adhesive base and a serotonin receptor antagonist is provided on a support. It was found that the above-mentioned problems can be achieved by forming the pressure-sensitive adhesive composition layer with a pressure-sensitive adhesive composition containing a specific pressure-sensitive adhesive base, a specific absorption promoter and a specific serotonin receptor antagonist in combination. .

Specifically, as the adhesive base , (a) a rubber-based adhesive containing a styrene-isoprene-styrene block copolymer and a rosin-based tackifier , or (b) a crosslinked acrylic adhesive, It has been found that the skin permeability of the 5-HT ₃ receptor antagonist is improved when a propylene glycol monofatty acid ester is added to the adhesive base as an absorption accelerator. In particular, when a large amount of propylene glycol monofatty acid ester is blended, the skin permeability of the 5-HT ₃ receptor antagonist is significantly improved. Moreover, even if a large amount of propylene glycol monofatty acid ester is blended, skin irritation does not increase.

  In addition, when a rosin-based tackifier is selected as a tackifier to be blended with a rubber-based tackifier, even if a large amount of propylene glycol monofatty acid ester is blended as an absorption accelerator, it suppresses bleeding of the absorption accelerator. Can do. Even when a crosslinked acrylic pressure-sensitive adhesive is used as the pressure-sensitive adhesive base, bleeding of propylene glycol monofatty acid ester can be suppressed.

As the 5-HT ₃ receptor antagonist, a 5-HT ₃ receptor antagonist having a hydrochloride structure is used, but in the pressure-sensitive adhesive composition layer, at least a part of the hydrochloric acid is dissociated into a basic state. Thus, the skin permeability can be further enhanced.

The percutaneous absorption type patch of the present invention has a simple layer structure, and it is effective that the 5-HT ₃ receptor antagonist penetrates the skin and reaches the blood only by being applied to the skin surface at a desired location. An amount of drug can be administered continuously. The present invention has been completed based on these findings.

According to the present invention, in a transdermal absorption patch in which an adhesive composition layer containing an adhesive base and a serotonin receptor antagonist is provided on a support,
(1) A rubber-based pressure-sensitive adhesive containing (a) a styrene-isoprene-styrene block copolymer and a rosin-based tackifier, or (b) a polyvalent isocyanate-based crosslinking agent, a polyvalent epoxy resin. An acrylic pressure-sensitive adhesive crosslinked with a crosslinking agent selected from the group consisting of a system crosslinking agent and a polyvalent metal crosslinking agent,
(2) serotonin receptor antagonists, I 5-HT ₃ receptor antagonists or 5-HT ₃ receptor antagonist der base state at least partly dissociated in the hydrochloric acid with the hydrochloride salt structure, and And the 5-HT ₃ receptor antagonist having a hydrochloride structure is at least one 5-HT ₃ receptor antagonist selected from the group consisting of granisetron hydrochloride, azasetron hydrochloride, ondansetron hydrochloride, and ramosetron hydrochloride And
(3) The percutaneous absorption, wherein the pressure-sensitive adhesive composition further contains propylene glycol monofatty acid ester as an absorption accelerator in a proportion of 25% by weight to 45% by weight based on the total amount of the pressure-sensitive adhesive composition. A mold patch is provided.

The 5-HT ₃ receptor antagonist transdermal absorption patch of the present invention is excellent in skin permeability, storage stability and skin adhesiveness, and has little skin irritation. In addition, the transdermal patch of the present invention has a simple formulation and a simple manufacturing process.

In the present invention, a 5-HT ₃ receptor antagonist having a hydrochloride structure is used as a serotonin receptor antagonist. This 5-HT ₃ receptor antagonist is preferably contained in the pressure-sensitive adhesive composition in a base state in which at least a part of the hydrochloric acid is dissociated. 5-HT ₃ receptor antagonists are used as antiemetics, for example, to suppress emesis that often develops during administration of cancer chemotherapeutic agents.

Examples of the 5-HT ₃ receptor antagonist having a hydrochloride structure used in the present invention include those called by general names such as granisetron hydrochloride, azasetron hydrochloride, ondansetron hydrochloride, and ramosetron hydrochloride. In addition to these, examples of the 5-HT ₃ receptor antagonist having a hydrochloride structure include (+)-8,9-dihydro-10-methyl-7-[(5-methyl-4-imidazolyl) methyl]. Pyrido [1,2-a] indole-6 (7H) -one hydrochloride, (R) -5- (2,3-dihydro-1H-indol-1-ylcarbonyl) -4,5,6,7- Tetrahydro-1H-benzimidazole hydrochloride, endo-N- (3,9-dimethyl-3,9-diazabicyclo [3,3,1] non-7-yl) -1H-indazole-3-carboxamide dihydrochloride And so on. Among these, granisetron hydrochloride, azasetron hydrochloride, ondansetron hydrochloride, and ramosetron hydrochloride are preferable. These 5-HT ₃ receptor antagonists can be used alone or in combination of two or more. In the present invention, the 5-HT ₃ receptor antagonist having a hydrochloride structure is at least one 5-HT ₃ receptor antagonist selected from the group consisting of granisetron hydrochloride, azasetron hydrochloride, ondansetron hydrochloride, and ramosetron hydrochloride. It is a medicine.

The blending ratio of the 5-HT ₃ receptor antagonist to the total amount of the pressure-sensitive adhesive composition may be an amount effective for treatment, but is preferably 1 to 40% by weight, more preferably 2 to 35% by weight, and particularly preferably 3 to 30% by weight. If the blending ratio is too small, it will be difficult to obtain sufficient skin permeability even if a large amount of the propylene glycol monofatty acid ester as an absorption accelerator is blended. If the blending ratio is too large, the initial release amount becomes too large, which may cause a side effect due to a rapid increase in the blood concentration of the drug. In many cases, the skin permeation rate can be brought to the most preferable level by containing a 5-HT ₃ receptor antagonist at a blending ratio of 8 to 30% by weight based on the total amount of the pressure-sensitive adhesive composition.

The 5-HT ₃ receptor antagonist used in the present invention has a hydrochloride structure, but exhibits higher skin permeability in a base state in which hydrochloric acid is dissociated. In addition, it is desirable to dissociate all or part of hydrochloric acid with a basic substance in advance. By adding a basic substance to the pressure-sensitive adhesive composition after the addition of the 5-HT ₃ receptor antagonist having a hydrochloride structure, a basic state in which at least a part of hydrochloric acid is dissociated can be obtained. As the basic substance, inorganic substances such as sodium hydroxide and potassium hydroxide; organic substances such as monoethanolamine and triethanolamine can be used. The basic substance can be used in a stoichiometric amount ratio required for dissociation of hydrochloric acid.

  In the present invention, propylene glycol monofatty acid ester is used as an absorption enhancer (also referred to as “transdermal absorption enhancer”). Examples of the fatty acid include saturated or unsaturated monocarboxylic acids having 6 to 30 carbon atoms, preferably 9 to 21 carbon atoms. Preferable specific examples of the propylene glycol monofatty acid ester include propylene glycol monocaprylate, propylene glycol monolaurate, and propylene glycol monooleate.

The blending ratio of the propylene glycol monofatty acid ester to the total amount of the pressure-sensitive adhesive composition is more than 10% by weight and less than 50% by weight, preferably 15 to 45% by weight, more preferably 20 to 40% by weight. In this invention, it is 25 weight%-45 weight%. When this blending ratio is too small, the skin permeation rate of the 5-HT ₃ receptor antagonist is slow, and the transdermal absorbability of the drug tends to be insufficient. When the blending ratio is too large, bleeding from the pressure-sensitive adhesive composition layer of propylene glycol monofatty acid ester with time is likely to occur.

In the present invention, (a) a rubber-based pressure-sensitive adhesive containing a styrene-isoprene-styrene block copolymer and a rosin-based tackifier , or (b) a crosslinked acrylic pressure-sensitive adhesive is used as the pressure-sensitive adhesive base. By using a specific adhesive base, it has excellent properties such as adhesion to the skin surface, skin permeability (transdermal absorbability) of 5-HT ₃ receptor antagonist, storage stability (bleed resistance), etc. Moreover, a transdermal patch with little skin irritation can be obtained.

  A styrene-isoprene-styrene block copolymer (hereinafter sometimes referred to as “SIS block copolymer”) is formed by first polymerizing styrene by, for example, anionic living polymerization to form a polystyrene block (living polymer). Then, isoprene is polymerized in the presence of this polystyrene block to form an isoprene block, and finally, styrene is polymerized in the presence of a styrene-isoprene block copolymer (living polymer) to form a polystyrene block. Can be synthesized. According to such a sequential polymerization method, generally a linear block copolymer can be obtained.

  The styrene-isoprene-styrene block copolymer can be synthesized by a coupling reaction of a styrene-isoprene block copolymer (living polymer) synthesized by an anion living polymerization method. According to the coupling reaction method, although depending on the type of coupling agent, a branched block copolymer can be generally obtained.

  The styrene-isoprene-styrene block copolymer may be composed only of a styrene-isoprene-styrene triblock copolymer, but a mixture of this triblock copolymer and a styrene-isoprene diblock copolymer. There may be.

  The styrene content of the styrene-isoprene-styrene block copolymer is preferably 10 to 35% by weight, more preferably 12 to 30% by weight, and still more preferably 14 to 25% by weight. If the styrene content is too small, the pseudo-crosslinking effect due to the polystyrene phase is lowered, and the properties as a thermoplastic elastomer are impaired. When there is too much styrene content, rubber elasticity will fall and it will become hard too much. Since the styrene-isoprene-styrene block copolymer functions as a pseudo-crosslinking point at a normal temperature, the styrene-isoprene-styrene block copolymer can be retained therein even if it contains a large amount of liquid components such as propylene glycol monofatty acid ester. .

  The content of the styrene-isoprene block copolymer component in the styrene-isoprene-styrene block copolymer is preferably 85% by weight or less, more preferably 80% by weight or less. The styrene-isoprene-styrene block copolymer may be a mixture of two or more kinds of copolymers having different diblock copolymer component contents.

  Examples of commercially available styrene-isoprene-styrene block copolymers include, for example, styrene-isoprene-styrene block copolymers (trade names “Califlex TR-1107” and “Califlex TR-1111”) manufactured by Shell Chemical, Japan. Styrene-isoprene-styrene block copolymers (trade names “JSR5000” and “JSR5100”) manufactured by synthetic rubber (JSR), styrene-isoprene-styrene block copolymers (trade name) manufactured by Nippon Zeon "Quintac 3421", "Quintac 3520").

  The blending ratio of the styrene-isoprene-styrene block copolymer is preferably 20 to 40% by weight, more preferably 25 to 35% by weight, based on the total amount of the pressure-sensitive adhesive composition. If this blending ratio is too small, it will be difficult to retain a large amount of propylene glycol monofatty acid ester, and the cohesive strength of the pressure-sensitive adhesive composition will also decrease. If this blending ratio is excessive, the blending ratio of other components may decrease, and the balance of various characteristics may deteriorate.

  In the present invention, a rosin tackifier is selected and used as a tackifier used in combination with a styrene-isoprene-styrene block copolymer. When a rosin tackifier is selected from various tackifiers and used, it not only exhibits an appropriate adhesion to the skin surface compared to the case of using other tackifiers, but also propylene glycol monofatty acid. Even if a large amount of ester is blended, bleeding can be effectively suppressed and stably retained in the pressure-sensitive adhesive composition layer over time.

  Examples of rosin-based tackifiers include rosin esters (for example, trade names “Pine Crystal KE-311”, “Pine Crystal KE-100”, “Superester S-100”, manufactured by Arakawa Chemical Co., Ltd.), hydrogenated rosin. Examples thereof include esters [for example, trade name “Foral 105” manufactured by Rika Hercules Co., Ltd.], hydrogenated rosin, natural resin rosin, and the like. Among these, rosin ester and hydrogenated rosin ester are preferable.

Along with the rosin tackifier, other tackifiers can be used in combination. Examples of other tackifiers include various types of tackifiers such as terpene, synthetic resin (C ₅ ), synthetic resin (C ₉ ), phenol resin, and xylene resin; alicyclic petroleum resins, And other tackifiers such as a malon indene resin, a styrene resin, and a dicyclopentadiene resin.

  The blending ratio of the rosin-based tackifier is preferably 25 to 55% by weight, more preferably 30 to 50% by weight, and particularly preferably 35 to 45% by weight based on the total amount of the pressure-sensitive adhesive composition. If the blending ratio is too small, the adhesive force to the skin surface tends to be insufficient, and if it is too large, the blending ratio of other components is decreased, and the balance of various characteristics is likely to deteriorate.

  The rubber-based pressure-sensitive adhesive containing the styrene-isoprene-styrene block copolymer can contain various additives such as a filler, an antioxidant, and a softener as necessary in addition to the tackifier. . Examples of the filler include calcium carbonate, zinc oxide, titanium oxide, and talc. The blending ratio of the filler is usually 0 to 15% by weight, preferably 0 to 10% by weight, based on the total amount of the pressure-sensitive adhesive composition. As the antioxidant, phenolic antioxidants such as dibutylhydroxytoluene (abbreviated as “BHT”) and dibutylhydroxyanisole (abbreviated as “BHA”) are preferable. The antioxidant is usually 0 to 5% by weight, preferably 0.1 to 3% by weight, based on the total amount of the pressure-sensitive adhesive composition. Examples of the softener include liquid paraffin, polybutene, castor oil, cottonseed oil, palm oil, coconut oil, and process oil. An appropriate amount of the softening agent can be used as necessary.

  In the present invention, a cross-linked acrylic pressure-sensitive adhesive can be used as the pressure-sensitive adhesive base. Examples of the acrylic pressure-sensitive adhesive include homopolymers of (meth) acrylic acid esters having an alkyl group having 4 to 12 carbon atoms such as butyl acrylate, isononyl acrylate, 2-ethylhexyl acrylate, and isooctyl acrylate; Copolymerized with one or more other copolymerizable monomers such as (meth) acrylic acid, vinyl acetate, styrene, vinyl pyrrolidone, acrylamide, hydroxyethyl acrylate, hydroxypropyl acrylate, etc. A copolymer comprising: Other monomers are usually used in the range of 2 to 50% by weight.

  The acrylic pressure-sensitive adhesive can be obtained by using a peroxide such as benzoyl peroxide as an initiator in an organic solvent such as toluene, hexane, or ethyl acetate, and polymerizing the monomer in a nitrogen atmosphere. . The acrylic pressure-sensitive adhesive obtained by this method is called a solvent-type acrylic pressure-sensitive adhesive. An emulsion acrylic pressure-sensitive adhesive obtained by emulsifying and dispersing the monomer in water with an emulsifier and then polymerizing can also be used.

  In order to crosslink the acrylic pressure-sensitive adhesive, after polymerization, the acrylic pressure-sensitive adhesive is polyvalent isocyanate-based crosslinking agent (also referred to as “polyisocyanate-based crosslinking agent”), polyvalent epoxy resin-based crosslinking agent, polyvalent metal-based crosslinking agent. Crosslink using a crosslinking agent such as These crosslinking agents are generally added to the pressure-sensitive adhesive composition when it is prepared. Other types of crosslinking agents include urea resins and polyamines, but they may react with drugs in the adhesive composition. In addition, as a crosslinking method, there is an electron beam crosslinking method, but the drug may react with other components or be altered by electron beam irradiation. Therefore, a polyvalent isocyanate-based crosslinking agent, a polyvalent epoxy resin-based crosslinking agent, and a polyvalent metal-based crosslinking agent are preferable in that they react stably with the acrylic pressure-sensitive adhesive.

  Crosslinking acrylic adhesive reduces skin irritation while maintaining adequate adhesion to the skin surface, and effectively suppresses bleeding even when a large amount of propylene glycol monofatty acid ester is contained. can do. As a result, a large amount of propylene glycol monofatty acid ester can be contained to enhance drug release properties.

  The amount of the crosslinking agent used is preferably 0.01 to 5 parts by weight, more preferably 0.05 to 2 parts by weight with respect to 100 parts by weight of the acrylic pressure-sensitive adhesive (acrylic polymer). Therefore, it is appropriately selected in consideration of adhesive properties, bleeding properties of medicinal components, and the like.

  The transdermal patch of the present invention has a pressure-sensitive adhesive composition on a support or a release liner (also referred to as a separator) by a calendar method or a solution coating method, which is a general method for producing a transdermal patch. It can manufacture by forming a physical layer. The transdermal patch of the present invention generally has a layer structure of support / adhesive composition layer / release liner. A raw material having such a layer structure is cut or punched into an appropriate shape to obtain a product.

The calendar method is used in the case of a rubber-based pressure-sensitive adhesive containing a styrene-isoprene-styrene block copolymer. First, after kneading the styrene-isoprene-styrene block copolymer and the antioxidant at a temperature of about 120 to 140 ° C. for about 5 to 20 minutes, a tackifier is added, and further about 10 to 20 minutes. Kneading for a period of time. The kneading temperature and time are preferably adjusted in the above range in consideration of the blending amount of each component. When other additive components such as a filler are added as necessary, kneading is appropriately performed so as to uniformly disperse. Next, the temperature of the mixture is lowered to a temperature of about 80 to 120 ° C., and propylene glycol monofatty acid ester as an absorption accelerator is added little by little, and kneaded each time. Finally, a 5-HT ₃ receptor antagonist that has been dissociated into hydrochloric acid by adding a basic substance in advance to a basic state is added and kneaded for about 5 to 10 minutes, so that each component becomes uniform. An adhesive composition (also referred to as a plaster) is prepared. The drug can be mixed and dissolved and dispersed in propylene glycol monofatty acid ester, which is an absorption promoter, and added to the mixture in that state. The pressure-sensitive adhesive composition thus obtained is spread on a release liner to a thickness of about 30 to 250 μm.

  In the solution coating method, when using a rubber adhesive containing a styrene-isoprene-styrene block copolymer, a styrene-isoprene-styrene block copolymer, a tackifier, an absorption accelerator, a filler, an oxidation All components such as an inhibitor are uniformly dissolved and dispersed by stirring for about 1 to 10 hours in an organic solvent such as n-hexane, toluene and ethyl acetate.

In the case of a solvent polymerization type acrylic pressure-sensitive adhesive, the reaction solution after the completion of polymerization is used as it is, or a solution diluted with a viscosity suitable for coating by adding an organic solvent is used. In the case of an emulsion type acrylic pressure-sensitive adhesive, the emulsion liquid after completion of polymerization is used as it is, or a liquid to which an appropriate amount of a thickener is added is used. Next, a solution or emulsion containing an acrylic pressure-sensitive adhesive is added with a 5-HT ₃ receptor antagonist that has been mixed and dissolved in propylene glycol monofatty acid ester in advance, and further for about 10 to 120 minutes. Stir for the time. In order to crosslink the acrylic pressure-sensitive adhesive, an appropriate amount of a crosslinking agent is further added.

  The solution or emulsion liquid thus obtained is uniformly applied on a release liner such as a polyester film treated with a silicone, using a coating machine such as a knife coater, a comma coater, or a reverse coater. After the application, the solvent is volatilized by placing for about 1 to 10 minutes in a dry heat atmosphere maintained at a temperature of about 40 to 120 ° C. At that time, appropriate drying conditions are set according to the type of solvent and the thickness of the pressure-sensitive adhesive composition layer to be applied.

  The transdermal patch of the present invention can be obtained by laminating a support on the surface of the pressure-sensitive adhesive composition layer obtained by the above method. Depending on the type of the support, a release liner may be laminated on the surface of the pressure-sensitive adhesive composition layer after forming the pressure-sensitive adhesive composition layer on the support.

  Examples of the support include a film, a nonwoven fabric, Japanese paper, cotton cloth, a knitted fabric, a laminate composite of a nonwoven fabric and a film, and the like. Examples of the support material include polyethylene, polypropylene, polyethylene terephthalate, polybutylene terephthalate, polyethylene naphthalate, polystyrene, nylon, cotton, acetate rayon, rayon, rayon / polyethylene terephthalate, polyacrylonitrile, polyvinyl alcohol, acrylic resin, Ester polyurethane, ether polyurethane, styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer, styrene-ethylene-propylene-styrene block copolymer, styrene-butadiene rubber, ethylene-vinyl acetate copolymer Examples thereof include a polymer and cellophane. As the support, a support that hardly adsorbs the drug and does not easily release the drug from the support side is preferable.

  Examples of the release liner include silicone-treated polyester film, silicone-treated polyethylene laminate fine paper, and silicone-treated glassine paper. The release liner is preferably made of a material that hardly absorbs / adsorbs a drug.

  Hereinafter, the present invention will be described more specifically with reference to examples and comparative examples. The test methods for various properties are as follows.

(1) Drug skin penetration test:
The abdominal skin of a hairless mouse (male, 7 weeks old) was excised, and a preparation punched out to 15 mmφ was applied to the skin and mounted on a Franz type diffusion cell. The receiver solution (purified water) was filled in the diffusion cell, and the cell temperature was kept at 32 ° C. during the experiment with circulating water. Every 2 hours after the preparation was applied to the skin, a fixed amount of the receiver solution was collected up to 24 hours, and the concentration of the drug was measured by high performance liquid chromatography (HPLC). The measurement results were plotted as a graph with time on the horizontal axis and the cumulative amount of drug permeation on the vertical axis. The gradient α of the portion where the cumulative permeation amount curve becomes a straight line having a constant inclination angle was calculated to determine the flux (skin permeation rate).

(2) Rabbit skin primary irritation test:
One week before administration of the test substance, the back skin of a rabbit (male, 18 weeks old at the time of test) was shaved with an electric clipper and shaved with an electric razor. Each test substance (25 mm × 25 mm) was affixed to the healthy skin on the shaved back, and then fixed with an elastic bandage [Shinshitai, manufactured by Nichiban Co., Ltd.] and an adhesive cloth elastic bandage [Elastopore, Nichiban Co., Ltd.]. The test substance was slowly peeled off and removed 24 hours after application, and the skin reaction was observed with the naked eye immediately after removal, 1 hour, 24 hours and 48 hours later. Skin reaction was evaluated according to Draiz criteria. The skin reaction scores (erythema, edema) after 1 hour and 48 hours after removal were totaled, and this sum was divided by [number of test animals × 2] to calculate the skin irritation index. Skin irritation can be evaluated according to the following criteria.

<Criteria for determining skin irritation>
Skin irritation index 0-2 ... weak irritant,
Skin irritation index 3-5 ... medium irritant,
Skin irritation index of 6 or more: Strong irritant.

<Criteria for skin reaction>
A. Formation of erythema and crust 0 ... No erythema,
1 ... very mild erythema,
2 ... obvious erythema,
3 ... Medium to strong erythema,
4 ... Light crust formation on deep crimson erythema.

B. Edema 0 ... no edema,
1 ... very mild edema,
2 ... obvious edema (clearly separated from surroundings),
3 ... Medium edema (swells about 1mm),
4… Strong edema (swelling of 1 mm or more, spreading to the surroundings).

(3) Adhesion to rabbit skin:
One week before administration of the test substance, the back skin of a rabbit (male, 18 weeks old at the time of test) was shaved with an electric clipper and shaved with an electric razor. Each test substance (5 mm width × 70 mm) was applied to the healthy skin on the shaved back, and then fixed with an elastic bandage (Shinshitai, manufactured by Nichiban Co., Ltd.) and an adhesive cloth elastic bandage (Elastopore, Nichiban Co., Ltd.). . 24 hours after application, the skin adhesive strength was measured with a universal tensile compression tester at a peeling angle of 90 degrees and a peeling speed (crosshead moving speed) of 100 mm / min.

(4) Check for bleed:
The release liner of the test substance was peeled off, and the presence or absence of leaching of the liquid substance on the release liner was judged with the naked eye. When it was difficult to understand, the surface of the release liner was rubbed with a finger and the surface was confirmed with the naked eye. By rubbing with a finger, judgment with the naked eye becomes easy even with very slight bleeding.

[Example 1]
According to the formulation shown in Table 1, a styrene-isoprene-styrene block copolymer [manufactured by Nippon Zeon Co., Ltd., trade name “Quintac 3520”], rosin ester [manufactured by Arakawa Chemical Co., Ltd., trade name “Pine Crystal KE” -311 "], an antioxidant (BHT), propylene glycol monolaurate, and azacetron hydrochloride (dissociated hydrochloric acid with sodium hydroxide and added as a base, ie, azasetron), to prepare a coating solution. Specifically, a coating solution was prepared by adding 80 parts by weight of toluene as a solvent to 100 parts by weight of the total amount of the above components and stirring and dissolving. This coating solution was applied on a 30 μm-thick polyethylene film (support) and then dried at 110 ° C. for 2 minutes to prepare a patch having a pressure-sensitive adhesive composition layer thickness of 50 μm. The results are shown in Table 1.

  As is apparent from the results in Table 1, this patch exhibits an appropriate adhesive strength to the skin surface, has a high drug skin permeation rate, and has low skin irritation. Further, this patch has excellent storage stability because no bleed is observed even though the pressure-sensitive adhesive composition layer contains 25% by weight of propylene glycol monolaurate.

[Comparative Example 1]
Except that the blending ratio of propylene glycol monolaurate as an absorption accelerator was changed from 25% by weight to 5% by weight, and the blending ratio of other components other than drugs was changed as shown in Table 1 accordingly. A patch was prepared in the same manner as in Example 1. The results are shown in Table 1.

  The blending ratio of the drug azasetron was 10% by weight as in Example 1, but it can be seen that the skin permeation rate of the drug was almost halved. From the comparison results of Example 1 and Comparative Example 1, it is percutaneous absorption that the proportion of propylene glycol monofatty acid ester exceeds 10% by weight, more preferably 15% by weight or more, and particularly preferably 20% by weight or more. It turns out that it is preferable from a viewpoint of property.

[Comparative Example 2]
A patch was prepared in the same manner as in Example 1 except that the absorption accelerator was changed from propylene glycol monolaurate to isopropyl palmitate. The results are shown in Table 1. In this patch, the content of azasetron in the pressure-sensitive adhesive composition layer was 10% by weight, but the skin permeation rate of the drug was low.

[Comparative Example 3]
A patch was prepared in the same manner as in Example 1 except that the absorption accelerator was changed from propylene glycol monolaurate to polyoxyethylene (2) lauryl ether and the blending ratio of each component was changed as shown in Table 1. did. The results are shown in Table 1. This patch had excellent skin irritation although it was excellent in drug skin permeability.

[Comparative Example 4]
A patch was prepared in the same manner as in Example 1 except that the tackifier was changed from rosin ester to terpene resin (trade name “YS Resin PX1150N” manufactured by Yasuhara Chemical Co., Ltd.). The results are shown in Table 1.

  This patch was excellent in drug skin permeability, but had propylene glycol monolaurate bleed, and its storage stability was insufficient. From the comparison result between Example 1 and Comparative Example 4, it is understood that when a SIS block copolymer is used, bleeding can be suppressed by using a rosin-based tackifier.

[Comparative Example 5]
A patch was prepared in the same manner as in Example 1 except that the tackifier was changed from rosin ester to alicyclic petroleum resin (trade name “Arcon P100” manufactured by Arakawa Chemical Co., Ltd.). The results are shown in Table 1.

  This patch was excellent in drug skin permeability, but had propylene glycol monolaurate bleed, and its storage stability was insufficient. From the comparison result between Example 1 and Comparative Example 5, it is understood that when a SIS block copolymer is used, bleeding can be suppressed by using a rosin-based tackifier.

[Example 2]
A patch was prepared in the same manner as in Example 1 except that the absorption accelerator was changed from propylene glycol monolaurate to propylene glycol monocaprylate. The results are shown in Table 1.

  As is apparent from the results in Table 1, this patch exhibits an appropriate adhesive strength to the skin surface, has a high drug skin permeation rate, and has low skin irritation. Furthermore, this patch has excellent storage stability because no bleed is observed even though the pressure-sensitive adhesive composition layer contains 25% by weight of propylene glycol monocaprylate.

[Example 3]
An acrylic pressure-sensitive adhesive was prepared by copolymerizing monomer components consisting of 87% by weight of 2-ethylhexyl acrylate, 10% by weight of vinyl acetate, and 3% by weight of acrylic acid. Specifically, 20 parts by weight of the monomer component was charged into a flask equipped with a stirrer, a thermometer, and a cooling tube, and ethyl acetate was added as a solvent so that the entire monomer component was 50% by weight. Polymerization was carried out under stirring and reflux for 20 hours in a nitrogen stream using 0.5% by weight of lauroyl peroxide as a radical polymerization initiator. To the reaction solution was added propylene glycol monolaurate, which had been mixed and dissolved and dispersed in the whole amount of azasetron (basic state), and finally stirred. Finally, a bifunctional isocyanate-based crosslinking agent (manufactured by Nippon Polyurethane Industry, product) 0.3 parts by weight of the name “Coronate L”) was added to obtain a coating solution. The blending ratio of each component is as shown in Table 1. A patch was prepared in the same manner as in Example 1 except that this coating solution was used. The results are shown in Table 1.

  As is apparent from the results of Table 1, this patch exhibits a moderate adhesive force on the skin surface by using a cross-linked acrylic adhesive as the adhesive base, and has a high skin permeation rate of the drug. Skin irritation is small. Furthermore, this patch has excellent storage stability because no bleed is observed even though the pressure-sensitive adhesive composition layer contains 30% by weight of propylene glycol monolaurate.

[Example 4]
The drug was changed from 10% by weight of azasetron to 3% by weight of granisetron (basic state), and the blending ratio of components other than propylene glycol monolaurate was changed accordingly, as shown in Table 1. A patch was prepared in the same manner as in Example 1 except that the thickness of the composition layer was changed from 50 μm to 20 μm. The results are shown in Table 1. This patch had a small drug blending ratio of 3% by weight, but had good skin adhesiveness, drug permeation rate and skin irritation.

[Example 5]
A patch was prepared in the same manner as in Example 1 except that the drug was changed from azasetron to ondansetron (basic state). The results are shown in Table 1.

  As is apparent from the results in Table 1, this patch exhibits an appropriate adhesive strength to the skin surface, has a high drug skin permeation rate, and has low skin irritation. Further, this patch has excellent storage stability because no bleed is observed even though the pressure-sensitive adhesive composition layer contains 25% by weight of propylene glycol monolaurate.

[Example 6]
Except that the drug was changed from 10% by weight of azasetron to 3% by weight of ramosetron (basic state), and the mixing ratio of components other than propylene glycol monolaurate was changed accordingly, as shown in Table 1. A patch was prepared in the same manner as in Example 1. The results are shown in Table 1. This patch had a small drug blending ratio of 3% by weight, but had good skin adhesiveness, drug permeation rate and skin irritation.

<Discussion>
As is apparent from the results in Table 1, the transdermal patches of the present invention (Examples 1 to 6) are excellent in skin permeability and skin adhesiveness of 5-HT ₃ receptor antagonists, and are irritating to the skin. It can be seen that there are few. It can be seen that it is preferable from the viewpoint of transdermal absorbability that the proportion of the propylene glycol monofatty acid ester exceeds 10% by weight, more preferably 15% by weight or more, particularly preferably 20% by weight or more (Example 1 and Comparison with Comparative Example 1). Moreover, when using the rubber-type adhesive which contains a SIS block copolymer as an adhesive base, when a rosin-type tackifier is used, it turns out that a bleed can be suppressed and it is excellent in storage stability (Example 1). And comparison with Comparative Examples 4 and 5.

  As shown in Comparative Examples 2 and 3, when an absorption promoter other than propylene glycol monofatty acid ester is used, the skin permeation rate of the drug is low even if the content of the drug is large (Comparative Example 2). Even when the skin permeability was good, phenomena such as strong skin irritation (Comparative Example 3) were observed.

  The transdermal absorption patch of the present invention can be used for suppressing emesis and treating irritable bowel syndrome at the time of administration of a cancer chemotherapeutic agent.

Claims (1)

In the percutaneous absorption type patch in which an adhesive composition layer containing an adhesive base and a serotonin receptor antagonist is provided on a support,
(1) A rubber-based pressure-sensitive adhesive containing (a) a styrene-isoprene-styrene block copolymer and a rosin-based tackifier, or (b) a polyvalent isocyanate-based crosslinking agent, a polyvalent epoxy resin. An acrylic pressure-sensitive adhesive crosslinked with a crosslinking agent selected from the group consisting of a system crosslinking agent and a polyvalent metal crosslinking agent,
(2) serotonin receptor antagonists, I 5-HT ₃ receptor antagonists or 5-HT ₃ receptor antagonist der base state at least partly dissociated in the hydrochloric acid with the hydrochloride salt structure, and And the 5-HT ₃ receptor antagonist having a hydrochloride structure is at least one 5-HT ₃ receptor antagonist selected from the group consisting of granisetron hydrochloride, azasetron hydrochloride, ondansetron hydrochloride, and ramosetron hydrochloride And
(3) The percutaneous absorption, wherein the pressure-sensitive adhesive composition further contains propylene glycol monofatty acid ester as an absorption accelerator in a proportion of 25% by weight to 45% by weight based on the total amount of the pressure-sensitive adhesive composition. Mold patch.