JPH06199660A - Patch and its production - Google Patents

Abstract

PURPOSE:To obtain a patch having excellent water vapor transmission low irritation to the skin and excellent releasability of medicine. CONSTITUTION:A tacky agent comprising a rubber-based tacky agent, cellulose particles of one or more celluloses selected from the group consisting of crystalline cellulose, methyl cellulose and hydroxypropyl cellulose, having 1-150mum particle diameters, a polyhydric alcohol, water and a medicine is laminated to one side of a substrate having water vapor transmission and the cellulose particles exist in a particulate state in the tacky agent layer to give a patch. The cellulose particles of one or more celluloses selected from the group consisting of crystalline cellulose, methyl cellulose and hydroxypropyl cellulose, having 1-150mum particle diameters, are dispersed into a mixed solution of the polyhydric alcohol and water to give a dispersion. The dispersion and the medicine are blended with the rubber-based tacky agent and the blend is applied to one side of the substrate having water vapor transmission by hot-melt coating.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a patch having good moisture permeability, low skin irritation and excellent drug release, and a method for producing the same.

[0002]

BACKGROUND OF THE INVENTION A patch is a preparation for administering a drug to the circulatory system of the body through the skin, in which an adhesive layer composed of an adhesive and a drug is laminated on one surface of a support. It is excellent in the sustainability of blood concentration and the convenience of drug administration method. The adhesives used in this patch include acrylic adhesives, rubber adhesives, silicone adhesives, etc. Among them, rubber adhesives are widely used because they have excellent adhesiveness and elasticity. ing. When a rubber-based pressure-sensitive adhesive was used as the pressure-sensitive adhesive of the patch, when it was applied to the skin surface due to its hydrophobic components, skin problems such as rash due to the pressure-sensitive adhesive were likely to occur.

As a patch for solving such a problem, Japanese Patent Application Laid-Open No. 1-297069 discloses a pressure-sensitive adhesive composition comprising a rubber-based pressure-sensitive adhesive and a water-absorbing polymer that absorbs water and gels and swells as a base material. Laminated patches have been proposed, and Japanese Patent Publication No. 5
JP-A-4-44688 proposes a patch in which a pressure-sensitive adhesive composition comprising a rubber-based pressure-sensitive adhesive, a water-soluble polyol and a water-swellable polymer is laminated on a breathable base material.

In the above-mentioned patch, the polarity of the rubber-based adhesive is improved and the rash caused by the adhesive is reduced, but the sweat produced during the sweating exercise is absorbed by the water-absorbing polymer or the water-swelling polymer to evaporate water. Is less likely to occur, and the moisture permeability gradually deteriorates, causing unevenness.

Further, Japanese Patent Publication No. 3-67044 proposes a poultice which comprises a rubber-based pressure-sensitive adhesive to which a hydrophilic polymer aqueous solution comprising a hydrophilic polymer, a polyhydric alcohol and water and a medicinal component are added. However, this poultice has a defect that it has a poor moisture-releasing property although it has a water vaporization route and improves moisture permeability.

[0006]

In view of the above-mentioned drawbacks, the present invention provides a patch having good moisture permeability, low skin irritation, and good drug release from an adhesive layer, and a method for producing the same. The purpose is to provide.

[0007]

The rubber-based pressure-sensitive adhesive used in the present invention comprises a rubber elastic body, a tackifier and a softening agent.

Examples of the rubber elastic body include natural rubber, styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer, styrene-ethylene / butadiene-styrene block copolymer, and styrene-olefin. -Styrene block copolymers, polyisoprene, polybutene, polyisobutylene and the like, styrene-isoprene-styrene block copolymers, styrene-butadiene-styrene block copolymers, styrene-ethylene-butadiene-styrene block copolymers , ABA type block copolymers such as styrene-olefin-styrene block copolymers are preferably used.

Commercially available products of the above ABA type block copolymer include Califlex T manufactured by Shell Chemical Co., Ltd.
R-1101, TR-1102, TR-1107 etc. are mentioned.

The content of the rubber elastic body in the rubber adhesive is
When the amount is too small, the adhesive strength is lowered, and when the amount is too much, the adhesive strength becomes too high.
~ 25% by weight.

As the above-mentioned tackifier, those generally used as tackifiers for rubber-based pressure-sensitive adhesives can be used. Examples thereof include rosin-based resins, polyterpene resins, coumarone-indene resins, petroleum-based resins, and terpene-phenols. Examples include resins.

The content of the tackifier in the rubber-based adhesive is
When the amount is too small, the adhesive strength is lowered, and when the amount is too large, the adhesive strength becomes too high. Therefore, 20 to 50% by weight is preferable, and 25 to 45% by weight is more preferable.

Examples of the softening agent include liquid paraffin, liquid polybutene, mineral oil, lanolin, liquid polyisoprene, liquid polyacrylate, hexamethyltetracosan, hexamethyltetracohexaene and α-olefin oligomer. To be

If the content of the softening agent in the rubber-based pressure-sensitive adhesive is low, the pressure-sensitive adhesive strength will be high, and if it is high, the pressure-sensitive adhesive strength will be low and adhesive residue will remain.
Is preferable, and more preferably 30 to 55% by weight.

If necessary, a filler such as calcium carbonate or titanium oxide, an antiaging agent such as butylhydroxytoluene, or the like may be added to the rubber-based pressure-sensitive adhesive.

The cellulose particles used in the present invention are selected from the group consisting of crystalline cellulose, methyl cellulose and hydroxypropyl cellulose, and one kind or a combination of two or more kinds is used. The particle size of the cellulose particles is from 1 to 150 μm, and preferably from 10 to 120 μm, because if the particle size is too small, the drug release property deteriorates, and if it is too large, the dispersibility in the adhesive becomes poor.

The above-mentioned crystalline cellulose powder is pure microcrystalline cellulose in which α-cellulose is partially depolymerized with a mineral acid and mainly contains a crystalline region of cellulose (11th revised Japanese Pharmacopoeia Manual). , D-537), for example, the product name Avicel manufactured by Asahi Kasei.

The above-mentioned methylcellulose is methyl ether of cellulose (11th revised Japanese Pharmacopoeia Manual, D
-934), for example, Shin-Etsu Chemical Co., Ltd., trade name Metroze SM-25.

The above-mentioned hydroxypropyl cellulose is a hydroxypropyl ether of cellulose (11th revised Japanese Pharmacopoeia manual, D-773), for example, manufactured by Shin-Etsu Chemical Co., trade name Shin-Etsu HPCMF-P, manufactured by Nippon Soda Co., Ltd., Product name HPC-H and the like can be mentioned.

If the amount of cellulose particles added is too small, the polyhydric alcohol and water will not be uniformly dispersed in the adhesive,
The moisture permeability of the pressure-sensitive adhesive layer becomes poor, and if the amount is too large, the pressure-sensitive adhesiveness will decrease.
Parts by weight, preferably 5 to 35 parts by weight.

Examples of the polyhydric alcohol used in the present invention include glycerin, ethylene glycol, propylene glycol, butylene glycol, hexylene glycol, polyethylene glycol, polypropylene glycol, polyoxyethylene-polyoxypropylene copolymer and the like. can give.

The above polyhydric alcohols may be added alone or in combination of two or more kinds. If the amount of addition is too small, the moisture permeability of the pressure-sensitive adhesive layer deteriorates, and if it is too large, the pressure-sensitive adhesive layer is added. Since it becomes difficult to disperse in the adhesive and the adhesive remains after peeling off the patch, the amount is 1 to 30 parts by weight, preferably 5 to 25 parts by weight, relative to 100 parts by weight of the rubber-based pressure-sensitive adhesive.

If the amount of water present in the patch of the present invention is too small, the drug release property becomes poor, and if it is too large, the tackiness becomes poor.
It is 5 to 25 parts by weight, and preferably 1 to 15 parts by weight.

The drug used in the present invention may be any drug which can permeate a biological membrane transdermally, and typical drugs include indomethacin, isosorbide nitrate and ketoprofen.

The drug used in the present invention is not limited to those mentioned above, and examples thereof include non-steroidal anti-inflammatory agents, corticosteroid agents, antihistamine agents, antipruritic agents, antihypertensive agents, anesthetic agents, antifungal agents, Antiepileptic agent, coronary vasodilator,
Hormones, muscle relaxants, anti-inflammatory / analgesics, local stimulants and the like can be mentioned.

Examples of the non-steroidal anti-inflammatory agents include piroxicam, phenylbutazone, acetylsalicylic acid, flufenamic acid, ibuprofen, ketoprofen, flurbiprofen, sulindac, indomethacin, diclofenac, amphenac, fenbufen, tinolidine, emorfazone, etc. Can be given.

Examples of the corticosteroid agents include pretonisolone, clobetasol propionate and the like. Examples of the antihistamine include the following:
Examples include diphenhydramine, diphenylimidazole and chlorpheniramine. As the above antipruritic agent,
Examples include crotamiton.

Examples of the above-mentioned antihypertensive agents include clonidine, nifedipine, propranol and the like. Examples of the anesthetic include lidocaine and benzocaine.

Examples of the antifungal agent include clotrimazole, pentamycin and the like. Examples of the antiepileptic agent include nitrozepam, meprobamer and the like.

Examples of the coronary vasodilators include nitroglycerin and isosorbide dinitrate. Examples of the hormone agent include estradiol and the like.

Examples of the muscle relaxant include eperisone hydrochloride. As the above anti-inflammatory and analgesic agents,
Examples thereof include methyl salicylate, glycol salicylate, glycyrrhizinic acid, glycyrrhetinic acid, borneol, abacus powder and berberyl hydrochloride.

Examples of the above local stimulants include capsicum powder, capsicum extract, capsicum tincture, capsaicin, nonyl acid vanillyl amide, turpentine oil, dl-camphor, benzyl nicotinate, nicotinic acid-β-butoxyethyl, peppermint oil, 1 -Menthol, eucalyptus oil and the like.

The amount of the above-mentioned drug added varies depending on the type of drug and the purpose of use of the patch, but if it is too small, the desired drug effect cannot be expected, and if it is too large, further drug effect cannot be expected and drug damage occurs. As a result, the compatibility with the rubber-based pressure-sensitive adhesive is deteriorated, so that it is 0.1 to 30 parts by weight with respect to 100 parts by weight of the rubber-based pressure-sensitive adhesive.

In order to improve the absorption of the drug in the body, lactic acid, maleic acid, fumaric acid, N-lauroylsarcosine (salt), polyoxyethylene alkyl ether (salt), polyoxyethylene alkylphenyl ether. An absorption promoter such as (salt) may be added to the pressure-sensitive adhesive.

The support used in the present invention preferably has a moisture permeability and is flexible enough to follow the expansion and contraction of the skin when applied, and examples thereof include polyester, polyethylene, polyvinyl chloride, and polychloride. Examples thereof include perforated films of plastics such as vinylidene, polyethylene-vinyl acetate copolymer, polyurethane and cellulose acetate having a pore size of 0.1 to 60 μm, woven or non-woven fabrics of these plastics, paper and polyurethane films.

The thickness of the non-woven fabric, woven fabric or paper is 5 to 2000
The thickness of the polyurethane film and the perforated plastic film is preferably 5 to 100 μm.

The pressure-sensitive adhesive of the present invention comprises the above-mentioned rubber-based pressure-sensitive adhesive, cellulose particles, polyhydric alcohol, water and a drug, and is laminated on one surface of the above-mentioned support to form a pressure-sensitive adhesive layer. The particles are present as particles in the pressure-sensitive adhesive layer. The thickness of the pressure-sensitive adhesive layer varies depending on the purpose of use, but is preferably 10 to 400 μm.

The patch is usually provided with a release paper on its surface in order to protect the surface of the adhesive layer until use. As the release paper, polyester film, polypropylene film, polyethylene-coated high-quality paper, polyethylene-coated glassine paper, and polyolefin-coated glassine paper treated with silicon are preferably used. The thickness of the release paper is preferably 1000 μm or less, more preferably 20 to 200 μm.

As the method for producing the patch of the present invention, any method may be adopted as long as the cellulose particles are present in the pressure-sensitive adhesive layer in the form of particles, for example, 100 parts by weight of a rubber-based pressure-sensitive adhesive and crystalline cellulose. 70% of a mixture consisting of 1 to 40 parts by weight of cellulose particles having a particle size of 1 to 150 μm and 0.1 to 30 parts by weight of a drug selected from the group consisting of methyl cellulose and hydroxypropyl cellulose.
1 to 30 parts by weight of polyhydric alcohol and 1 to 70 parts by weight of water are added to the melt obtained by heating and melting at ~ 110 ° C, and 5
After kneading for about 60 minutes, a hot melt coater may be used to coat one surface of the support having moisture permeability at 70 to 110 ° C.

However, the production method of the present invention 2 is preferable, in which a dispersion liquid in which cellulose particles are dispersed in a mixed liquid of a polyhydric alcohol and water is used.

In the production method of the present invention 2, first, the rubber-based pressure-sensitive adhesive is melted and kept at 70 to 110 ° C. The melt-kneading temperature is generally 70 to 200 ° C., and after kneading at a high temperature,
It may be cooled and maintained at 70 to 110 ° C., and preferably performed in a nitrogen atmosphere.

On the other hand, cellulose particles are dispersed in a mixed liquid of polyhydric alcohol and water to prepare a dispersion liquid. Since crystalline cellulose is not dissolved in water, it may be added to and dispersed in the mixed solution as it is, but methyl cellulose and hydroxypropyl cellulose are dissolved in water at low temperature, and therefore added to the mixed solution at 70 to 110 ° C so as not to be dissolved. Need to be distributed.

Water is added to a rubber-based pressure-sensitive adhesive at 70 to 110 ° C., and hot-melt coating is performed within that temperature range, so that water evaporates and decreases. Therefore, 1 to 70 parts by weight of water is added to 100 parts by weight of the rubber-based adhesive so that 0.5 to 25 parts by weight of water remains in the adhesive layer after coating.

The drug may be added to the rubber-based pressure-sensitive adhesive as it is, or may be dispersed in the above dispersion liquid and added together with the cellulose particles.

If the kneading time of the rubber-based pressure-sensitive adhesive, the dispersion and the drug is too short, the cellulose particles will not be uniformly dispersed, and if it is too long, water will evaporate and the content will decrease, so that it is 5-60. Minutes, preferably 20 to 45 minutes. Although any kneading method may be adopted, generally, a stirring and mixing method is used, and if the rotation speed of stirring is too slow, it takes time for the cellulose particles to be uniformly dispersed, and if it is too fast, shearing occurs. Since the cellulose particles are broken by the stress and become smaller, the speed is preferably 10 to 75 rpm.

In the second aspect of the present invention, the kneaded material thus kneaded is applied to one surface of the support having moisture permeability with a hot melt coating machine. If the temperature of the kneaded product becomes low, it becomes difficult to apply it, and if it becomes high, water easily evaporates.
The pressure-sensitive adhesive layer is laminated by holding at 0 to 110 ° C. and applying.
The release paper may be coated with the kneaded product to form a pressure-sensitive adhesive layer, and then transferred onto one surface of a support having moisture permeability and laminated.

[0047]

EXAMPLES Next, examples of the present invention will be described. In the following, "parts" means "parts by weight". Also, cellulose particle dispersibility test, water content test, rat sticking test,
The evaluation methods and measurement methods for the moisture permeability test and the human patch test are as follows.

1) Cellulose Particle Dispersibility Test The presence state of cellulose particles in the adhesive layer of the adhesive patch (area 3.14 cm ² ) was evaluated using a microscope. ◯: Particles are present in the pressure-sensitive adhesive layer. X: The adhesive layer does not exist in the form of particles.

2) Water content test The amount of the patch (area: 1 cm ² ) was measured with respect to 100 parts of the rubber-based adhesive by the Karl Fischer coulometric titration method using a Hiranuma trace moisture measuring device (AQ Aqua Counter manufactured by Hiranuma Sangyo Co., Ltd.). .

3) Rat Adhesion Test Skin Transferability An adhesive patch (area: 3.
14 cm ² ) was attached, and after 12 hours, this was peeled off and collected. The recovered patch was subjected to extraction treatment with 30 ml of methanol, and the residual amount of the drug in the patch was measured by high performance liquid chromatography. The amount of the drug remaining in the patch was shown as a percentage. In addition, n is 4 and shown as an average value.

Skin irritation The erythema state of the skin 30 minutes after the peeling of the patch in the skin migration test was visually observed and evaluated according to the following 3 grades. 0: No erythema 1: Slightly erythema barely discernible 2: Clear erythema Incidentally, n was 4 and shown as an average value.

4) Moisture Permeability Test It was conducted according to JIS Z 0208. 12 g of anhydrous calcium chloride was placed in a cup, the mouth of the cup was sealed with an adhesive patch, placed in a constant temperature and humidity chamber at a temperature of 40 ± 1 ° C. and a humidity of 90 ± 2%, and allowed to stand for 24 hours, after which the mass increase of calcium chloride was measured. . 5) Human patching test A patch (area 12 cm ² ) was patched on the forearm of a healthy person for 12 hours, and the patching property of the patch, adhesive residue, and irritation by the patch were determined as follows. Adhesiveness ○: Residual patch area of patch is 95% or more △: Residual patch area of patch is greater than 75% and smaller than 95% ×: Residual patch area of patch is 75% or less Adhesive residue ○: Adhesive after peeling is skin Didn't stay on top. X: The adhesive remained on the skin after peeling. Irritation 0: No erythema 1: Mild erythema barely discernible 2: Clear erythema

Examples 1 to 16 and Comparative Examples 1 to 12 Styrene-isoprene-styrene block copolymer (Califlex TR-1107, manufactured by Shell Chemical Co.)
15 parts by weight, alicyclic hydrogenated petroleum resin (Arakawa Chemical Co.,
40 parts by weight of trade name Alcorn-P90, 5 parts by weight of polybutene (manufactured by Nisseki Chemical Co., Ltd., product name HV-300) and 40 parts by weight of liquid paraffin (manufactured by Nikko Pharmaceutical Co., Ltd., trade name Liquid Paraffin Pharmacopoeia) are melt-mixed. (Made by Tokushu Kika Co., Ltd., trade name TK Combimix 2T-100 type), heated to 150 ° C. while stirring and purging with nitrogen, and melted,
A rubber adhesive was obtained.

The obtained rubber-based pressure-sensitive adhesive was cooled to the temperature (pressure-sensitive adhesive temperature) shown in Tables 1 to 3 while stirring, and
Prescribed amount of crystalline cellulose (Asahi Kasei Co., Ltd., trade name Avicel), methyl cellulose (Shin-Etsu Chemical Co., Ltd., trade name Metroses SM-25) or hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd., trade name Shin-Etsu HPCMF-P)
Was added to and dispersed in a mixed liquid of glycerin and water, and the drug and the drug were sequentially added to the rubber-based pressure-sensitive adhesive and kneaded at a rotation speed of 65 rpm for a predetermined time to obtain a kneaded product. The resulting kneaded product was supplied to a hot melt coating machine (Yuri Roll Machine Co., Ltd., trade name GPD300E), and coated at a predetermined coating temperature shown in Tables 1 to 3 on polyethylene-coated high-quality paper at a thickness of 150 μm, Form an adhesive layer and apply a thickness of 3 on the adhesive layer.
A 0 μm polypropylene nonwoven fabric was laminated to obtain a patch. The physical properties of the obtained patch were measured, and the results are shown in Tables 4-6.

Comparative Example 13 14 parts of hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd., Shin-Etsu HPCMF-P) having a particle diameter of 70 to 130 μm was dissolved in a mixed solution of 14 parts of glycerin and 2.5 parts of water at 25 ° C. A patch was prepared in the same manner as in Example 5 except that the adhesive was added to the rubber-based adhesive, and the physical properties were measured in the same manner. The results are shown in Table 6.

[0056]

[Table 1]

[0057]

[Table 2]

[0058]

[Table 3]

[0059]

[Table 4]

[0060]

[Table 5]

[0061]

[Table 6]

[0062]

EFFECTS OF THE INVENTION The patch of the present invention comprises a rubber-based pressure-sensitive adhesive having at least one particle size selected from the group consisting of crystalline cellulose, methyl cellulose and hydroxypropyl cellulose.
A patch having a pressure-sensitive adhesive layer composed of cellulose particles having a particle size of ˜150 μm, a polyhydric alcohol, water and a drug laminated on one surface of a support having moisture permeability, wherein the cellulose particles are in a particulate form in a rubber-based pressure-sensitive adhesive layer. Since it is in a dispersed state and contains 0.5 to 25 parts by weight of water, it has good moisture permeability, low irritation to the skin, and good drug release from the adhesive layer. The method for producing the patch of the present invention is 70 to 110 ° C.
To the rubber-based pressure-sensitive adhesive of, a dispersion liquid in which cellulose particles having a particle diameter of 1 to 150 μm are dispersed in a mixed liquid of polyhydric alcohol and water is added, and the mixture is stirred and kneaded for 5 to 60 minutes, and then 70 to 110
Since hot-melt coating is performed at a temperature of ° C, a patch in which cellulose particles are uniformly dispersed in the rubber-based pressure-sensitive adhesive layer in a particulate form can be easily produced.

Claims (2)

[Claims] 1. A rubber-based pressure-sensitive adhesive 100 parts by weight, at least one selected from the group consisting of crystalline cellulose, methyl cellulose and hydroxypropyl cellulose, having a particle diameter of 1 to 1.
An adhesive layer composed of 1 to 40 parts by weight of 150 μm cellulose particles, 1 to 30 parts by weight of a polyhydric alcohol, 0.5 to 25 parts by weight of water and 0.1 to 30 parts by weight of a drug is used as a support having moisture permeability. A patch, which is laminated on one surface, and wherein the cellulose particles are present in the pressure-sensitive adhesive layer in the form of particles. 2. Cellulose particles having a particle diameter of 1 to 150 μm, selected from the group consisting of crystalline cellulose, methyl cellulose and hydroxypropyl cellulose, in 100 parts by weight of a rubber-based pressure-sensitive adhesive in a molten state at 70 to 110 ° C. 1 to 40 parts by weight of a polyhydric alcohol is dispersed in a mixed solution of 1 to 30 parts by weight and 1 to 70 parts by weight of water, and 0.1 to 30 parts by weight of a drug is added, and kneading is performed for 5 to 60 minutes. After that, the method for producing a patch according to claim 1, wherein the hot-melt coating machine is applied to one surface of the support having moisture permeability at 70 to 110 ° C.