JP2011126908A - Percutaneous absorption type preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a dissolution aid of tulobuterol for a percutaneous absorption type preparation, and an application method of the dissolution aid. <P>SOLUTION: The dissolution aid of tulobuterol for the percutaneous absorption type preparation including at least one selected from the group consisting of a 12-16C fatty acid ester, an 8-10C fatty acid monoglyceride, a 6-10C dibasic acid ester, a 2-5 additive molar number of polyoxyethylene alkyl ether and a 2-5 additive molar number of polyoxyethylene alkylphenyl ether as effective component(s); and an aid method for dissolution of tulobuterol in a plaster layer including formulating the dissolution aid in the plaster layer, are disclosed. <P>COPYRIGHT: (C)2011,JPO&amp;INPIT

Description

  The present invention relates to a percutaneous absorption preparation for continuously applying tulobuterol to the skin surface by applying it to the skin surface, and more specifically, it has excellent skin adhesiveness when applied to the skin surface, and tulobuterol. The present invention relates to a percutaneous absorption preparation having excellent initial absorbability and effective blood concentration.

Tulobuterol has a bronchodilator effect by selectively stimulating the sympathetic β ₂ receptor, and is used to treat chronic bronchitis, bronchial asthma, etc. for the purpose of reducing dyspnea in patients with airway stenosis. Widely used.

  Tulobuterol is generally administered in vivo by tablets, but it is difficult to administer to children, etc., difficulty in administration, occurrence of side effects accompanying rapid increase in drug blood concentration, and sustained efficacy. There are problems such as lack of. Therefore, in order to solve these problems, in recent years, transdermal preparations for administering a drug into a living body through the skin surface have been developed for various drugs. Regarding tulobuterol, percutaneous absorption preparations have been proposed in Patent Document 1 (LTS Roman), Patent Document 2 (Zambon), Patent Documents 3 and 4 (Nitto Denko) and the like.

  These proposals are mainly preparations containing tulobuterol having a solubility higher than that of the adhesive in the plaster layer and a part of tulobuterol dispersed in a crystalline state in the plaster layer. In general, it is considered that the higher the concentration of the drug in the plaster layer, the higher the transdermal absorption rate of the drug, and the higher the content of the drug in the plaster layer, the longer the duration of drug release. However, it is difficult to stably dissolve and maintain a drug at a high concentration in a polymer generally used for a plaster layer, and in order to satisfy both the percutaneous absorption rate and the sustained release of the drug. As described in the above-mentioned prior publication, a method is used in which the drug is contained in the paste layer at a high concentration equal to or higher than the saturation solubility, and a part of the drug is held in the paste layer in a crystalline state. Yes.

Japanese Patent Laid-Open No. 5-194202 Japanese Patent Application Laid-Open No. 5-238953 JP-A-7-285854 Japanese Patent Publication No. 7-25669

  However, in a preparation in which a solid drug crystal is present in the paste layer, for example, the drug crystal is likely to be deposited at the paste layer interface (surface) in contact with the skin, and the skin adhesiveness of the preparation is reduced. . Also, since the diffusion rate of drug molecules in the polymer is much slower than that in the liquid, the precipitation of drug crystals in the plaster layer does not proceed rapidly, and the drug crystals in the plaster layer gradually. It is expected that the skin adhesiveness and drug release properties of the preparation will change over time due to the progress of conversion. As described above, by containing the drug at a concentration equal to or higher than the saturation solubility in the adhesive, a preparation in which a part of the drug in the plaster layer is present in a crystalline state may have a problem in quality stability. However, it is not necessarily said that the preparation is excellent in transdermal absorbability, sustained drug efficacy and skin adhesion.

  In view of the above circumstances, as a result of intensive studies, the present inventors have succeeded in obtaining a transdermal preparation in which tulobuterol is dissolved at a high concentration of 5% by weight or more in the plaster layer.

That is, the present invention
(1) A transdermal preparation in which a plaster layer containing tulobuterol and an adhesive is laminated on a support, and 5 wt% or more of tulobuterol is contained in the plaster layer in a dissolved state A transdermally absorbable preparation characterized by the above.
(2) The transdermal preparation according to (1), wherein the adhesive is an acrylic adhesive or a rubber adhesive.
(3) The acrylic pressure-sensitive adhesive contains a polymer obtained by polymerizing a (meth) acrylic acid alkyl ester having an alkyl group having 4 to 12 carbon atoms in a proportion of 50% by weight or more. Percutaneous absorption preparation.
(4) The acrylic pressure-sensitive adhesive has 60 to 98 wt% of (meth) acrylic acid alkyl ester having 4 to 12 carbon atoms in the alkyl group, and has at least one unsaturated double bond in the molecule, and The percutaneous absorption preparation according to (2) above, comprising a copolymer obtained by copolymerizing a functional monomer having a functional group in the side chain in a proportion of 2 to 40% by weight.
(5) The functional group of the functional monomer is a group selected from the group consisting of carboxyl group, hydroxyl group, sulfonic acid group, amino group, amide group, alkoxyl group, cyano group and acyloxy group (4) A transdermally absorbable preparation according to 1.
(6) The functional monomer is (meth) acrylic acid, (meth) acrylic acid 2-hydroxyethyl ester, styrene sulfonic acid, (meth) acrylamide, vinylpyrrolidone, (meth) acrylic acid 2-aminoethyl ester, The transdermal preparation according to (4) above, which is a monomer selected from the group consisting of acrylonitrile, (meth) acrylic acid 2-methoxyethyl ester and vinyl acetate.
(7) The transdermally absorbable preparation according to the above (2), wherein the rubber-based pressure-sensitive adhesive contains at least one polymer selected from polyisobutylene and a styrene / diene / styrene block copolymer. (8) In the plaster layer, an ester of a fatty acid having 12 to 16 carbon atoms, a monoglyceride of a fatty acid having 8 to 10 carbon atoms, an ester of a dibasic acid having 6 to 10 carbon atoms, an addition mole number of 2 to 5 Any one of the above (1) to (7) containing 5 to 50% by weight of at least one additive selected from the group consisting of polyoxyethylene alkyl ether and polyoxyethylene alkylphenyl ether having 2 to 5 addition moles The transdermally absorbable preparation described.
(9) C12-16 fatty acid ester, C8-10 fatty acid monoglyceride, C6-10 dibasic acid ester, addition mole number 2-5 polyoxyethylene alkyl ether, and addition A solubilizing agent for tulobuterol for a percutaneous absorption preparation, containing as an active ingredient at least one selected from the group consisting of polyoxyethylene alkylphenyl ethers having 2 to 5 moles.
(10) A method for assisting dissolution of tulobuterol in a paste layer, which comprises blending the dissolution aid described in (9) above into the paste layer.
Is included.

  The percutaneous absorption type preparation of the present invention is one in which a high concentration of tulobuterol is present in the paste layer in a dissolved state. The preparation of the present invention retains the tulobuterol in the plaster layer in a completely dissolved state without precipitation of drug crystals even at high concentrations. It is a percutaneous absorption type preparation that is excellent in the effect of sustaining efficacy by maintaining the effective blood concentration for a long time, and that changes in adhesive physical properties such as skin adhesive properties with time are reduced.

  The percutaneous absorption-type preparation of the present invention retains in the plaster layer in a state in which tulobuterol, which is a medicinal ingredient, is completely dissolved at a high concentration, so that the drug release properties and adhesive physical properties associated with drug crystal precipitation over time can be obtained. There is no change over time, and the percutaneous absorption of the drug, especially the percutaneous absorption rate at the initial stage of administration, is also excellent in sustaining the efficacy by maintaining the effective blood concentration for a long time, and adhesion such as skin adhesion Changes in physical properties over time are reduced.

10 is a graph showing changes over time in the blood concentration of tulobuterol in Experimental Example 3.

  Tulobuterol used in the transdermally absorbable preparation of the present invention must be dissolved in the adhesive in the plaster layer and exist in a dissolved state. If tulobuterol is present in a crystalline state in the plaster layer, the tulobuterol crystals will precipitate over time, and the skin adhesiveness, transdermal absorbability and drug release of the preparation will change over time, which is not preferable.

  Here, the presence of tulobuterol in a dissolved state means that the plaster layer is uniform when the tulobuterol crystals are observed in the plaster layer or when observed with an optical microscope.

  Conventionally, tulobuterol is present in a state of being dissolved in the plaster layer, so that only 3% by weight or less is obtained, and for the first time by the present invention, 5% by weight or more, preferably 10% by weight or more is obtained. Obtained.

  In the present invention, the desired purpose is sufficiently achieved when the concentration of tulobuterol is 5% by weight or more in the plaster layer.

  The adhesive contained in the plaster layer is not particularly limited as long as the tulobuterol dissolves in the plaster layer and the solubility is 5% by weight or more, but is an acrylic adhesive from the viewpoint of skin adhesiveness and the like. A rubber-based pressure-sensitive adhesive is particularly preferably used.

  The acrylic pressure-sensitive adhesive is made of an acrylic polymer, and examples of the acrylic polymer include a homopolymer of (meth) acrylic acid alkyl ester or a copolymer thereof. Here, the alkyl in the (meth) acrylic acid alkyl ester is preferably a linear or branched alkyl having 4 to 12 carbon atoms. As such (meth) acrylic acid alkyl ester, specifically, (Meth) acrylic acid butyl ester, (meth) acrylic acid t-butyl ester, (meth) acrylic acid pentyl ester, (meth) acrylic acid hexyl ester, (meth) acrylic acid heptyl ester, (meth) acrylic acid octyl ester, ( (Meth) acrylic acid isooctyl ester, (meth) acrylic acid nonyl ester, (meth) acrylic acid isononyl ester, (meth) acrylic acid decyl ester, (meth) acrylic acid undecyl ester, (meth) acrylic acid dodecyl ester, (Meth) acrylic acid 2-ethylhexyl ester, etc. And the like. The (meth) acrylic acid alkyl ester is preferably polymerized in a proportion of 50% by weight or more, more preferably 60% by weight or more.

  In addition, as the acrylic polymer used in the present invention, a copolymer of the above (meth) acrylic acid alkyl ester and one or more of the following monomers can also be suitably used.

  The monomer has at least one unsaturated double bond in the molecule and has a functional group such as a carboxyl group, a hydroxyl group, a sulfonic acid group, an amino group, an amide group, an alkoxyl group, a cyano group, and an acyloxy group. Functional monomer in side chain [for example, alkyl group of (meth) acrylic acid alkyl ester was modified with linear or branched alkoxy group having 1 to 4 carbon atoms (for example, methoxy group, ethoxy group, etc.) Alkoxy-modified monomer of (meth) acrylic acid alkyl ester {specifically, (meth) acrylic acid 2-methoxyethyl ester, (meth) acrylic acid 2-ethoxyethyl ester, etc.}), acrylonitrile, vinyl acetate, propion Vinyl acid, vinyl pyrrolidone, vinyl caprolactam, (meth) acrylic acid, (meth) acrylic acid 2-hydro Phenoxyethyl ester, styrene sulfonic acid, (meth) acrylamide, (meth) 2-aminoethyl ester acrylate.

  When using a copolymer comprising (meth) acrylic acid alkyl ester and the above functional monomer as the acrylic polymer, 60 to 98% by weight of (meth) acrylic acid alkyl ester, preferably 65 to 98% by weight. It is preferable to copolymerize 97% by weight and the above monomer in a proportion of 2 to 40% by weight, preferably 3 to 35% by weight.

  Examples of rubber adhesives include polyisobutylene / polybutene, styrene / diene / styrene block copolymer, styrene / butadiene, nitrile, chloroprene, vinylpyridine, polyisobutylene, butyl, isoprene / isobutylene. Examples thereof include rubber-based pressure-sensitive adhesives made of a system. Among them, polyisobutylene, styrene / diene / styrene block copolymer (for example, styrene / butadiene / styrene block copolymer (SBS), styrene / isoprene / styrene block copolymer) from the viewpoint of solubility in tulobuterol and skin adhesiveness. Are preferably used, and these may be used as a mixture.

  Moreover, in order to obtain moderate adhesive strength and drug solubility, rubber-based pressure-sensitive adhesives can be used by mixing the same components or different components having different average molecular weights. For example, taking polyisobutylene as an example, a high molecular weight polyisobutylene having an average molecular weight of 300,000 to 2,500,000, a medium molecular weight polyisobutylene having an average molecular weight of 10,000 to 200,000 and / or an average A mixture with a low molecular weight polyisobutylene having a molecular weight of 500 to 4,000 is preferred. Here, high molecular weight polyisobutylene is 10 to 80 wt%, preferably 20 to 50 wt%, medium molecular weight polyisobutylene is 0 to 90 wt%, preferably 10 to 80 wt%, and low molecular weight polyisobutylene is 0 wt%. It is suitable to blend in a proportion of ˜80 wt%, preferably 10˜60 wt%.

  The average molecular weight in the present invention is a viscosity average molecular weight calculated from the Flory viscosity equation.

  In order to impart appropriate tackiness to the rubber adhesive, for example, a rosin resin, polyterpene resin, coumarone-indene resin, petroleum resin, terpene-phenol resin, xylene resin, etc. May be. One or two or more types of tackifiers can be blended in a proportion of 50% by weight or less, preferably 5 to 40% by weight, based on the rubber-based pressure-sensitive adhesive.

  In the present invention, an additive as a solubilizing agent in the plaster layer so that the solubility of tubuterol in the plaster layer can be further increased and a high concentration of tulobuterol can be maintained in a completely dissolved state. Can be blended. Additives to be blended are excellent in compatibility with adhesives, sufficiently dissolve tulobuterol, do not cause separation of adhesive components and additives over time, and do not adversely affect adhesive properties and release properties For example, an ester of a fatty acid having 12 to 16 carbon atoms, a monoglyceride of a fatty acid having 8 to 10 carbon atoms, an ester of a dibasic acid having 6 to 10 carbon atoms, and an addition mole number of 2 as a nonionic surfactant. It is possible to use at least one selected from polyoxyethylene alkyl ethers of -5 and polyoxyethylene alkyl phenyl ethers of addition mole number of 2-5.

As esters of fatty acids of the 12-16 carbon atoms, specifically, lauric acid (C ₁₂₎ hexyl, myristic acid (C ₁₄₎ isopropyl, C ₁ to C ₁₂ -C ₁₆ fatty acid such as palmitic acid (C ₁₆₎ Isopropyl esters with -C ₁₀ alkyl.

Specific examples of the monoglycerides of fatty acids having 8 to 10 carbon atoms include monoglycerides of C _{8 to} C ₁₀ fatty acids such as caprylic acid (C ₈ ) monoglyceride and capric acid (C ₁₀ ) monoglyceride.

Specific examples of the dibasic acid ester having 6 to 10 carbon atoms include a dibasic acid of C _{6 to} C ₁₀ such as adipic acid (C ₆ ) diisopropyl, dioctyl adipate, and sebacic acid (C ₁₀ ) diethyl ( esters of C ₁ -C ₁₀₎ alkyl.

  The polyoxyethylene alkyl ether having 2 to 5 addition moles and the polyoxyethylene alkyl phenyl ether having 2 to 5 addition moles have 6 to 18, preferably 8 to 12 carbon atoms in the alkyl group. Specific examples of the oxyethylene alkyl ether include polyoxyethylene lauryl ether, polyoxyethylene oleyl ether, and polyoxyethylene cetyl ether. Specific examples of the polyoxyethylene alkyl phenyl ether include polyoxyethylene nonylphenyl ether. And polyoxyethylene octyl phenyl ether.

  Among them, isopropyl myristate which is an ester of a fatty acid having 12 to 16 carbon atoms, caprylic acid monoglyceride which is a monoglyceride of fatty acid having 8 to 10 carbon atoms, diisopropyl adipate which is an ester of a dibasic acid having 6 to 10 carbon atoms, addition An addition mole number 2-5 polyoxyethylene octyl phenyl ether which is a polyoxyethylene alkylphenyl ether having 2-5 moles is preferable, and isopropyl myristate is more preferably used.

  The additive is desirably blended in the proportion of 5 to 50% by weight, preferably 10 to 40% by weight, more preferably 20 to 40% by weight in the plaster layer. When the amount of the additive is less than 5% by weight, it tends to be difficult to keep the higher concentration of tulobuterol completely dissolved in the plaster layer, and conversely, 50% by weight. In the case of exceeding the cohesive strength, the cohesive strength of the plaster layer tends to be reduced, and adhesive residue or the like tends to occur on the skin surface during peeling.

  Moreover, when the said additive is mix | blended with the adhesive which has a crosslinkable functional group, it is desirable to perform a crosslinking process by a suitable crosslinking means. By performing the cross-linking treatment, the pressure-sensitive adhesive becomes a so-called gel state, and it is possible to suppress the outflow of the additive component contained therein and to impart an appropriate cohesive force to the plaster layer. The cross-linking reaction was carried out using physical cross-linking by irradiation such as ultraviolet ray irradiation or electron beam irradiation, and cross-linking agents such as polyisocyanate compounds, organic peroxides, organic metal salts, metal alcoholates, metal chelate compounds, and polyfunctional compounds. Chemical crosslinking treatment or the like is used.

  The thickness of the plaster layer containing the above-mentioned pressure-sensitive adhesive and tulobuterol is preferably 20 to 100 μm in order to withstand long-time sticking to the skin surface and to hardly cause adhesive residue on the skin surface during peeling and removal. 20-50 micrometers is more preferable.

  The support used in the percutaneous absorption type preparation of the present invention is not particularly limited as long as it can form and support a plaster layer containing tulobuterol on one side, but in general, tulobuterol does not substantially migrate. In particular, it is preferable to have an appropriate flexibility that can follow the curvature and movement of the skin surface to such an extent that no significant discomfort occurs when it is applied to the skin surface.

  Specifically, polyethylene-based, polypropylene-based, polyester-based, polyvinyl acetate-based, ethylene / vinyl acetate copolymer, polyvinyl chloride-based, polyurethane-based plastic films, aluminum foil, metal foil such as tin foil, non-woven fabric A monolayer film made of woven fabric, paper, or the like, or a laminated film of these can be used.

The thickness of the support is usually 5 to 500 μm, preferably 5 to 200 μm. These supports are preferably subjected to corona discharge treatment, plasma treatment, oxidation treatment or the like on the surface on which the paste layer is laminated in order to improve adhesion to the paste layer and anchoring properties.

  The method for producing the percutaneously absorbable preparation of the present invention is not particularly limited. For example, tubuterol and an adhesive are completely dissolved in an organic solvent such as ethyl acetate, hexane, and toluene, and the obtained solution is applied to one side of the support. The method of apply | coating and drying and forming a plaster layer on the surface of a support body etc. are mentioned. It can also be produced by applying the above solution on a protective release liner, drying to form a paste layer on the release liner, and then bonding the support to the paste layer. Can do.

  The percutaneously absorbable preparation of the present invention is used to prevent the plaster layer from adhering to instruments, containers, etc. during manufacture, transportation or storage, and to prevent deterioration of the preparation. It is desirable to cover and protect the exposed surface of the plaster layer with a release liner until immediately before application. And it peels off at the time of use, the surface of a paste layer is exposed, and it affixes on skin and administers.

  The release liner is not particularly limited as long as it can be easily peeled off from the paste layer at the time of use. For example, the release treatment is performed by applying a silicone resin, a fluororesin, or the like on the surface in contact with the paste layer. A film such as polyester, polyvinyl chloride, polyvinylidene chloride, polyethylene terephthalate, paper such as high-quality paper or glassine paper, or a laminate film of high-quality paper or glassine paper and polyolefin is used.

  The thickness of the release liner is usually 12 to 200 μm, preferably 50 to 100 μm.

The dosage of the transdermal preparation of the present invention varies depending on the age, weight, symptoms, etc. of the patient, but usually the preparation containing 0.1-5 mg of tulobuterol per dose for an adult is used for the skin 1 Affix to 50 cm ² once a day to about once every two days.

  EXAMPLES Hereinafter, examples and experimental examples will be shown to describe the present invention in detail, but the present invention is not limited by these. In the following examples, parts and% mean parts by weight and% by weight, respectively.

Example 1
Under an inert gas atmosphere, 50 parts of acrylic acid 2-ethylhexyl ester, 25 parts of acrylic acid 2-methoxyethyl ester and 25 parts of vinyl acetate were polymerized in ethyl acetate to prepare an acrylic pressure-sensitive adhesive solution. Tulobuterol was added to this solution so that the blending amount in the plaster layer was 10%, mixed and sufficiently stirred, and then applied to the release liner so that the thickness after drying was 40 μm, and dried. Thus, a plaster layer was formed. Next, the plaster layer was bonded to a support (polyester film having a thickness of 12 μm) to obtain a transdermal preparation of the present invention.

Example 2
To the acrylic pressure-sensitive adhesive solution obtained in Example 1, tulobuterol and polyoxyethylene octylphenyl ether (added mole number of oxyethylene 3, OP-3, manufactured by Nikkor Co., Ltd.) as an additive were added to the plaster layer. After adding, mixing and mixing well so that the blending amounts would be 10%, the percutaneous absorption type preparation of the present invention was obtained in the same manner as in Example 1.

Example 3
Under an inert gas atmosphere, 95 parts of 2-ethylhexyl acrylate and 5 parts of acrylic acid were polymerized in ethyl acetate to prepare an acrylic pressure-sensitive adhesive solution. To this solution, tubuterol and isopropyl myristate as an additive were added and mixed so that the blending amounts in the plaster layer were 20% and 30%, respectively, and a polyisocyanate compound (Coronate HL, Nippon Polyurethane Co., Ltd.) as a crosslinking agent. The product was added to the acrylic pressure-sensitive adhesive so as to be 0.15%, mixed and sufficiently stirred, and then coated on the release liner and dried so that the thickness after drying was 60 μm. A plaster layer was formed. Next, the plaster layer was bonded to the nonwoven fabric side of the support (a laminated film of a polyester nonwoven fabric having a basis weight of 12 g / m ² and a polyester film having a thickness of 6 μm) to obtain a transdermal preparation of the present invention. In addition, in order to advance a crosslinking reaction, after bonding a support body, it heated at 70 degreeC for 60 hours.

Example 4
To the acrylic pressure-sensitive adhesive solution obtained in Example 3, tulobuterol and isopropyl myristate and caprylic acid monoglyceride as additives were added so that the blending amounts in the plaster layer were 10%, 40% and 5%, respectively. After mixing and stirring sufficiently, the percutaneous absorption preparation of the present invention was obtained in the same manner as in Example 3.

Example 5
50 parts of polyisobutylene (VISTANEX MML-140, manufactured by Exxon Chemical Co., Ltd.), 30 parts of polyisobutylene (HIMOL 6H, manufactured by Nippon Petrochemical Co., Ltd.) and alicyclic petroleum resin (softening point 100 ° C., Alcon P-100, Arakawa Chemical) 20 parts) was dissolved in hexane to prepare a rubber polymer solution. To this solution, tulobuterol and isopropyl myristate as an additive were added, mixed and mixed thoroughly in the plaster layer to 5% and 40%, respectively, and then dried on a release liner. The plaster layer was formed by applying and drying so that the subsequent thickness was 40 μm. Next, the plaster layer was bonded to the nonwoven fabric side of the support (a laminated film of a polyester nonwoven fabric having a basis weight of 12 g / m ² and a polyester film having a thickness of 6 μm) to obtain a transdermally absorbable preparation of the present invention.

Example 6
To the rubber-based polymer solution obtained in Example 5, tubuterol and diisopropyl adipate as an additive were added and mixed so that the blending amounts in the plaster layer were 5% and 30%, respectively, and sufficiently stirred. After that, the percutaneously absorbable preparation of the present invention was obtained in the same manner as Example 5.

Example 7
80 parts of styrene / butadiene / styrene block copolymer (SBS) (styrene / butadiene = 30/70 (weight ratio), Cariflex TR-1101, manufactured by Shell Chemical Co., Ltd.) and alicyclic petroleum resin (softening point 105 ° C., A rubber polymer solution was prepared by dissolving 20 parts of Escolez 5300 (manufactured by Exxon Chemical Co., Ltd.) in toluene. To this solution, tulobuterol and isopropyl myristate as an additive were added and mixed so that the blending amounts in the plaster layer were 5% and 40%, respectively, and stirred well. The transdermal absorption type preparation of the invention was obtained.

Example 8
Styrene / isoprene / styrene block copolymer (SIS) (styrene / isoprene = 14/86 (weight ratio), Cariflex TR-1107, Shell Chemical Co., Ltd.) 70 parts, polyisobutylene (HIMOL 4H, Nippon Petrochemical Co., Ltd.) 10 parts and 20 parts of an alicyclic petroleum resin (softening point 100 ° C., Alcon P-100, manufactured by Arakawa Chemical Co., Ltd.) were dissolved in toluene to prepare a rubber polymer solution. To this solution, tulobuterol and isopropyl myristate as an additive were added and mixed so that the blending amounts in the plaster layer were 5% and 40%, respectively, and stirred well. The transdermal absorption type preparation of the invention was obtained.

Comparative Example 1
Instead of the acrylic adhesive solution of Example 1, 45 parts of acrylic acid tridecyl ester, 25 parts of 2-methoxyethyl acrylate and 30 parts of vinyl acetate were polymerized in ethyl acetate under an inert gas atmosphere. A percutaneous absorption preparation was obtained in the same manner as in Example 1 except that the obtained acrylic adhesive solution was used.
Note that, by visual or microscopic observation, crystals of tulobuterol were dispersed in the plaster layer of this preparation.

Comparative Example 2
Instead of the rubber-based polymer solution of Example 5, a rubber-based polymer solution obtained by dissolving 70 parts of polyisoprene (IR2200, manufactured by Nippon Synthetic Rubber) and 30 parts of an alicyclic petroleum resin in hexane was used. A percutaneous absorption type preparation was obtained in the same manner as in Example 5 except that it was used.
Note that, by visual or microscopic observation, crystals of tulobuterol were dispersed in the plaster layer of this preparation.

  Table 1 shows the composition of the plaster layer of the transdermal preparations obtained in Examples 1-8 and Comparative Examples 1-2.

Experimental example 1
Stability of adhesive properties (adhesive strength) over time for the transdermal preparations obtained in Examples 1 to 8 and Comparative Examples 1 and 2 and the transdermal preparations stored at 40 ° C. for 1 month Was examined.

<Adhesion test method>
Each strip-shaped sample cut to a width of 12 mm was affixed to a bakelite plate, and a roller with a load of 850 g (300 g for Examples 3 and 4) was reciprocated once, and left to stand. Below, the tensile load at the time of peeling at a speed | rate of 300 mm / min in the direction of 180 degree | times was measured using the tensile testing machine (Shopper type tensile testing machine: Ueshima Seisakusho make).
The results are shown in Table 2.

  The preparations of Examples 1 to 8 showed stable adhesive properties from the beginning, and no change in adhesive strength over time was observed. On the other hand, in the preparations of Comparative Examples 1 and 2, a decrease in adhesive force, which is considered to be caused by drug crystal precipitation with time in the plaster layer, was observed.

Experimental example 2
For the transdermal preparations obtained in Examples 1 and 5 and Comparative Examples 1 and 2 and the transdermal preparations stored for 1 month at 40 ° C., dissolution test in the Japanese Pharmacopoeia general test method Method 2 examined the time-dependent stability of the drug release from the preparation.
The results are shown in Table 3.

<Dissolution test method>
Dissolution tester: NTR-V36 (Toyama Sangyo Co., Ltd.)
Sample size: 10cm ²
Test solution: distilled water, 32 ° C., 500 ml
Paddle rotation speed: 50 rotations / minute Measurement method: UV spectrophotometric method (211 nm)

  The preparations of Examples 1 and 5 showed a stable drug release from the initial stage, and no change in the drug release during storage over time was observed. On the other hand, in the preparations of Comparative Examples 1 and 2, a decrease in drug release, which was considered to be caused by drug crystal precipitation with time in the plaster layer, was observed.

Experimental example 3
The transdermal preparations obtained in Examples 1 and 5 and Comparative Examples 1 and 2 were applied to the back of a rabbit whose hair had been removed, and changes in the blood concentration of tulobuterol after application were examined.
The results are shown in FIG.

<Blood concentration test method>
Sample size: 10cm ²
Attached site: Back of the rabbit with hair removal Applied time: 24 hours Blood concentration measurement method: Gas chromatograph method (electron capture ionization detector)

  The preparations of Examples 1 and 5 were excellent in both rising and sustaining blood concentration at the initial application stage. In contrast, the preparations of Comparative Examples 1 and 2 were excellent in sustainability, but the initial rise in blood concentration was not satisfactory.

Claims (2)

  Esters of fatty acids having 12 to 16 carbon atoms, monoglycerides of fatty acids having 8 to 10 carbon atoms, esters of dibasic acids having 6 to 10 carbon atoms, polyoxyethylene alkyl ethers having 2 to 5 addition moles, and 2 addition moles A solubilizing agent for tulobuterol for a percutaneous absorption preparation, comprising as an active ingredient at least one selected from the group consisting of -5 polyoxyethylene alkylphenyl ethers.   A method for assisting dissolution of tulobuterol in a paste layer, comprising blending the dissolution aid according to claim 1 into the paste layer.

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