JPH0769869A - Bunitrolol-containing patch preparation - Google Patents

Abstract

(57) [Summary] [Objective] To provide a patch preparation for transdermal administration of bunitrolol or a salt thereof as a β-blocker. Provided is a nitrrole-containing patch preparation having a plaster layer that has good release into the body and is less irritating to the patch skin. [Structure] An acrylic polymer containing (meth) acrylic acid alkyl ester as a main monomer is made to contain a relatively large amount of a compatible organic liquid component with bunitrolol and / or a pharmaceutically acceptable salt thereof. Then, a cross-linking treatment is performed to form the plaster layer 3. As the support, a laminate of non-porous sheet 1 and perforated sheet 2 is used, a plaster layer is formed on the side of the perforated sheet, and the plaster is embedded inside the perforated sheet so as to reach the lamination interface. Let

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a bunitrolol-containing patch for exerting a desired pharmacological effect by continuously administering bunitrolol which is a β-blocker and a pharmacologically acceptable salt thereof through the skin into a living body. Regarding the formulation, in particular, the stability and skin permeability of the contained bunitrolol are excellent, there is little irritation to the skin surface to be applied, the phenomenon of adhesive residue at the time of peeling and anchor anchorage between the support and the plaster layer It is intended to provide a patch preparation which is less likely to occur.

[0002]

BACKGROUND OF THE INVENTION Bunitrolol is a β-blocker represented by the following general formula [1- (2-cyanophenoxy) -2-hydroxy-3-tert-butylaminopropane] and has an adrenergic β-receptor blocking action. , Hydrochloride as a therapeutic agent for essential hypertension and angina, which has an endogenous sympathetic nerve-stimulating action, an α ₁ -receptor blocking action, a Ca ²⁺ intracellular inflow inhibition action, and a plasma renin activity lowering action It is commercially available in the form of an oral preparation.

[0003]

[Chemical 1]

On the other hand, as a preparation for in-vivo administration of a drug, it is a dosage form capable of preventing the occurrence of various side effects without being metabolized by the first-pass effect in the liver and allowing continuous administration for a long time. Various types of adhesive preparations in the form of adhesive tapes or sheets have been proposed.

Usually, such a patch preparation is first of all used in order to prevent the patch preparation from falling off the skin surface to which it is applied.
It requires a certain amount of skin adhesion, but the greater the skin adhesion, the stronger the physical irritation when peeling and removing it from the skin surface, causing pain and peeling of the stratum corneum when peeling. May cause unnecessary irritation or damage to the user and cause pain to the user.

Therefore, it is necessary to moderately reduce the skin adhesiveness in relation to the reduction of skin irritation, and the skin adhesive force is sacrificed to some extent, or the insufficient skin adhesive force is overwritten by a separately prepared adhesive sheet. I am supplementing with a coat.

[0007] Other required characteristics of the patch preparation include cohesiveness of the plaster layer (prevention of adhesive residue at the time of peeling removal) and anchoring property between the support and the plaster layer (at the time of peeling removal). Adhesive retention phenomenon) and the stability of the drug contained in the plaster layer over time (prevention of drug degradation) and the release of the drug from the plaster layer (transdermal absorbability). and so on. Therefore, in developing such a patch preparation, it is necessary to study various items.

[0008]

DISCLOSURE OF THE INVENTION In developing the patch preparation for transdermally administering bunitrolol as the β-blocker and / or its pharmacologically acceptable salt into the living body in the present invention, A physically effective amount of bunitrolols can be administered in vivo, it is less irritating to the skin surface to be applied, and there is no adhesive residue when peeling and removing the patch preparation from the skin surface. It is an object of the present invention to provide a patch preparation having good anchoring property.

[0009]

[Means for Solving the Problems] In order to achieve the above object, as a result of first studying a plaster having low skin irritation, a relatively large amount of an organic liquid component having a plasticizing effect on an acrylic polymer is contained. And a patch preparation having a soft feel to the plaster layer is obtained, and when this plaster layer contains bunitrolol and / or a pharmacologically acceptable salt thereof,
It was found to show excellent transdermal absorbability.

However, when a plaster layer having such a composition is laminated on the surface of a plastic film as a support or on the surface of a perforated sheet of a laminated film of a plastic film and a perforated sheet, a plaster layer is formed. The content of the component may fluctuate, and in particular, the organic liquid component in the plaster layer blooms at the laminating interface between the support and the plaster layer, so that the anchoring force may not be sufficient. As a result, it was also found that, after the patch preparation was applied to the skin surface and used, when the patch preparation was peeled off from the skin surface, anchorage failure might occur to cause adhesive residue phenomenon.

Then, as a result of further studies to obtain a patch preparation having a good anchoring property, which is one of the important issues for practical use, a laminated structure of a support having a specific two-layer structure and a plaster layer was found. It has been found that, by setting a specific state, a patch preparation containing bunitrolol having excellent anchoring properties can be obtained, and the present invention has been completed.

That is, according to the present invention, an acrylic polymer obtained by polymerizing an alkyl (meth) acrylate as a main component monomer, an organic liquid component compatible with the acrylic copolymer, bunitrolol and / or Alternatively, a plaster layer containing a pharmacologically acceptable salt of bunitrolol and subjected to a crosslinking treatment is formed on the side of the perforated sheet of the support which is a laminated structure of a non-perforated sheet and a perforated sheet. A patch preparation comprising the above, wherein the plaster layer is embedded inside the perforated sheet and reaches the lamination interface with the non-perforated sheet.

The plaster layer in the medicated patch of the present invention comprises an acrylic polymer obtained by polymerizing an alkyl (meth) acrylate as a main component monomer and an organic liquid compatible with the acrylic copolymer. It has a composition containing components and is obtained by crosslinking treatment. In the present invention, an acrylic polymer is used as the polymer constituting the plaster layer, but natural rubber, various synthetic rubbers, silicone-based polymers and other polymers and organic liquid components described below are used. The compatibility is not sufficient, and a relatively large amount of the organic liquid component cannot be retained in the plaster layer, and the organic liquid component may be exuded from the plaster layer during the storage of the patch preparation, which is not preferable. Further, when the plaster layer is subjected to a crosslinking treatment, it is difficult to adjust the degree of crosslinking. Furthermore, the release and stability of bunitrolol and its pharmacologically acceptable salts to the skin surface contained in the plaster layer are not constant in the plaster layer having such a composition and are difficult to use. Is.

Examples of the (meth) acrylic acid alkyl ester as a main component monomer for obtaining the acrylic polymer include butyl ester, pentyl ester, hexyl ester, heptyl ester, octyl ester, nonyl ester and decyl ester. , 40% by weight or more, preferably 50% by weight or more, as the main component monomer, a (meth) acrylic acid alkyl ester having an alkyl group having 4 to 18 carbon atoms, such as undecyl ester, undecyl ester, dodecyl ester, and tridecyl ester. The alkyl group may be linear or branched. These (meth) acrylic acid alkyl esters may be used alone or in combination of two or more during the polymerization. Further, if necessary, the alkyl group has 3 or less carbon atoms (meta).
A lower alkyl ester such as acrylic acid methyl ester, (meth) acrylic acid ethyl ester, or (meth) acrylic acid propyl ester is used as an amount of the (meth) acrylic acid alkyl ester having an alkyl group having 4 to 18 carbon atoms. A copolymer may be used instead of the part.

Further, as the acrylic polymer used in the present invention, a copolymer obtained by copolymerizing the above-mentioned (meth) acrylic acid alkyl ester with a copolymerizable monomer can be used. As such a copolymerizable monomer, a polar monomer or a vinyl-based monomer is used.

Examples of polar monomers that can be copolymerized include (meth) acrylic acid, itaconic acid, maleic acid, maleic anhydride, carboxyl group-containing monomers such as crotonic acid, styrene sulfonic acid and allyl sulfonic acid. , Sulfopropyl (meth) acrylate, (meth) acryloyloxynaphthalene sulfonic acid, sulfoxyl group-containing monomers such as acrylamidomethyl propane sulfonic acid, (meth) acrylic acid hydroxyethyl ester, (meth) acrylic acid hydroxypropyl ester, etc. Hydroxy group-containing monomer, (meth) acrylamide, dimethyl (meth) acrylamide, N-butylacrylamide, N-
Amido group-containing monomers such as methylol (meth) acrylamide and N-methylolpropane (meth) acrylamide, (meth) acrylic acid aminoethyl ester, (meth) acrylic acid dimethylaminoethyl ester, (meth) acrylic acid tert-butyl ester Alkylaminoalkyl group-containing monomers such as aminoethyl ester, (meth) acrylic acid methoxyethyl ester, (meth) acrylic acid alkoxyalkyl ester such as (meth) acrylic acid ethoxyethyl ester, (meth) acrylic acid tetrahydrofurfuryl Alkoxy groups such as esters, methoxyethylene glycol esters of (meth) acrylic acid, methoxydiethylene glycol esters of (meth) acrylic acid, and methoxypolyethylene glycol esters of (meth) acrylic acid Sid bond) containing (meth) acrylic acid esters, include (meth) acrylonitrile, these monomers can be copolymerized in combination one or two or more kinds.

Examples of vinyl monomers include vinyl acetate, vinyl propionate and other vinyl esters, N-vinyl-2-pyrrolidone, methylvinylpyrrolidone, vinylpyridine, vinylpiperidone, vinylpyrimidine, vinylpiperazine, vinyl. Pyrazine, vinylpyrrole, vinylimidazole, vinylcaprolactam,
Examples thereof include vinyl monomers having a nitrogen atom-containing heterocyclic ring such as vinyl oxazole, and these monomers can be used alone or in combination of two or more kinds thereof to be copolymerized.

The polar monomer and the vinyl-based monomer may be used alone or in combination of two or more kinds and may be copolymerized with the above-mentioned (meth) acrylic acid alkyl ester. Among them, a carboxyl group-containing monomer, a hydroxy group-containing monomer, which has a functional group serving as a cross-linking point when a cross-linking treatment is performed, and from the viewpoint of improving the cohesive force by increasing the glass transition temperature of the acrylic polymer, It is preferable to polymerize a monomer, an amide group-containing monomer, a (meth) acrylic acid alkoxyalkyl ester, and an alkoxy group (or an oxide bond in a side chain) -containing (meth) acrylic acid ester as a copolymerization component. From the viewpoint of improving cohesive force and solubility of bunitrolol, it is preferable to copolymerize vinyl esters and vinyl monomers having a nitrogen atom-containing heterocycle.

The copolymerization amount of the above-mentioned copolymerizable polar monomer and / or vinyl monomer is adjusted to adjust the cohesive force of the acrylic polymer-based plaster layer, and Although it can be arbitrarily set by adjusting the solubility of bunitrolol, the copolymerization amount is usually 50% by weight or less, preferably 2 to 40% by weight.

The most preferable composition of the acrylic polymer in the patch preparation containing bunitrolol of the present invention is as follows:
(Meth) acrylic acid alkyl ester / (meth) acrylic acid / vinyl monomer having a nitrogen atom-containing heterocycle in the range of (50 to 99) / (1 to 10) / (0 to 40)% by weight. The polymer obtained by copolymerization prepared in, the stability, release, low skin irritation of bunitrolol contained,
It is preferable because it has a well-balanced skin adhesiveness.

The organic liquid component contained in the plaster layer of the patch preparation of the present invention together with the above acrylic polymer exhibits the action of plasticizing the plaster layer by being compatible with the acrylic polymer. In the present invention, by plasticizing the plaster layer, it is possible to give a soft feeling to the skin when applied to the skin surface, and to further impart a suitable cohesive force by performing a crosslinking treatment, and after use It is possible to reduce skin irritation as much as possible at the time of peeling and removing. Further, since the free diffusion property of bunitrolol in the plaster layer is also good, the release property to the skin surface is also good.

In order to exert such an action, the content of the organic liquid component is 25 to 200 parts by weight, preferably 40 to 180 parts by weight, particularly preferably 60 to 100 parts by weight with respect to 100 parts by weight of the acrylic polymer. It is desirable to set it in the range of 180 parts by weight. If the content of the organic liquid component is too small, a sufficient plasticizing effect cannot be exerted, and reduction in skin irritation cannot be expected so much. On the other hand, if the content of the organic liquid component is too high, the plaster layer will be plasticized too much and the cohesive force will decrease. Shows a tendency to increase sex.

As such an organic liquid component, it is liquid at room temperature and is compatible with the acrylic polymer, and specifically, ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol, polyethylene glycol, Glycols such as polypropylene glycol, olive oil, castor oil, squalene, oils and fats such as lanolin, ethyl acetate, ethyl alcohol, dimethyldecyl sulfoxide, methyl octyl sulfoxide, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, dimethyllaurylamide, dodecyl. Organic solvents such as pyrrolidone and isosorbitol, liquid surface-active agents, hydrocarbons such as liquid paraffin, ethoxylated stearyl alcohol, glycerin ester, fluorine Ester, isopropyl myristate, isotridecyl myristate, diethyl sebacate, ethyl laurate, N-methylpyrrolidone, ethyl oleate, oleic acid, diisopropyl adipate, isopropyl palmitate, octyl palmitate, 1,3-butanediol Examples thereof include organic compounds that are liquid at room temperature, and one or more of these are compounded and used. Among these, from the viewpoint of reducing skin irritation and promoting percutaneous absorption of bunitrolol contained, isopropyl myristate, diethyl sebacate, octyl palmitate, ethyl oleate, diethyl phthalate,
It is preferable to use one or a combination of liquid substances such as fatty acid esters such as diisopropyl adipate, fatty acids such as monocapric acid and oleic acid, and surfactants such as sorbitan monocaprylate.

Further, in the present invention, a crosslinking treatment is carried out in order to enhance the internal cohesive force of the plaster layer and to impart appropriate softness, skin adhesiveness and cohesiveness to the skin. That is, after the patch preparation of the present invention is applied to the skin surface by forming the plaster layer as a crosslinked structure, cohesive failure does not occur inside the plaster layer even if shear stress is applied from the outside, and moreover, skin adhesion A viscoelastic body having a creep characteristic capable of exerting a force is used.

Examples of such a crosslinking treatment include physical crosslinking by irradiation with radiation such as ultraviolet irradiation and electron beam irradiation, polyisocyanate compound, organic peroxide, organic metal salt, metal alcoholate, metal chelate compound, melamine. Chemical crosslinking treatment using a crosslinking agent such as a derivative or a polyfunctional compound can be adopted. When radiation or an organic peroxide is used among these crosslinking means, a decomposition reaction of bunitrolol may occur, and also highly reactive isocyanates, metal salts or organic metal salts used for ordinary crosslinking reaction. In some cases, the viscosity of the solution may increase after compounding, resulting in poor workability. It is also possible to preliminarily copolymerize a polyfunctional monomer such as diacrylate with an acrylic polymer as an adhesive, but depending on the type, the solution viscosity during coating may increase. , Handle with care.

Therefore, in the present invention, among these cross-linking agents, metal alcoholates and metal chelate compounds made of titanium or aluminum are preferable in terms of reactivity and handleability. These cross-linking agents do not cause thickening phenomenon of the solution until coating and drying, and are extremely excellent in workability. These cross-linking agents are usually used in an amount of 0.1 parts by weight per 100 parts by weight of the acrylic polymer.
It is blended in the range of about 01 to 5 parts by weight. Even when the acrylic polymer constituting the plaster layer does not have a functional group that reacts with the cross-linking agent, by subjecting it to an alkali treatment or the like before the cross-linking treatment, a structure capable of cross-linking treatment is obtained. It can be modified.

If necessary, antioxidants, various pigments, various fillers, percutaneous absorption enhancers, stabilizers, drug dissolution aids, drug dissolution inhibitors, etc. are added to the plaster layer having the above structure. 2 to 100 parts by weight of the acrylic polymer
It can be added in the range of about 50 parts by weight.

In the patch preparation of the present invention, bunitrolol and / or a pharmacologically acceptable salt of bunitrolol is contained in the plaster layer in a dissolved or dispersed state. The pharmacologically acceptable salt in the present invention is a basic drug in which bunitrolol has an amino group in the molecule, and therefore, for example, hydrochloride, sulfate, nitrate, acetate, phosphate, maleate is used. , Fumarate, tartrate, citrate, hydrobromide, mesylate and the like.

The content of bunitrolol and / or a pharmacologically acceptable salt of bunitrolol is usually 4 to 25% by weight, preferably 5 to 25% by weight, in the plaster. If the content is less than 4% by weight, it is not possible to expect an effective amount of bunitrolol for treatment or prevention, and if it exceeds 25% by weight, bunitrolol may cause skin irritation and a pharmacological effect. It is economically disadvantageous because there is a limit to

The patch preparation of the present invention comprises the above-mentioned plaster layer laminated and formed on one surface of a support, and a non-porous sheet and a perforated sheet laminated structure is used as the support. The plaster layer is formed on the side of the perforated sheet of this laminate, and the plaster layer is embedded inside the perforated sheet and the embedded plaster reaches the lamination interface with the non-perforated sheet. I am trying. The degree of embedding of the plaster is such that the laminate interface between the non-perforated sheet and the perforated sheet in the support is forcibly peeled off as described in the examples below, and the bakelite by the plaster exposed from the inside of the perforated sheet. Adhesive force to plate (pull speed 300mm /
Min., 24 mm width) is preferably 5 g or more, and more preferably 8 g or more, from the viewpoint of practical anchorage. The non-perforated sheet means a sheet that is not subjected to an intentional perforation means such as a perforation treatment or a foaming treatment. It means a sheet having voids communicating with the front and back surfaces.

Examples of the material of the non-porous sheet include polyester, nylon, saran, polyethylene, polypropylene, polyvinyl chloride, polyvinylidene chloride, ethylene / ethyl acrylate copolymer, ethylene / vinyl acetate copolymer, ethylene / vinyl. Various plastics such as alcohol copolymer, polytetrafluoroethylene, surlyn, polyurethane, rayon, vinylon, acryl, acetate and triacetate, and metal foil can be used, and a single layer sheet or a laminated sheet made of these may be used. Of these non-perforated sheets, those in which the organic liquid component in the plaster layer and the drug for percutaneous absorption do not penetrate, that is, so-called strike-through is preferable, and a sheet made of polyester, polytetrafluoroethylene, polyethylene, polypropylene or the like is used. Is desirable.

On the other hand, as the perforated sheet, a sheet, paper, woven fabric, non-woven fabric, knitted fabric or the like obtained by perforating the non-perforated sheet or subjecting it to continuous foaming treatment can be used. Among these perforated sheets, in order to sufficiently embed the plaster layer, it is preferable to use a perforated sheet made of non-woven fabric or woven fabric, and in this case, the basis weight is 5 to 30 g /
m ^2, it is preferred from the viewpoint of improving anchoring property between the plaster layer in particular employed ones 8 to 20 g / m ^2.

The support used in the medicated patch of the present invention is a laminate of the above-mentioned non-porous sheet and perforated sheet, and the lamination method is not particularly limited, and the extrusion molding method, thermocompression bonding method, polyester type A bonding method using a known adhesive such as an adhesive is adopted. The thickness of the resulting support is not particularly limited, considering the flexibility when the patch preparation of the present invention is applied to the skin surface and the anchoring property of the plaster layer and the perforated sheet, the thickness of the non-porous sheet is 0.5-50 μm,
The thickness of the perforated sheet is preferably 10 to 5 μm.
00 μm, preferably 10 to 200 μm, and the total thickness of the support is 11 to 550 μm, preferably 1
It is set to about 5 to 225 μm. In addition, since the plaster layer is embedded in the perforated sheet, it is difficult to express the thickness, but the thickness of the plaster layer obtained by subtracting the thickness of the support from the total thickness of the patch preparation is 3
The thickness is set to 0 to 200 μm, preferably 40 to 180 μm, and particularly preferably 50 to 150 μm.

The patch preparation of the present invention forms the plaster layer on the side of the perforated sheet in such a support, and the formed plaster layer is embedded inside the perforated sheet and laminated with the non-perforated sheet. It reaches the interface (the surface of the adhesive layer when the non-perforated sheet and the perforated sheet are bonded together with an adhesive). As the method for forming the plaster layer on the surface of the support, a method of directly applying a solution in which the plaster component is dissolved on the side of the perforated sheet of the support and drying it (direct copying method) or preliminarily applying the plaster component on the separator surface The dissolved solution is applied and dried to form a plaster layer, which is attached to the perforated sheet side of the support,
There is a method of transferring under pressure (transfer method). When the cohesive force of the plaster layer is relatively small, the plaster layer is embedded inside the perforated sheet even by the transfer method, but in order to make sure that the plaster layer is embedded inside the perforated sheet to improve the anchoring force, It is preferable to use the copying method.

Further, in the patch preparation of the present invention, it is desirable that the surface of the plaster layer formed on the surface of the support is covered and protected with a known separator until it is used. It is preferable that the liquid components and the drug for transdermal absorption are sterilized and packed so as not to reduce volatilization.

The patch preparation of the present invention thus obtained is easy to handle when it is applied to the skin surface, is capable of following the movement of the skin after being applied to the skin surface, and has a good feeling of wearing during application (causing a feeling of discomfort). The size of the patch preparation is 5 to 10 in terms of releasing an effective amount of bunitrolol.
0 cm ^2, preferably 10~75cm ^2, particularly preferably cut to be in the range of 10 to 50 cm ^2. The shape of the medicated patch is not particularly limited to a square, a circle, or a rectangle.

[0037]

EFFECTS OF THE INVENTION As described above, the patch preparation of the present invention comprises a plaster layer obtained by subjecting an acrylic polymer containing an alkyl (meth) acrylate as a main monomer and an organic liquid component to a crosslinking treatment. In addition, since it contains bunitrolol and / or a pharmacologically acceptable salt of bunitrolol as a drug for percutaneous absorption, it has good skin adhesiveness and little skin irritation, and thus has stability and drug stability. The release property is also good.

Further, such a plaster layer is formed on the side of a perforated sheet of a support having a laminated structure of a non-perforated sheet and a perforated sheet, and the formed plaster layer is embedded inside the perforated sheet. Since it reaches the laminated interface with the non-porous sheet,
It is extremely excellent in anchoring property and does not cause adhesive residue phenomenon due to anchorage breaking when the patch preparation is peeled off from the skin surface.

[0039]

EXAMPLES Examples of the present invention will be shown below and will be described more specifically. In the following, parts and% mean parts by weight and% by weight.

Example 1 Acrylic polymer solution was prepared by copolymerizing 72 parts of acrylic acid 2-ethylhexyl ester, 25 parts of N-vinyl-2-pyrrolidone and 3 parts of acrylic acid in ethyl acetate. To 50 parts of the amount of acrylic polymer in this solution,
Bunitrolol 10 parts, isopropyl myristate 40
1 part of aluminum tris (acetylacetonate) per 100 parts of acrylic polymer.
Was added as a 1% ethyl acetate solution, and ethyl acetate was further added to adjust the coating viscosity to obtain a plaster solution.

The obtained plaster solution was extrusion-molded with a polyester film (thickness: 12 g / m ² ) on a polyester non-woven fabric (weight: 12 g / m ² ). The non-woven fabric side of the support had a plaster layer thickness of 80 μm after drying. Thus coated and dried to form a crosslinked plaster layer.

Then, a polyester separator (thickness: 75 μm) was attached to the surface of the formed plaster layer to obtain a butyrolol-containing patch preparation of the present invention.

Example 2 The acrylic polymer used in Example 1 was used as an acrylic polymer obtained by polymerizing 97 parts of 2-ethylhexyl acrylate and 3 parts of acrylic acid, and aluminum tris ( The amount of acetylacetonate) was adjusted to 0.8 part to obtain a plaster solution.

The obtained plaster solution was applied on a polyester separator (thickness: 75 μm) so that the thickness after drying was 80 μm, and dried to form a crosslinked plaster layer in advance. Then, the obtained plaster layer was attached to the non-woven fabric side of the support used in Example 1 to obtain a butyrolol-containing patch preparation of the present invention.

Example 3 Example 3 was repeated except that aluminum tris (acetylacetonate) was used as a cross-linking agent in the amount of 1.5 parts of dipropoxy-bis (acetylacetonato) titanium. The patch preparation containing bunitrolol of the present invention was obtained.

Example 4 A bunitrolol-containing patch preparation of the present invention was obtained in the same manner as in Example 2, except that 40 parts of isopropyl myristate as the organic liquid component used in Example 2 was mixed as diethyl sebacate.

Example 5 A patch preparation containing bunitrolol of the present invention was obtained in the same manner as in Example 1 except that the amount of the acrylic polymer was 40 parts and the amount of isopropyl myristate was 50 parts.

Example 6 In Example 2, 25 parts of isopropyl myristate as an organic liquid component and 15 parts of diethyl sebacate were used.
The bunitrolol-containing patch preparation of the present invention was obtained in the same manner as in Example 2, except that the formulation was further added.

Example 7 Example 1 was repeated except that the amount of the acrylic polymer was 40 parts, the content of bunitrolol was 15 parts as bunitrolol hydrochloride, and the amount of isopropyl myristate was 45 parts.
The patch preparation containing bunitrolol of the present invention was obtained in the same manner as in.

Comparative Example 1 Example 1 was repeated except that 10 parts of bunitrolol was mixed with 90 parts of the acrylic polymer prepared in Example 1 to prepare a plaster solution, and no crosslinking agent was added thereto. In the same manner as above, a patch preparation containing bunitrolol (no organic liquid component contained in the plaster layer and no cross-linking) was prepared.

Comparative Example 2 A patch preparation containing bunitrolol (containing an organic liquid component in the plaster layer was prepared in the same manner as in Comparative Example 1) except that 15 parts of bunitrolol was added to 85 parts of the acrylic polymer in Comparative Example 1. And not crosslinked).

Comparative Example 3 The adhesive solution obtained in Example 1 was applied to one side of a polyester support film (non-porous, 25 μm thick) to give a thickness of 8 after drying.
It was applied so as to have a thickness of 0 μm and dried to form a crosslinked plaster layer.

Then, a polyester separator (thickness of 75 μm) was attached to the surface of the obtained plaster layer and covered to prepare a patch preparation containing bunitrolol.

Comparative Example 4 The plaster solution obtained in Example 1 was applied onto a polyester separator (thickness: 75 μm) so that the thickness after drying was 80 μm, and a plaster layer crosslinked by drying was previously prepared. Formed.

Next, the obtained plaster layer was attached to the non-woven fabric side of the support used in Example 1 to prepare a patch preparation containing bunitrolol.

Comparative Example 5 A patch preparation containing bunitrolol was prepared in the same manner as in Comparative Example 4 except that 1.5 parts of titanium acetoacetonate was added to 100 parts of the acrylic polymer in Comparative Example 4.

Comparative Example 6 A bunitrolol-containing patch preparation was prepared in the same manner as in Comparative Example 4 except that diethyl sebacate was used instead of isopropyl myristate as the organic liquid component in Comparative Example 4.

Comparative Example 7 In Comparative Example 4, 50 parts of the acrylic polymer was added to 40 parts,
A bunitrolol-containing patch preparation was prepared in the same manner as in Comparative Example 4 except that isopropyl myristate was changed to 50 parts.

Comparative Example 8 In Comparative Example 4, 25 parts of isopropyl myristate as an organic liquid component and 15 parts of diethyl sebacate were used.
A bunitrolol-containing patch preparation was prepared in the same manner as in Comparative Example 4 except that the formulation was further added.

The following characteristics of the patch preparations obtained in Examples and Comparative Examples were evaluated. The results are shown in Table 1.

<Skin patch test> The patch preparations obtained in Examples and Comparative Examples were treated with 5 cm ² (22.5 mm × 22.5 m).
m) and cut on the skin of the human upper arm for 24 hours. Then, the skin transfer amount was calculated from the difference in the content of bunitrolol in the patch preparation before and after application. Also,
When the patch preparation was peeled from the skin surface, the remaining of the plaster layer on the skin surface (paste residue due to anchorage destruction) was visually observed.

<Confirmation Test for Embedding in Perforated Sheet> It is confirmed that the plaster layer is embedded inside the perforated sheet in the patch preparation and that the plaster layer reaches the lamination interface with the non-perforated sheet. Therefore, the separator was peeled from the patch preparations obtained in Examples and Comparative Examples, and instead, a 12 μm-thick polyester film (without peeling treatment) was stuck and laminated.

Then, this was cut into a strip having a width of 24 mm, and only the non-perforated sheet was forcibly peeled off to expose the laminated interface with the perforated sheet.

The exposed perforated sheet surface of the patch preparation cut into strips was stuck to a Bakelite plate, and the roller having a load of 300 g was used to make one reciprocating press contact, and then 300 in 180 ° direction.
The patch preparation was peeled off at a speed of mm / min, and the adhesive force at that time was measured.

[0065]

[Table 1]

As is clear from the results shown in Table 1, it was found that the patch preparation of the present invention has a suitable skin adhesiveness and an excellent anchoring property, and the amount of bunitrolol transferred to the skin has no practical problem. . In particular, the patch preparations of Comparative Examples 1 and 2 which are not cross-linked plaster layers have a smaller amount of skin transfer as compared to the Example products, and the patch preparations of Comparative Examples 4 to 8 have sufficient plaster layer inside the perforated sheet. Since it was not embedded in the above, it had a practical problem in terms of anchoring property and adhesive residue.

[Brief description of drawings]

FIG. 1 is a cross-sectional view showing an example of a patch preparation containing bunitrolol of the present invention, which is an example in which a woven cloth is used as a perforated sheet of a support.

[Explanation of symbols]

 1 non-perforated sheet 2 perforated sheet 3 plaster layer

 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Inventor Saburo Otsuka 1-2-1, Shimohozumi, Ibaraki City, Osaka Prefecture Nitto Denko Corporation

Claims (4)

[Claims] 1. An acrylic polymer obtained by polymerizing a (meth) acrylic acid alkyl ester as a main component monomer, and an organic liquid component compatible with the acrylic copolymer.
The perforated sheet side of the support, wherein the plaster layer containing bunitrolol and / or a pharmacologically acceptable salt of bunitrolol and subjected to a crosslinking treatment is a laminated structure of a non-perforated sheet and a perforated sheet. A patch preparation comprising the above-mentioned, wherein the plaster layer is embedded inside the perforated sheet and reaches the lamination interface with the non-perforated sheet. 2. An acrylic polymer comprising a (meth) acrylic acid alkyl ester having an alkyl group having 4 to 18 carbon atoms and a polar monomer and / or vinyl monomer copolymerizable therewith. The patch preparation containing bunitrolol according to claim 1, which is a copolymer. 3. The patch preparation containing bunitrolol according to claim 1, wherein the content of the organic liquid component is 25 to 200 parts by weight with respect to 100 parts by weight of the acrylic polymer. 4. The patch preparation containing bunitrolol according to claim 1, wherein the crosslinking treatment is carried out by adding a crosslinking agent of either a metal alcoholate or a metal chelate.