JP3495733B2 - Patch containing felbinac - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a felbinac-containing patch, and more particularly, to an anti-inflammatory analgesic containing felbinac, which is an anti-inflammatory analgesic drug, as a medicinal ingredient for treating back pain, myalgia, periarthritis and the like. It relates to a patch.

[0002]

2. Description of the Related Art Felbinac (4-biphenylacetic acid) is an active metabolite of fenbufen, a non-steroidal anti-inflammatory analgesic, and is a drug showing a strong anti-inflammatory analgesic effect. Since this drug is not suitable for oral administration, it has been studied as a transdermal preparation, and so far, gels, liquids and poultices containing the drug have been marketed.
However, gels and liquids have problems such as difficulty in quantitative administration, low bioavailability, adhesion to clothes, and frequent administration (for example, administration several times a day). In addition, although poultices have been developed to improve the problems of these gels and liquids, they cannot be applied for a long time because of their weak adhesive force, their bioavailability is low, and their drug efficacy is persistent. There was a problem that it was not enough. Therefore, in JP-A-4-321624 (Patent Document 1), a styrene-isoprene-styrene block copolymer is used as a main component of a base, and crotamiton (Crotamito) is used.
An anti-inflammatory analgesic patch using n) as an essential solubilizer was proposed.

[0003]

[Patent Document 1] Japanese Unexamined Patent Publication No. 4-321624

[0004]

However, even the anti-inflammatory analgesic patch described in JP-A-4-321624 is still insufficient when felbinac is used as the anti-inflammatory analgesic, as described below. The present inventors have found that this is not the case. That is, the above-mentioned Japanese Patent Laid-Open No.
In the anti-inflammatory analgesic patch described in JP-A-321624, the work process is complicated due to the use of crotamiton as a solubilizing agent for the drug, and the adhesive strength is decreased over time due to bleeding of crotamiton (leaching to the surface). Was not enough in terms of being seen.

The present invention has been made in view of the above-mentioned problems of the prior art. The adhesion to the skin is maintained at a high level for a long time, the skin is less irritating, and the preparation is stable. It is an object of the present invention to provide a felbinac-containing patch, which has good properties, has a high drug release property, an excellent anti-inflammatory action, and a long-lasting drug effect.

[0006]

As a result of intensive studies to achieve the above object, the inventors of the present invention found the following findings and completed the present invention. That is, conventionally, it is recognized by those skilled in the art that, in a dispersive patch containing no solubilizer, the drug is present in a crystalline state, so that the transdermal absorbability of the drug is lowered and a sufficient drug effect is not expected. It had been. Nevertheless, in a felbinac-containing patch containing a specific component in a specific ratio and having a specific thickness,
Despite being a dispersion-type patch containing no solubilizing agent, the drug release is high and a sufficient pharmacological action is maintained for a long time, and the adhesion to the skin is maintained at a high level for a long time, The present inventors have found that the formulation has excellent stability and little skin irritation, and have reached the present invention.

That is, the felbinac-containing patch of the present invention comprises a styrene-isoprene-styrene block copolymer 10 to 40% by weight, a rosin resin 5 to 30% by weight, a plasticizer 20 to 70% by weight, and 1-menthol 0. 0.01 to 7% by weight, and felbinac 1.1 to 10 as a medicinal component
A patch containing 1% by weight, wherein the patch does not contain crotamiton, which is a solubilizer for the felbinac, and the felbinac is dispersed in the patch in a semi-molten state, and The thickness of the patch is 50-30
The patch is 0 μm.

In the felbinac-containing patch of the present invention, the felbinac is uniformly dispersed in the patch in a semi-molten state, that is, in a molten state and in a finely crystalline state. ing. The present invention
Erbinac-containing patches also contain styrene-isoprene-
Styrene block copolymer, rosin resin, plasticizer and
In a base containing l-menthol, fe
A patch containing rubinac, which comprises styrene-iso
Plane-styrene block copolymer 10 to 40% by weight,
Rosin resin 5 to 30% by weight, plasticizer 20 to 70% by weight
%, L-menthol 0.01-7% by weight, and felbi
It contains 1.1 to 10% by weight of Nak,
Does not contain crotamiton, which is a solubilizing agent,
And a thickness of 50 to 300 μm, and the above-mentioned felbinac
Is a fine crystalline state and a molten state in the base
Is evenly distributed in the state where
The molten felbinac is released from the base
As described above, the above-mentioned Felbi that is uniformly dispersed in a crystalline state
As NAK dissolves into the base material at any time,
A patch that releases the specified felbinac.
It The method for producing the patch of the present invention comprises styrene-isoprene.
-Styrene block copolymer, rosin resin, plasticizer
And l-menthol (if other additives are included,
Furthermore, mix those ingredients) in the above proportions.
As a mixture, heat and stir in an inert atmosphere to dissolve
Then, the ratio of Felbinac, which is a medicinal ingredient, to the above
Add to the above melt by heating and stir so that it becomes liquid by heat.
A method for manufacturing, which comprises a step of stirring to obtain a uniform melt.
It The production method of the present invention also includes this step and the uniform
With a release coating after spreading the melt directly onto the substrate
Cover or once the homogeneous melt is on the release coating
And spread it on the support, and spread the melt on the support.
And a step of transferring the same by pressure bonding.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION In the felbinac-containing patch of the present invention, a styrene-isoprene-styrene block copolymer, a rosin resin, a plasticizer and 1-menthol are contained in a base material each having a specific blending ratio, Felbinac as a medicinal component is contained in a specific blending ratio.
First, various base components used for constituting the patch of the present invention will be described in detail.

The styrene-isoprene-styrene block copolymer according to the present invention is a block copolymer of styrene and isoprene having polystyrene at both ends, and such a styrene-isoprene-styrene block copolymer is used. As a polymer, Califlex TR
-1107, TR-1111, TR-1112 or TR
-1117 (trade name, manufactured by Shell Chemical Co., Ltd.), JSR
SIS-5000 or 5002 (trade name, manufactured by Japan Synthetic Rubber Co., Ltd.), Quintac 3530 or 3421 (trade name, manufactured by Nippon Zeon Co., Ltd.), Sorprene 428 (trade name, manufactured by Philip Petroleum Co., Ltd.), etc. ,
One kind or a combination of two or more kinds can be used.

The blending amount of the above styrene-isoprene-styrene block copolymer is 10 to 40% by weight, preferably 15 to 35% by weight based on the whole patch. By adjusting this blending ratio, the stability of the preparation (patch),
Adhesiveness, long-term skin adhesion (adhesion persistence), drug percutaneous absorption, drug dispersibility, pain during peeling, incidence of skin irritation, etc. are greatly improved. In addition, when the above-mentioned compounding amount is less than 10% by weight, the cohesive force and shape retention of the base are deteriorated. On the other hand, when the above-mentioned compounding amount exceeds 40% by weight, the adhesive force is decreased and the adhesive (patch) is It causes non-uniformity and lower workability.

The rosin resin according to the present invention is a resin based on rosin or a rosin derivative, and rosin ester, hydrogenated rosin ester, maleated rosin and the like can be preferably used. As such a rosin resin,
Ester gum A, AA-G, H or HP (trade name, manufactured by Arakawa Chemical Co., Ltd.), Harrier Star L, S or P (trade name,
Arakawa Chemical Co., Ltd.), Pine Crystal KE-100
(Trade name, manufactured by Arakawa Chemical Co., Ltd.), KE-311 (trade name, manufactured by Arakawa Chemical Co., Ltd.), Hercoline D (trade name, manufactured by Rika Hercules Co., Ltd.), Foral 85 or 105
(Trade name, manufactured by Rika Hercules Co., Ltd.), steberite ester 7 or 10 (trade name, manufactured by Rika Hercules Co., Ltd.)
Manufactured by Rika Hercules Co., Ltd., etc., and one kind or a combination of two or more kinds can be used.

The amount of the above-mentioned rosin resin is 5 to 30% by weight, preferably 10 to 25% by weight, based on the whole patch.
Is. By using this blending ratio, the stability of the preparation, the adhesive strength, the stickiness, the percutaneous absorption of the drug, the dispersibility of the drug, the pain at the time of peeling, the incidence of skin irritation, etc. are greatly improved. If the amount is less than 5% by weight, the adhesive strength, sticking durability, and dispersibility of the drug will be reduced, and the increase in viscosity of the plaster will cause nonuniformity of the plaster and lower workability. On the other hand, if the above content exceeds 30% by weight, the percutaneous absorbability and shape retention of the drug are deteriorated, and the pain during peeling,
The incidence of skin irritation and stickiness increase.

The plasticizer according to the present invention has good compatibility with other base components and imparts flexibility to the base, and includes almond oil, olive oil, camellia oil, persic oil, peanut oil, and olefinic acid. Liquid polyisoprene, liquid polybutene, liquid paraffin and the like can be preferably used.
As such a plasticizer, one kind or a combination of two or more kinds can be used, and liquid paraffin is particularly preferable.

The blending amount of the above plasticizer is 20% of the total amount of the patch.
˜70 wt%, preferably 30-60 wt%. By adjusting this blending ratio, the stability of the formulation,
Adhesiveness, adhesion persistence, drug percutaneous absorbability, drug dispersibility, pain during peeling, incidence of skin irritation, etc. are greatly improved. If the above-mentioned compounding amount is less than 20% by weight, the adhesive strength, the percutaneous absorbability of the drug and the dispersibility of the drug will be lowered, and the increase of the viscosity of the paste will cause non-uniformity of the paste and lower workability. . On the other hand, if the above-mentioned content exceeds 70% by weight, the stability, cohesive force, and shape retention of the preparation are deteriorated, and pain at the time of peeling, stickiness and the like increase.

In the patch of the present invention, 1-menthol is further contained in the base material in addition to the above-mentioned styrene-isoprene-styrene block copolymer, rosin resin and plasticizer. The amount of l- menthol, Ru 0.01 to 7 wt% der of the total patch. By setting this blending ratio, it is possible to obtain a dispersion type patch in which felbinac is uniformly dispersed in a semi-molten state even when 1-menthol is contained.

In the patch of the present invention, felbinac as a medicinal component, namely 4-biphenyl, is added to a base containing the above-mentioned styrene-isoprene-styrene block copolymer, rosin resin, plasticizer and 1-menthol. Acetic acid is contained in a specific blending ratio. The compounding amount of felbinac in the patch of the present invention is 1.
It is 1 to 10% by weight, preferably 2 to 8% by weight, particularly preferably 3 to 7% by weight. By setting this blending ratio, the transdermal absorbability of the drug, the sustainability of the drug effect, the dispersibility of the drug, etc. are greatly improved. If the amount is less than 1.1% by weight, the percutaneous absorbability of the drug and the sustainability of the drug effect are deteriorated, and sufficient drug effect cannot be obtained. On the other hand, if the blending amount exceeds 10% by weight, the dispersibility of the drug is deteriorated and the paste is made non-uniform.

The patch of the present invention does not contain crotamiton, which is a solubilizing agent which has been recognized as essential in the past, although it contains the above-mentioned felbinac.
That is, the patch of the present invention contains the above-mentioned styrene-isoprene-styrene block copolymer, rosin resin, plasticizer, l-menthol and felbinac, and contains crotamiton which is a solubilizer for the felbinac. Alternatively, it may consist essentially of a styrene-isoprene-styrene block copolymer, a rosin resin, a plasticizer, 1-menthol and felbinac.

As described above, since the felbinac-containing patch of the present invention does not contain crotamiton, which is a solubilizer, the adhesive force does not decrease with time due to bleeding of crotamiton, and the work resulting from its use does not occur. The process is not complicated. Further, in the felbinac-containing patch of the present invention, it is necessary that felbinac is dispersed in a semi-molten state. Therefore, regarding solubilizers for felbinac other than crotamiton (that is, those capable of apparently dissolving felbinac in the base material beyond its saturation solubility), the amount of solubilizer for which felbinac is completely melted It is necessary to contain no solubilizer for felbinac (excluding 1-menthol). As described above, the inclusion of no solubilizing agent other than crotamiton tends to more reliably prevent the decrease in adhesive strength over time due to bleeding of the solubilizing agent. Examples of solubilizing agents other than such crotamiton include benzyl alcohol and diisopropanolamine.

Further, in the patch of the present invention having the above composition, although felbinac is not completely incorporated into the base in a crystalline state, it does not contain crotamiton which is the solubilizing agent. , Felbinac is uniformly dispersed in the base material in a semi-molten state, that is, a state in which a molten state and a fine crystalline state coexist. In this case, as the molten drug is released from the base, the drug uniformly dispersed in a crystalline state is dissolved into the base at any time. Thereby, in the patch of the present invention, stable drug release at a constant rate over a long period of time is realized. Therefore, JP-A-4-32162
In the felbinac-containing dispersion type patch of the present invention, the drug is not present in the base in a molten state due to the solubilizing agent as in the solubilizing agent-containing patch described in Japanese Patent No. 4 Is highly released and a sufficient pharmacological action is sustained for a long time.

The patch of the present invention preferably further contains polyisobutylene in addition to the above-mentioned styrene-isoprene-styrene block copolymer, rosin resin, plasticizer, l-menthol and felbinac. It may consist essentially of a styrene-isoprene-styrene block copolymer, a rosin-based resin, a plasticizer, 1-menthol, polyisobutylene and felbinac.

The polyisobutylene according to the present invention is a polymer of isobutylene, and examples of such polyisobutylene include Opanol B-3, B-10, B-15,
B-50, B-100, B-200 (trade name, BASF
Co., Ltd.), Vistanex LM-MS, LM-MH,
MML-80, MML-100, MML-120, MM
L-140 (trade name, manufactured by Exxon Chemical Co., Ltd.), Tetrax 3T, 4T, 5T, 6T (trade name, manufactured by Nippon Petrochemical Co., Ltd.) and the like, and may be used alone or in combination of two or more kinds. Can be used.

The amount of the polyisobutylene blended is preferably 6 to 40% by weight, more preferably 6.
It is 5 to 20% by weight. By using this blending ratio, the stability of the preparation, the adhesive strength, the stickiness, the percutaneous absorption of the drug, the dispersibility of the drug, the pain at the time of peeling, the incidence of skin irritation, etc. are greatly improved. When the above-mentioned amount is less than 6% by weight, the adhesive strength and the adhesion persistence are lowered, and the rate of occurrence of pain during peeling and skin irritation tends to increase. On the other hand, if the blending amount exceeds 40% by weight, the shape retention property tends to decrease and the stickiness tends to increase.

The patch of the present invention comprises an inorganic filler, a synthetic polymer in addition to the above-mentioned styrene-isoprene-styrene block copolymer, rosin resin, plasticizer, l-menthol, felbinac and optionally polyisobutylene. , Tackifiers, antioxidants, UV absorbers, antihistamines, antibacterial agents, may further contain other additive components such as fragrances, if necessary, among them may further contain an antioxidant. preferable. Therefore, the patch of the present invention,
It may consist essentially of a styrene-isoprene-styrene block copolymer, a rosin resin, a plasticizer, 1-menthol, polyisobutylene, an antioxidant and felbinac.

As such other additional components, inorganic fillers (aluminum hydroxide, hydrous aluminum silicate,
Synthetic aluminum silicate, kaolin, titanium oxide, talc, zinc oxide, hydrous silica, magnesium carbonate, calcium hydrogen phosphate, magnesium silicate, diatomaceous earth, silicic anhydride, bentonite, etc., synthetic polymer (polyacrylic acid-based polymer) , Synthetic polyisoprene rubber, polystyrene, polybutadiene rubber, silicone rubber, styrene-
Butylene-styrene block copolymer, styrene-isoprene block copolymer, etc.), tackifier (terpene resin, petroleum resin, etc.), antioxidant (ascorbic acid, propyl gallate, butylhydroxyanisole, dibutylhydroxytoluene ( BHT), nordihydroguaiaretinic acid, tocopherol, tocopherol acetate, etc.),
UV absorbers (para-aminobenzoic acid, para-aminobenzoic acid ester, para-dimethylaminobenzoic acid amyl, salicylate ester, methyl anthranilate, umbelliferone, esculin, benzyl cinnamate, cinoxate,
Guaiazulene, urocanic acid, 2- (2-hydroxy-5-methylphenyl) benzotriazole, 4-methoxybenzophenone, 2-hydroxy-4-methoxybenzophenone, octabenzone, dioxybenzone, dihydroxydimethoxybenzophenone, sulin benzone, benzolercinol, octyl Dimethylparaaminobenzoate, ethylhexylparamethoxycinnamate, etc., antihistamines (isopentyl chloride, diphenhydramine hydrochloride, iproheptin hydrochloride, diphenylpyraline hydrochloride, cyproheptadine hydrochloride, triprrolidine hydrochloride, promethazine hydrochloride, homochlorcyclidine hydrochloride, alimemazine tartrate, diphenhydramine tannate, Diphenylpyraline theoclate, clemastine fumarate,
Chlorpheniramine maleate, dimethindene maleate, mequitazine, etc.), antibacterial agents (paraoxybenzoic acid ester, benzoic acid, benzoate, salicylate, sorbic acid, sorbate, dehydroacetate, 4-isopropyl-3-methyl) Phenol, 2-isopropyl-5-methylphenol, hinokitiol, cresol, 2,4
4-trichloro-2'-hydroxydiphenyl ether, 3,4,4'-trichlorocarbanide, chlorobutanol, benzalkonium chloride, benzethonium chloride, etc.), a cooling agent, and a fragrance other than 1-menthol.

The blending amount of such other additive components is preferably 0.01 to 7% by weight, more preferably 0.1 to 5% by weight, based on the whole patch. Of these other additive components, the amount of the antioxidant added is preferably 0.
It is 1 to 5% by weight, more preferably 0.5 to 2% by weight. If the above-mentioned amount is less than the lower limit, deterioration of the base material occurs over time, the amount of the paste remains, and stickiness tends to increase.On the other hand, if the amount exceeds the upper limit, the cohesive strength of the preparation and the shape retention Properties tend to decrease, and pain during peeling, stickiness, etc. tend to increase.

The thickness of the patch of the present invention (patch layer) prepared using the above-mentioned components (excluding the thickness of the support and the release coating described later) is 50 to 300 μm, preferably 80. Is about 200 μm. By adjusting the thickness within this range, the adhesiveness, cohesive force, adhesion persistence, pain at the time of peeling, etc. are greatly improved. The thickness is 5
If the thickness is less than 0 μm, the tackiness and sticking durability will be reduced, while if the thickness exceeds 300 μm, the cohesive force and shape retention will be reduced.

The patch of the present invention as described above is highly stretchable and can be stretched freely in the vertical and horizontal directions. As described above, the patch of the present invention has a high stretchability together with excellent adhesiveness, so that it has a stretchable support which is difficult to use in the conventional solubilizing agent-containing patch. It can be used and a high level of sticking feeling is achieved.

The above-mentioned patch containing felbinac of the present invention is
It has the following excellent properties. 1) It has excellent adhesiveness by making it an oily patch,
It can be attached to elbows, knees, etc. without bending for a long time. 2) Since the drug is dispersed in a semi-molten state at a concentration equal to or higher than the saturated solubility, the expected drug effect is exhibited for a long time. 3) Since it is an oily base that does not contain water, it has an excellent heat retaining effect on the application site and can be used for chronic inflammation and the like. 4) Since no solubilizer, absorption promoter, etc. are used, the work process is simplified and the stability of the preparation over time is excellent. 5) By using an oil-based patch, the thickness can be reduced and the fit feeling during sticking is excellent. 6) The conventional solubilizing agent-containing patch (plaster) was not sufficiently tacky, so that its size was limited to about 80 cm ² or less. On the other hand, the patch of the present invention has extremely high adhesiveness due to the fact that it does not contain a solubilizer, and the size thereof can be 100 cm ² or more. As described above, the patch of the present invention can be made to have the same size as a conventional poultice, and more excellent in adhesiveness and elasticity than the poultice.

The above-mentioned patch of the present invention is preferably spread on a support. As such a support, a support that does not affect the release of the drug from the patch of the present invention is desirable, and a stretchable or non-stretchable support can be used. Examples of the support usable in the present invention include polyethylene, polypropylene, polybutadiene, ethylene vinyl acetate copolymer, polyvinyl chloride, polyester, nylon, polyurethane, and other synthetic resin films, sheets, sheet-like porous bodies, sheet-like bodies. Examples include foams, woven or non-woven fabrics, papers, woven fabrics, non-woven fabrics, and laminates of these.

Among these patch bases, stretchability is required.
A support having is preferable, and particularly a stretchable polyester woven fabric.
Is preferred. Also, such elastic polyester woven
As the cloth, sample width 50mm, sample length 200mm and stretch
30% mod under long strength 200mm / min measurement condition
Lath (tensile strength) test, longitudinal strength 200g
~ 3kg and transverse strength 100g ~ 600g
Is preferred. Furthermore, the basis weight of the support according to the present invention
(Weight per unit area) is 100 ± 30g / m ²And
Preferably.

As described above, since the patch of the present invention has a high expansion / contraction rate, it is difficult to use a conventional solubilizer-containing patch, and a highly elastic support is particularly preferable. Makes it possible to use stretchable polyester woven fabrics. By using such a stretchable polyester woven fabric, the patch of the present invention tends to be excellent in the following points. That is, i) The conventional solubilizing agent-containing patch was easily peeled off due to its movement even when it was applied to a flexed portion such as a joint where the movement was strong. On the other hand, in the patch of the present invention, the polyester woven fabric expands and contracts freely in the vertical and horizontal directions according to the movement of the skin, so that it does not have a tight feeling and is firmly adhered for a long time. ii) Since the polyester woven fabric has appropriate flexibility, it is easy to stick and peel off. iii) The anchoring property is improved (the plaster penetrates into the support and the adhesive strength is retained), and the stretchability is retained.

Next, a preferred example of the method for producing the felbinac-containing patch of the present invention will be described.

First, a styrene-isoprene-styrene block copolymer, a rosin-based resin, a plasticizer and 1-menthol (polyisobutylene, and other additives when they are contained) are added in predetermined proportions. The mixture is mixed into a mixture, and the mixture is heated and stirred under an inert atmosphere such as nitrogen to obtain a dissolved substance. The temperature during stirring is preferably 110 to 200 ° C., and the stirring time is preferably 30 to 120 minutes. Subsequently, felbinac, which is a medicinal component, is added to the above-mentioned melt, and preferably 110 to 200 ° C., preferably 5 to 3 ° C.
Stir for 0 minutes to obtain a homogeneous lysate. In this melt, felbinac is preferably liquid due to heat.

Next, the melt is spread directly on the support by a conventional method and then covered with a release coating, or once the melt is spread on the release coating and then coated on the support. Alternatively, the melted product may be transferred by pressure onto the support. Examples of such a release coating include release paper that has been subjected to a release treatment (treatment for facilitating release), cellophane, or a synthetic resin film of polyethylene, polypropylene, polyester, or the like. By the above production method, the patch of the present invention in which felbinac is uniformly dispersed in the base material in a semi-molten state can be obtained.

Each base component in the above-mentioned production method,
The order of mixing the medicinal component and other additive components is only one example, and the method for producing the adhesive patch of the present invention is not limited to this mixing order.

[0037]

EXAMPLES Hereinafter, the felbinac-containing patch of the present invention will be described more specifically with reference to Examples, Reference Examples and Comparative Examples. The felbinac-containing patch of the present invention is the same as those described in the following examples. It is not limited. In Examples, Reference Examples and Comparative Examples, "parts" and "%" mean "parts by weight" and "% by weight", respectively, unless otherwise specified.

Reference Example 1 Styrene-isoprene-styrene block copolymer 25.0 parts (trade name: Califlex TR-1107) Liquid paraffin 47.0 parts Rosin resin 12.0 parts (trade name: ester gum H) Polyisobutylene 10.0 parts (trade name: Opanol B-10) Dibutylhydroxytoluene 1.0 part Felbinac 5.0 parts.

A patch was prepared according to the above-mentioned manufacturing method with the above formulation. That is, various components other than felbinac in the above formulation are mixed to form a mixture, and
Stir at 40 ° C. to 90 ° C. for 40 to 90 minutes to give a melt. Subsequently, felbinac, which is a medicinal component, was added to the melt, and the mixture was stirred at 130 to 180 ° C for 3 to 20 minutes to obtain a uniform melt. Next, this melt was placed on a support (woven fabric made of polyester) and the thickness of the obtained patch layer was 50.
After being spread to a size of μm, it was covered with a release coating (polyester film), and after cooling it was cut to the desired size to obtain a dispersion-type patch in which felbinac was uniformly dispersed in a semi-molten state. It was In addition, the polyester woven fabric used was a 30% modulus test (sample width 50 mm,
A sample length of 200 mm, an elongation strength of 200 mm / min, and an autograph AGS-100B (manufactured by Shimadzu Corporation) have a longitudinal strength of 210 to 300 g and a lateral strength of 1.
It was from 0.00 to 170 g and had a basis weight of 110 ± 20 g / m ² .

Reference Example 2 Styrene-isoprene-styrene block copolymer 30.0 parts (trade name: Califlex TR-1111) Liquid paraffin 39.0 parts Rosin-based resin 20.0 parts (trade name: Pine Crystal KE- 100) Polyisobutylene 6.0 parts (trade name: Opanol B-50) Dibutylhydroxytoluene 1.0 part Felbinac 4.0 parts.

A patch was prepared in the same manner as in Reference Example 1 except that the prescription was changed to the above and the thickness of the patch layer was 100 μm. As a result, felbinac was uniformly dispersed in a semi-molten state. A patch was obtained.

Reference Example 3 Styrene-isoprene-styrene block copolymer 20.0 parts (trade name: Califlex TR-1112) liquid paraffin 46.0 parts rosin resin 15.0 parts (trade name: steberite ester 7) ) Polyisobutylene 15.0 parts (Brand name: Opanol B-100) Dibutylhydroxytoluene 1.0 part Felbinac 3.0 parts.

A patch was prepared in the same manner as in Reference Example 1 except that the patch was changed to the above formulation and the thickness of the patch layer was 140 μm. As a result, felbinac was uniformly dispersed in a semi-molten state. A patch was obtained.

Reference Example 4 Styrene-isoprene-styrene block copolymer 23.0 parts (trade name: Califlex TR-1117) Liquid paraffin 40.0 parts Rosin resin 25.0 parts (trade name: KE-311) Polyisobutylene 8.0 parts (trade name: Opanol B-200) Dibutylhydroxytoluene 1.0 part Felbinac 3.0 parts.

A patch was prepared in the same manner as in Reference Example 1 except that the prescription was changed to the above and the thickness of the patch layer was 300 μm. As a result, felbinac was uniformly dispersed in a semi-molten state. A patch was obtained.

Reference Example 5 Styrene-isoprene-styrene block copolymer 20.0 parts (trade name: JSR SIS-5000) Liquid paraffin 41.0 parts Rosin resin 15.0 parts (trade name: Foral 105) Polyisobutylene 20.0 parts (trade name: Vistanex LM-MS) Dibutylhydroxytoluene 1.0 part Felbinac 3.0 parts.

A patch was prepared in the same manner as in Reference Example 1 except that the formulation was changed to the above and the thickness of the patch layer was 200 μm. As a result, felbinac was uniformly dispersed in a semi-molten state. A patch was obtained.

Reference Example 6 Styrene-isoprene-styrene block copolymer 15.0 parts (trade name: JSR SIS-5002) Liquid paraffin 58.0 parts Rosin resin 15.0 parts (trade name: steberite 10) Polyisobutylene 7.0 parts (trade name: Vistanex LM-MH) 1.0 part dibutylhydroxytoluene 4.0 parts felbinac.

A patch was prepared in the same manner as in Reference Example 1 except that the prescription was changed to the above and the thickness of the patch layer was 80 μm. As a result, felbinac was uniformly dispersed in a semi-molten state. A patch was obtained.

Reference Example 7 Styrene-isoprene-styrene block copolymer 35.0 parts (trade name: Quintac 3530) Liquid paraffin 35.0 parts Rosin-based resin 15.0 parts (trade name: Foral 85) Polyisobutylene 10 0.0 parts (trade name: Vistanex MML-140) Dibutylhydroxytoluene 1.0 parts Felbinac 4.0 parts.

A patch was prepared in the same manner as in Reference Example 1 except that the prescription was changed to the above and the thickness of the patch layer was 160 μm. As a result, felbinac was uniformly dispersed in a semi-molten state. A patch was obtained.

Reference Example 8 Styrene-isoprene-styrene block copolymer 25.0 parts (trade name: Quintac 3421) liquid paraffin 30.0 parts rosin resin 22.0 parts (trade name: pentaline 4820) polyisobutylene 15 0.0 parts (trade name: Tetrax 3T) Dibutylhydroxytoluene 1.0 part Felbinac 7.0 parts.

A patch was prepared in the same manner as in Reference Example 1 except that the patch was changed to the above formulation and the thickness of the patch layer was 120 μm. As a result, felbinac was uniformly dispersed in a semi-molten state. A patch was obtained.

Example 1 Styrene-isoprene-styrene block copolymer 25.0 parts (trade name: Sorprene 428) Liquid paraffin 36.0 parts Rosin resin 25.0 parts (trade name: Hercoline D) Polyisobutylene 7. 5 parts (trade name: Tetrax 5T) Dibutylhydroxytoluene 1.0 part 1-menthol 0.5 part Felbinac 5.0 parts.

A patch was prepared in the same manner as in Reference Example 1 except that the formulation was changed to the above and the thickness of the patch layer was 160 μm. As a result, felbinac was uniformly dispersed in a semi-molten state. A patch was obtained.

Example 2 Styrene-isoprene-styrene block copolymer 15.0 parts (trade name: Quintac 3421) liquid paraffin 40.0 parts rosin resin 10.0 parts (trade name: Harrier Star L) polyisobutylene 30.0 parts (trade name: Tetrax 6T) dibutylhydroxytoluene 1.0 part l-menthol 1.0 part felbinac 3.0 parts.

A patch was prepared in the same manner as in Reference Example 1 except that the formulation was changed to the above and the thickness of the patch layer was 180 μm. As a result, felbinac was uniformly dispersed in a semi-molten state. A patch was obtained.

Example 3 A patch was prepared in the same manner as in Example 1 except that polyisobutylene was not added.

Reference Example 9 A patch was prepared in the same manner as in Reference Example 3, except that the thickness of the patch layer was 50 μm.

Reference Example 10 A patch was prepared in the same manner as in Reference Example 3, except that the thickness of the patch layer was 80 μm.

Reference Example 11 A patch was prepared in the same manner as in Reference Example 3 except that the thickness of the patch layer was 200 μm.

Reference Example 12 A patch was prepared in the same manner as in Reference Example 3 except that the thickness of the patch layer was 300 μm.

Comparative Example 1 Styrene-isoprene-styrene block copolymer 20.0 parts (trade name: Califlex TR-1112) Liquid paraffin 52.0 parts Rosin resin 15.0 parts (trade name: KE-311) Polyisobutylene 5.0 parts (trade name: Tetrax 4T) Dibutyl hydroxytoluene 2.0 parts Crotamiton 5.0 parts Felbinac 1.0 parts.

A patch was prepared in the same manner as in Reference Example 5 except that the formulation was changed to the above formulation, that is, crotamiton was blended as a solubilizing agent for felbinac. As a result, felbinac was completely melted by the solubilizing agent. A soluble adhesive patch was obtained. In this comparative example,
Felbinac was dissolved in crotamiton and added to the melt.

Comparative Example 2 A patch was prepared in the same manner as in Reference Example 5 except that felbinac which was a medicinal component was not added.

Comparative Example 3 A patch was prepared in the same manner as Reference Example 3 except that the thickness of the patch layer was 30 μm.

Comparative Example 4 A patch was prepared in the same manner as in Reference Example 3, except that the thickness of the patch layer was 350 μm.

Test Example 1 (Stability Test: Adhesive Strength) Example 2, Reference Example 3, Reference Example 5, Reference Example 7 and Comparative Example 1
The stability of the adhesive force of the patch obtained in 1. was evaluated as follows. That is, each patch (size 10 cm x 14
cm) immediately after production (initial), stored at 40 ° C. for 3 months, and stored at 40 ° C. for 6 months, and the adhesive force was measured by a probe tack test method (apparatus used: PROVETACK TESTER). The results obtained are shown in Table 1.

[0069]

[Table 1]

As is clear from the results shown in Table 1, the adhesive patches obtained in Example 2, Reference Example 3, Reference Example 5 and Reference Example 7 were stable in adhesive strength, but were compared. The adhesive strength of the patch obtained in Example 1 decreased with time due to bleeding of crotamiton.

Test Example 2 (Stability Test: Hairless Mouse Skin Permeation Test) Using the initial patch of each of the patches obtained in Reference Example 5 and Comparative Example 1 and one stored at 40 ° C. for 6 months, the following procedure was performed. A hairless mouse skin permeation test was performed. That is, a patch cut to a diameter of 10 mm was applied to the exfoliated back skin of a hairless mouse (female, 7 weeks old), and the patch was attached to a flow-through type cell such that the dermis side became the receptor phase. And receptor fluid (phosphate buffer of pH 7.4)
Was flown at a flow rate of 0.8 ml / hr, and the amount of felbinac permeated into the receptor solution was measured using HPLC. The obtained results are shown in FIG.

As is clear from the results shown in FIG. 1, the patch obtained in Reference Example 5 showed stable drug release even after being stored at 40 ° C. for 6 months, and was obtained in Comparative Example 1. The drug release was stable and sustained over a long period of time as compared with the obtained patch.

Test Example 3 (Carrageenin paw edema test) 1 group of 1 male Wistar rat weighing about 135 g
5 animals each were used. Each of the patch obtained in Reference Example 5, the patch obtained in Comparative Example 2 and a commercially available felbinac-containing patch (trade name: Celtouch, manufactured by Nippon Redery Co., Ltd.) was cut into a size of 3 cm × 4 cm, and The patch (or patch) was applied to the right hind paw of the rat for 4 hours and then removed, and 0.1 ml of a 1% carrageenin solution was immediately subcutaneously injected to the same site to induce the reaction. The paw volume was measured 3 hours after the induction of the reaction, and the edema rate was calculated based on the paw volume before the injection. The obtained results are shown in FIG. The control is an example in which the patch (or patch) was not applied.

As is clear from the results shown in FIG. 2, no effect on the carrageenin paw edema was observed with the patch obtained in Comparative Example 2 containing no felbinac, but obtained in Reference Example 5. The patch showed a strong anti-inflammatory effect, and its strength was equivalent to that of the commercially available felbinac-containing patch.

Test Example 4 (Adhesion Test) The patch (size: 10 cm × 14 cm) obtained in Example 1 and Example 3 was applied to 30 healthy adult men and women on the left and right knees, respectively, and after about 6 hours. Adhesiveness and pain during peeling were evaluated according to the following criteria.

[Judgment Criteria] (Adhesiveness) Completely adhered 5 points, partial exfoliation of the edge 4 points, 1/3 or more exfoliated 3 points, 1/2 or more exfoliated 2 points, complete detachment 1 point (pain during exfoliation) No pain 5 points, less pain 4 points, a little pain 3
Table 2 shows the average value of the scores of 30 people.

[0077]

[Table 2]

As is clear from the results shown in Table 2, the adhesive patches obtained in Examples 1 and 3 have good adhesiveness, but the adhesive patch obtained in Example 1 is It can be said that this patch has excellent adhesiveness and little pain at the time of peeling and is very excellent in use.

Test Example 5 (Adhesion Test) The patches (size: 10 cm × 14 cm) obtained in Reference Examples 3, 9, 10, 11 and 12 and Comparative Examples 3 and 4 were used by 30 healthy adult men and women, respectively. It was attached to the knee, and after about 6 hours, the adhesiveness was evaluated according to the following criteria.

[Judgment Criteria] (Adhesiveness) Completely adhered 5 points, partial exfoliation at the edge 4 points, 1/3 or greater exfoliation 3 points, 1/2 or greater exfoliation 2 points, complete exfoliation 1 point Average of 30 persons The values are shown in Table 3.

Test Example 6 (Stability Test: Shape Retention) The patches (size: 10 cm × 14 cm) obtained in Reference Examples 3, 9, 10, 11 and 12 and Comparative Examples 3 and 4 were each heated at 50 ° C. After storing for 2 months at 1, the shape was evaluated according to the following criteria.

[Criteria] Good shape was maintained: ○ Some swelling of the plaster was observed: △ Severe swelling of the plaster was observed: × The results obtained are shown in Table 3.

[0083]

[Table 3]

As is clear from the results shown in Table 3, the adhesive patches obtained in Reference Examples 3, 9, 10, 11 and 12 were good in adhesiveness and in shape after storage at 50 ° C. for 2 months. However, the patch obtained in Comparative Example 3 did not have sufficient adhesiveness, and the patch obtained in Comparative Example 4 was 2 ° C at 50 ° C.
After storage for 6 months, the shape was not sufficient.

[0085]

As described above, according to the present invention,
Despite being a dispersive patch that does not contain crotamiton, which is a solubilizer, the drug release is high and its sufficient pharmacological action (anti-inflammatory action) is sustained for a long time, and its adherence to the skin is long. Maintained at a high standard over time,
It is possible to obtain a felbinac-containing patch with excellent stability of the preparation and less skin irritation.

Therefore, the present invention can provide a felbinac-containing patch useful as an external anti-inflammatory analgesic patch.

[Brief description of drawings]

FIG. 1 is a graph showing the results of a skin permeation test using hairless mice.

FIG. 2 is a graph showing the results of a carrageenin paw edema test in rabbits.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI A61P 29/00 A61P 29/00 (56) References JP-A-8-291055 (JP, A) JP-A-7-238014 (JP , A) JP-A-55-133310 (JP, A) International publication 98/024423 (WO, A1) International publication 96/008245 (WO, A1) (58) Fields investigated (Int.Cl. ⁷ , DB name) A61K 31/192 A61K 9/70 A61K 47/10 A61K 47/32 A61K 47/34 A61P 29/00

Claims (10)

(57) [Claims] 1. A styrene-isoprene-styrene block copolymer 10 to 40% by weight, a rosin resin 5 to 30% by weight, a plasticizer 20 to 70% by weight, and 1-menthol 0.0.
1 to 7% by weight, and felbinac as a medicinal ingredient 1.
A patch containing 1 to 10% by weight, wherein the patch does not contain crotamiton, which is a solubilizer for felbinac, and the felbinac is dispersed in the patch in a semi-molten state. And the thickness of the patch is 5
A patch having a thickness of 0 to 300 μm. Wherein said felbinac is uniformly dispersed in the adhesive patch in a state in which the thing and what the fine crystalline state of a molten state coexist, plaster of claim 1 Symbol placement. 3. Styrene-isoprene-styrene block
Copolymer, rosin resin, plasticizer and l-menthol
Felbinac as a medicinal component is contained in the base containing
Which is a styrene-isoprene-styrene block copolymer 10
-40% by weight, rosin resin 5-30% by weight, plasticizer 2
0-70 wt%, l-menthol 0.01-7 wt%,
And felbinac 1.1 to 10% by weight.
Contains crotamiton, a solubilizer for Erbinac
Not not be, and the thickness is 50~300μm, before
Felbinac is available in the state of being melted in the above base and in the form of fine crystals.
And are evenly dispersed in the coexisting state and melt
The felbinac being released from the base
Therefore, the felbinac is uniformly dispersed in the crystalline state.
Is dissolved in the base material at any time to stabilize
A patch, which releases the above-mentioned felbinac. 4. The patch according to claim 1, further comprising 6 to 40% by weight of polyisobutylene. 5. The patch according to any one of claims 1 to 4 , further comprising 0.1 to 5% by weight of an antioxidant. 6. The patch according to claim 1, further comprising a support made of a stretchable polyester woven fabric. 7. The stretchable polyester woven fabric has a sample width of 50 mm, a sample length of 200 mm and an elongation strength of 200 mm /
In the 30% modulus test under the measurement condition of min,
Longitudinal strength 200g-3kg and lateral strength 100g-
The adhesive patch according to claim 6, which shows 600 g. 8. The basis weight of the support is 100 ± 30 g / m.
The patch according to claim 6 or 7, which is ² . 9. The method according to any one of claims 1 to 5.
The method for producing a patch as described above, which comprises a styrene-isoprene-styrene block copolymer,
Gin-based resin, plasticizer and l-menthol (other additives
In case of containing
Mix in the indicated proportions to form a mixture and heat in an inert atmosphere.
Stir to give a dissolved substance, followed by the medicinal ingredient, felbi.
Nak is added to the melt in the above proportions and heated to
Include a step to stir the body to obtain a uniform melt.
Mu, the manufacturing method. 10. The method according to any one of claims 6 to 8.
A method for producing the patch according to claim 1, which comprises a styrene-isoprene-styrene block copolymer,
Gin-based resin, plasticizer and l-menthol (other additives
In case of containing
Mix in the indicated proportions to form a mixture and heat in an inert atmosphere.
Stir to give a dissolved substance, followed by the medicinal ingredient, felbi.
Nak is added to the melt in the above proportions and heated to
A step of stirring to form a uniform solution to obtain a uniform solution, and a step of directly spreading the uniform solution on the support and then peeling the solution.
Cover with a release coating or once remove the homogeneous melt.
After spreading on the release coating, the melted material is covered on the support.
And a step of pressure-transferring it onto a support.
Law.