JPH03291219A - New patch agent for external use and production thereof - Google Patents

Abstract

PURPOSE:To provide the subject patch agent for external use containing a specified glycoside monomer as its base component, excellent in softening of skin irradiation, reduction of pain in peeling, reduction of side effects such as madness, adhesion to the skin and peeling and useful for application to the outer skin. CONSTITUTION:A glycoside monomer represented by the formula (R is H or lower alkyl), e.g. glycosylethyl methacrylate is used as its base component and, as necessary, a (meth)acrylate polymer soluble in a water soluble polyvalent alcohol and water or in an organic solvent and capable of radical polymerization is used in combination therewith. Water and the polyvalent alcohol are blended therewith in a prescribed ratio and a specified amount of active components such as a skin irritant, an analgesic and antiphlogistic agent, a central nervous system-acting agent and an antihistamine are added thereto. The resultant mixture is irradiated with light such as ultraviolet rays in the presence of a polymerization initiator, especially a photopolymerization initiator for polymerization and crosslinking, thus giving the objective patch agent for external use. The resultant agent is capable of providing a preparation having excellent physical properties and excellent in adhesion characteristics, safety, softening of pains, etc., in use for human body.

Description

Detailed Description of the Invention [Field of Industrial Application] The present invention relates to a topical patch for alleviating skin irritation, alleviating pain during peeling, and for external application with excellent adhesion and peeling from the skin, and its manufacture. It is about the method.

[Conventional technology]

Conventionally known adhesive patches contain polymer compounds (synthetic rubbers such as natural rubber, styrene-butadiene rubber, polybutashene rubber, polyisobutylene rubber, polyisoprene rubber, phtyl rubber, and styrene-isoprene-styrene), tackifiers (e.g. rosin, dehydrogenated rosin or ester, terpene resin, petroleum resin such as 1,3 pentadiene), softener (e.g. polybutene, liquid paraffin, process oil, vegetable oil, naphthenic oil, etc.) and filler (e.g. It is composed of base ingredients such as calcium carbonate, zinc white, silica, etc.) and medicinal ingredients. still,
Tackifiers and ointments used in these base ingredients generally cause skin irritation (sensitivity, redness, edema, etc.).
Many substances have been suggested as causative agents for the development of side effects and skin disorders (contact dermatitis, etc.).

On the other hand, patch preparations based on acrylic polymers are formulated by synthesizing a polymer in the base by a solution polymerization method, an emulsion polymerization method, or the like, and adding a medicinal ingredient to the polymer.

Therefore, the drug release properties are not constant and the drug residual rate in the base is high. Also, since these bases are lipophilic acrylic polymers, their adhesive strength to the skin is too strong, which may cause part of the stratum corneum to be damaged when removed from the skin, causing irritation. There are many. Furthermore, acrylic polymers synthesized by solution polymerization contain residual solvent and residual monomer, while acrylic polymers synthesized by emulsion polymerization contain surfactants. It could be the cause.

The glycoside monomer used in the present invention is a compound synthesized for the first time by Nippon Seki, and it is known that this glycoside monomer can be easily polymerized. Furthermore, although it is speculated that the material may be applied to biocompatible materials such as medical tubes and artificial organs, there have been no reports of specific applications. Furthermore, there are no reports on patches that use glycoside monomers as a base, and there are no descriptions that suggest them.

Furthermore, at present, nothing is known about the various bases of patches and their composition with medicinal ingredients.

[Problem that the invention seeks to solve]

In view of the above technical situation, the present inventors aimed to eliminate these drawbacks.

In other words, (1) Reducing side effects such as skin irritation, i.e., there is no toxicity to the skin, and since it has excellent water absorbency, it is effective in reducing skin irritation by absorbing sweat accumulated on the base and skin surface. There is.

(2) Alleviation of pain during peeling from the skin The base of the present invention is hydrophilic and has a glycosyl group in the side chain of the polymer, so it has excellent affinity with the skin. Therefore, when the base is removed from the skin, it is removed smoothly without pulling the stratum corneum or hair, which is effective in alleviating pain.

(3) A topical patch that is easy to adhere to and peel off from the skin, i.e., easily adheres to any part of the human body surface;
To provide a patch that can be easily peeled off and that can be applied repeatedly without losing its adhesive properties.

(4) The composition of the base is a single component, does not require heating or stirring, and can be easily formulated in a short time using low energy such as light or electron beams.

As described above, it is an object of the present invention to develop an external patch containing a glycoside monomer that satisfies the requirements (1) to (4) for a patch.

[Means for solving problems]

As a result of intensive research to develop a patch that satisfies the requirements of +1) to (4) above, the present inventors discovered that the glycoside monomer represented by the above general formula (A) was used as a patch base for the first time. The present invention was completed by using it as an agent and further polymerizing and/or crosslinking it. In addition, we have discovered a patch that is far superior to conventional patches in terms of the combination formulation with the following base components and medicinal ingredients. In other words, the base component is a glycoside monomer (A) having the following general formula (A) (wherein, R represents a hydrogen atom or a lower alkyl group). For example, R in the general formula (A) is a hydrogen atom. or a glycoside monomer consisting of a lower alkyl group such as methyl, ethyl, propyl, etc. Among these, the most preferred is glycosylethyl methacrylate in which R is a methyl group.

The glycoside monomers used in the present invention include water, alcohols such as methanol, ethanol, propyl alcohol, and n-butyl alcohol, methyl acetate, ethyl acetate,
It is preferable to use it by dissolving it in a solvent such as butyl acetate, methyl ethyl ketone, or cellosolve. When dissolving in water,
Concentration 20-90% by weight, preferably 40-60% by weight,
When dissolving in ethanol, the concentration is adjusted to 30 to 80% by weight, preferably 40 to 60% by weight.

In the present invention, it is preferable to dissolve the glycoside monomer in water and use it in the form of a mixed solution of glycoside monomer and water, for the sake of stability and production. The proportion of water used is 20 to 90% by weight, preferably 40 to 60% by weight.

In addition, an electrolyte such as sodium chloride, calcium chloride, potassium chloride, ammonium chloride, magnesium chloride, etc. can also be used together with water.

The polyhydric alcohol is preferably water-soluble, such as ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol, trimethylene glycol, dipropylene glycol, 1.2-
Butanediol, 1,3-butanediol, 1,4-butanediol, 1,5-butanediol, hexanediol, neopentyl glycol, dibromneopentyl glycol, trimethylbentanediol, trimethylolethane, trimethylolpropane, pentaerystol,
Examples include dipentaerythol, glycerin, diglycerin, sorbitol, etc., and preferably glycerin, propylene glycol, 1,3-butanediol, etc. When adding polyhydric alcohol, the amount used is 10 to 70 of the total amount.
% by weight, preferably 10-30% by weight.

Examples of medicinal ingredients include salicylic acid, glycol salicylate, l-menthol, camphor, peppermint oil, thymol, benzyl nicotinic acid ester, capsicum extract, kabsaicin, vanillylamide nonylate, flubinac, butyl flufenamate, as skin irritants and analgesic anti-inflammatory agents. , piroxicam, indomethacin, ketoprofen,
pranoprofen, fenprasin, loxoprofen, anzenaf sodium, oxaprozin, emorfazone, tiaprofen, fenbufuene, fentiazac, diclozenaf sodium, diflunisal,
ibuprofenpiconol, mefenamic acid, pendazac, and suprofen and their ester derivatives,
Alternatively, there are buprenorphine hydrochloride, pentazocine, morphine putorphenol tartrate, etc.

Central nervous system acting agents (sleeping analgesics, antiepileptics, psychotic agents, etc.) include fluphenazine, thioridazine, diazepam, chlorpromazine, nitrazepam, estazolam, triazolam, nimetazebam, flunitrazepam, halocesazolam, flurazebam, clonazepam, proberidiazine, prochlorpera. Gin, Albrasulam, Brasebam, Flutazolam, Mexazolam, Oxazepam,
These include oxazolam, cloxazolam, lorazebam, fludiazepam, promazepam, and metazepam.

As antihypertensive agents, clonidine, altheroxirone,
Examples include recinacin, dihydroergotoxin mesylate, reserpine, prazosin, captopril, pindolol, and enalapril maleate.

Coronary vasodilators include nitroglycerin, nitroglycol, isosorbitcinitrate, papaverine hydrochloride, dipyridamole, efloxate, trimethacin, nicorandil, cinnarizine, nyridone, molsidomine, nifedipine, and the like.

As an antitussive expectorant, codeine phosphate, dihydrocodeine phosphate, ephedrine hydrochloride, chlorprenaline hydrochloride, phenotyrol hydrobromide, salbutamol sulfate, dimemorphan phosphate, azelastine hydrochloride, clenbuterol hydrochloride, tulobuterol hydrochloride, trimethoquinol hydrochloride, procaterol hydrochloride. , fromhexine hydrochloride, azelastine, tipepidine hibenzate, ketotifen fumarate, formotyol fumarate, pensproperine phosphate, and the like.

Examples of antihistamines include diphenhydramine hydrochloride, triprolidine hydrochloride, isothipendyl hydrochloride, promethacin hydrochloride, chlorpheniramine maleate, cyprohebutadine hydrochloride, lemastine fumarate, carbinoxamine maleate, and dimethindene maleate.

As antiarrhythmic agents, alprenolol, oxprenolol, bucumolol, bupranolol, pindolol,
These include indenolol, carteolol, bucumolol, procaterol, and timolol.

As a local anesthetic, lidocaine aminobenzoate ethyl;
Examples include procaine hydrochloride, dibucaine, and brocaine.

As adrenocortical hormones, hydrocortisone acetate, hydrocortisone, prednisolone, triamcinolone acetonide, dexamethacin phosphate, methylprednisolone, gyclorisine acetate, methylprednisolone acetate, fluocinolone acetonide, dexamethacin acetate, dexamethacin, fluorometholone, beta-phosphate Methacin sodium, betamethadun, hetamethacin valerate, heclomethacin propionate, fludroxycortide, hydrocortisone butyrate, betamethacin dipropionate, fluocinonide, clobetasol propionate, diflucortolone valerate, haldinide, amcinonide, frednisolone valerate, etc. It will be done.

These medicinal ingredients are within the range of 0.02 to 30% by weight,
They may be used alone or in combination of two or more as necessary.

In addition, a solubilizer or an absorption enhancer may be used to promote uniform dispersion of the medicinal ingredient in the base and to prevent recrystallization of the medicinal ingredient. As a solubilizer,
For example, isopropyl myristate, isopropyl valmitate, butyl stearate, hexyl laurate,
Higher fatty acid esters such as myristyl myristate, decyl oleate, octyldodecyl myristate, hexyldecyl dimethyloctanoate, polyoxyethylene alkyl ethers such as polyoxyethylene lauryl ether and polyoxyethylene oleyl ether, polyoxyethylene nonylphenyl Examples include ether, polyoxyethylene alkylphenyl ethers such as polyoxyethylene octylphenyl ether, crotamiton, and liquid paraffin.

Examples of absorption enhancers include dimethyl sulfoxide, sorbitol, urea, diethyl adipate, squalene, squalane, acetylated lanolin, lanolin acid, lanolin alcohol, salicylic acid, liquid paraffin,
Vaseline, l-menthol, camphor, salokol,
Examples include sodium laurate, higher fatty acid triglyceride, polyoxyalkylene glycol, fatty acid monoethanolamide, ethylene glycol monoethyl ether, and polyoxypropylene alkyl ether.

Also, the rack used in the present invention! Ingredients include ethylene glycol di(meth)acrylate, diethylene glycol di(meth)acrylate, triethylene glycol di(meth)acrylate, and tetraethylene glycol di(meth)acrylate.
Polyethylene glycol di(meth)acrylate, nonaethylene glycol di(meth)acrylate, etc.
Acrylate, polyethylene glycol di(meth)acrylate such as brobylene glycol di(meth)acrylate, dibrobylene glycol di(meth)acrylate, 1,3-butanediol di(meth)acrylate, 1
．． Diol di(meth)acrylates such as 4-butanediol di(meth)acrylate, neobentyl glycol di(meth)acrylate, trimethylolpropane tri(meth)acrylate, pentaerythritol penta(meth)acrylate, dipentaerythritol hexa(meth)acrylate, etc. ) acrylates and other polyhydric alcohols (meth)acrylates, polyester acrylates, polyurethane acrylates, epoxy acrylates and other polydiol acrylates, trimethoxysilylpropyl (
Alkoxysilylalkyl (meth)acrylates such as meth)acrylates can also be used.

The amount used is 0.03 to 10.0% by weight based on the total amount.
, preferably 0.5 to 5.0% by weight.

In addition, the external patch of the present invention includes the addition of a stabilizer for the purpose of maintaining the stability of the medicinal acid component, as well as the addition of excipients used in the preparation of the patch.

In addition, the glycoside monomers used as the base of the present invention are soluble in water-soluble polyhydric alcohols and water or organic solvents, and exhibit radical polymerization (can be used in combination with methacrylate polymers), as shown below. This (meth)acrylate has the general formula ()% formula%) () (However, in the formula, R2 is a hydrogen atom or a methyl group, R3 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and n is 1~
It is 23. ).

Examples of the (meth)acrylate represented by general formula (B) include 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, methoxyethyl acrylate, methoxyethyl methacrylate, ethoxyethyl (meth)acrylate, propoxyethyl (meth)acrylate, and butoxyethyl acrylate. Ethyl (meth)acrylate, diethylene glycol mono (meth)acrylate, methoxydiethylene glycol mono (meth)acrylate, methoxytriethylene glycol mono (meth)acrylate, ethoxytriethylene glycol mono (meth)acrylate, methoxy nonaethylene glycol mono (
Examples include meth)acrylate and methoxypolyethylene glycol mono(meth)acrylate. Among these, 2-hydroxyethyl methacrylate, methoxytriethylene glycol mono (meth)acrylate, methoxy nonaethylene glycol mono (meth)acrylate and the like are particularly preferred.

These (meth)acrylates may be used alone or in combination of two or more. The amount used is 2 to 3 caps 1% of the total amount.
, preferably 5 to 20% by weight.

To produce the topical patch according to the present invention, each of the monomers, polyhydric alcohol, and water are mixed in a predetermined ratio, a predetermined amount of medicinal acid is added, and polymerization is carried out in the presence of a polymerization initiator. The method of polymerization and crosslinking includes, for example, a method of irradiating light, especially ultraviolet rays, in the presence of a photopolymerization initiator, a method of heating in the presence of a thermal polymerization initiator, and a method of heating both in the presence of a thermal polymerization initiator. Usual radical polymerization techniques, such as a combined method, are used. In the present invention, it is particularly preferable to irradiate light, particularly ultraviolet rays, in the presence of a photopolymerization initiator because polymerization and crosslinking are accelerated more quickly.

Examples of the photopolymerization initiator include benzoin, benzoin alkyl ethers such as benzoin isopropyl ether and penzoin isophthyl ether, benzophenone,
Benzophenones such as methyl-0-benzoin benzoate, acetophenone, trichloroacetophenone, p
Acetophenones such as -t-butyltrichloroacetophenone, 2,2-dimethoxy2-phenylacetophenone, p-dimethylaminoacetophenone, xanthone,
Thioxanthone such as thioxanthone, 2-chloroxanthone, 2-isopropylthioxanthone, benzyl,
2-ethylanthraquinone, methylbenzoylformate, 2-hydroxy-1-phenylpropan-1-one, 2-hydroxy-4-isopropyl-2-methylpropiophenone, 1-hydroxycyclohexylphenyl ketone, tetramethylthium There are monosulfides, allyldiazonium salts, etc., and these are used in an amount of 0.02 to 2.0% by weight, preferably 0.05 to 0.5% by weight, based on the total amount of monomers normally used. .

Examples of ultraviolet lamps include low-pressure, medium-pressure, high-pressure, or ultra-high-pressure mercury lamps, xenon lamps, metal halide lamps, etc. Sunlight can also be used, but the wavelength emitted from these light sources is preferably 250 to 600 mμ. More preferably, light with a wavelength of 300 to 400 mμ acts effectively on polymerization and crosslinking. It is also possible to use ionizing radiation, such as an electron beam generated from an electron beam accelerator.

In addition, as a thermal polymerization initiator, azobisisobutyronitrile, benzoyl peroxide, lauroyl peroxide, methyl ethyl ketone peroxide, cyclohexanone peroxide, t-butyl hydroperoxide, di-t-butyl peroxide, di- Examples include t-aminoperoxide, dicumyl peroxide, t-butyl perbenzoate, etc., and these are 0.03 to 1.0% by weight, preferably 0.05 to 1.0% by weight, based on the total amount of commonly used monomers. 0
．． 5% by weight is used. The heating temperature is 50 to 90°C, preferably 60 to 80°C, and heating is performed for 0.5 to 6 hours, preferably 1 to 3 hours.

The external patch of the present invention can be polymerized and crosslinked directly on the support, or can be polymerized and crosslinked in advance in a separate device, and then the base can be transferred onto the support by a transfer method. In addition, the medicinal ingredients are added in advance to a mixture of polyhydric alcohol and water to be uniformly dispersed in the base.
It is necessary to uniformly disperse them, mix them with the glycoside monomer, and complete polymerization and crosslinking by irradiating them with ultraviolet rays.

This method has the advantage that a prescribed patch can be obtained from a low-viscosity liquid material in only one step, and is useful for energy saving and quality stabilization. In addition, there is an advantage that drugs with poor thermal stability and volatile drugs can be blended at room temperature, and it is very significant that it has become possible to develop new formulations containing these drugs. It is also a feature.

Next, the support for the external patch used in the present invention is not particularly limited, but includes woven fabrics such as cotton cloth, nonwoven fabrics, and plastic films. Film materials include, for example, polyolefins such as polyethylene, polypropylene, and polystyrene, polyesters such as polyethylene terephthalate, polyamides such as nylon 6 and nylon 66, polyvinyl alcohol, vinylidene chloride, polyurethane, and ethylene-vinyl acetate copolymer. Coalescing, metal foil, rubber, etc. can be used.

As an external patch, in addition to the usual application side, applications such as oral preparations, gelling agents, etc. are also fully possible due to the physical properties of the present invention.

Next, the manufacturing method of the present invention will be explained.

A mixed solution of glycoside monomer represented by general formula (A) according to claim (1)-water and/or 30-90% by weight of (meth)acrylate and 0603-10% by weight of the crosslinking component are mixed with 10-10% by weight of polyhydric alcohol. 70% by weight of the photopolymerization initiator and 0.02 to 2.0% by weight of the photopolymerization initiator are mixed.

The mixing conditions include mixing and stirring at room temperature using a stirrer such as a three-one motor at a rotational speed of 500 to 10.00 rpm.

Next, 0.02 to 30% by weight of the medicinal ingredient was uniformly dispersed in 10 to 1% of polyhydric alcohol, the mixture containing the above glycoside monomer as the main component was added, and a three-one motor was used to disperse it. The mixture is mixed and stirred at a rotational speed of 500 to 10,000 rpm for 1 to 5 minutes, and defoamed to obtain a uniform solution.

This solution was poured onto a polyester film held horizontally to the desired thickness, replaced with nitrogen, irradiated with ultraviolet rays for 5 minutes using a chemical lamp, and then the cured surface was covered with a release-treated PET film to achieve the desired adhesiveness. A patch for external use was obtained.

〔Example〕

The present invention will be specifically explained below using examples.

Example 1 Glucosylethyl methacrylate (manufactured by Nippon Sekihi Co., Ltd.) 45
0 part was dissolved in 450 parts of water to make a homogeneous aqueous solution, and 2-hydroxy-1-phenylpropan-1-one (manufactured by Merck Japan, trade name: Darocure 1)16)
1 part was added and thoroughly mixed to obtain a homogeneous solution. (This solution is referred to as Solution A.) Also, dissolve 30 parts of isosorbide nitrate in 69 parts of crotamiton to obtain a uniform dispersion, add this to the above Solution A, stir thoroughly, defoam, and make a uniform solution. I got it. This liquid was poured to a thickness of 300 nm onto a 50 nm thick PET film held horizontally with a groove to prevent the liquid from flowing out, and this was placed in a nitrogen atmosphere. 30W chemical lamp (
PET was placed under 15cs of FL30SBL manufactured by Raiji, irradiated with ultraviolet rays for 5 minutes, and then the cured surface was released.
It was covered with a film and used as a patch.

Example 2 Glucosylethyl methacrylate (manufactured by Nippon Sekihi Co., Ltd.) 45
0 part was dissolved in 450 parts of water to make a homogeneous aqueous solution, and 2-hydroxy-1-phenylpropan-1-one (manufactured by Merck Japan, trade name: Darocure 1)16)
1 part was added and thoroughly mixed to obtain a homogeneous solution. (This solution is referred to as Solution A.) Separately, 5 parts of estradiol was dissolved in 94 parts of crotamiton to obtain a uniform dispersion solution, and this was added to Solution A and thoroughly stirred to defoam, and then a uniform solution was obtained. .

This liquid was poured to a thickness of 300 mm onto a horizontal PET film with a thickness of 50 seconds provided with a groove to prevent the liquid from flowing out.

This material was placed under 15 CIl of a 30W chemical lamp (FL30SBL manufactured by Raijima) while maintaining a nitrogen atmosphere, and after irradiating it with ultraviolet rays for 5 minutes, the cured surface was covered with a release-treated PET film to form a patch. .

Example 3 Glucosylethyl methacrylate (manufactured by Nippon Sekihi Co., Ltd.) 40
0 part was dissolved in 400 parts of water to make a homogeneous aqueous solution, and 2-hydroxy-1-phenylpropan-1-one (manufactured by Merck Japan, trade name: Darocure 1)16)
After adding 1 part of tetraethylene glycol dimethacrylate and uniformly dispersing it, 100 parts of tetraethylene glycol dimethacrylate was further added to this solution to obtain a uniform dispersion.

(This solution is referred to as Solution A.) Separately, 30 parts of isosorbide nitrate was dissolved in 69 parts of crotamiton to obtain a uniform dispersion solution, and 100 parts of glycerin was added and stirred sufficiently to make a uniform solution. A uniform dispersion was obtained after adding it to Solution A and thoroughly stirring and defoaming.

This liquid was poured to a thickness of 30 On onto a 12-thick PET film held horizontally and provided with a groove to prevent the liquid from flowing out. This material was placed 15 cm under a 30 W chemical lamp (FL30SBL manufactured by Raijima) while maintaining a nitrogen atmosphere, and after irradiating it with ultraviolet rays for 5 minutes, the cured surface was covered with a release-treated PET film to form a patch. .

Example 4 Glucosylethyl methacrylate (manufactured by Nippon Sekihi Co., Ltd.) 45
0 part was dissolved in 450 parts of water to make a homogeneous aqueous solution, and 2-hydroxy-1-phenylpropan-1-one (manufactured by Merck Japan, trade name: Darocure 1)16)
1 part was added and thoroughly mixed to obtain a homogeneous solution. (This solution is referred to as Solution A.) Separately, dissolve 10 parts of ketoprofen in 89 parts of propylene glycol to obtain a uniform dispersion. Add this to Solution A, stir thoroughly to defoam, and then obtain a uniform solution. Ta. Thickness 50I with a hole to prevent this liquid from flowing out around the liquid! This material was poured onto a PET film kept horizontally at 300 m in thickness, and placed under a 30 W chemical lamp (FL30SBL manufactured by Nishima) by 15 parts m, while keeping it in a nitrogen atmosphere. After irradiating with ultraviolet rays for 5 minutes, the hardened surface was subjected to mold release treatment.
It was covered with ET film to prepare a patch.

Example 5 Glucosylethyl methacrylate (manufactured by Nihon Sakka Co., Ltd.) 45
0 part was dissolved in 450 parts of water to make a homogeneous aqueous solution, and to this was added 2-hydroxy-1-phenylpropan-1-one (manufactured by Merck Japan, trade name: Darochea 1) 16).
1 part was added and thoroughly mixed to obtain a homogeneous solution. (This liquid is referred to as Liquid A.) Separately, 710 parts of Chronidzi was dissolved in 89 parts of propylene glycol to obtain a uniform dispersion liquid, and this was dissolved in A.
A homogeneous solution was obtained after adding the mixture to the liquid and thoroughly stirring to defoam.

This liquid was poured to a thickness of 300 mm onto a 12 m thick PET film held horizontally and provided with a groove to prevent the liquid from flowing out.

This product was placed under 15all of a 30W chemical lamp (FL30SBL manufactured by Raijima) while being kept in a nitrogen atmosphere, and after irradiating it with ultraviolet rays for 5 minutes, the cured surface was covered with a release-treated PET film to form a patch. .

Example 6 Glucosylethyl methacrylate (manufactured by Nihon Sakka Co., Ltd.) 45
0 part was dissolved in 450 parts of water to make a homogeneous aqueous solution, and 2-hydroxy-1-phenylpropan-1-one (manufactured by Merck Japan, trade name: Darocure 1)16)
1 part was added and thoroughly mixed to obtain a homogeneous solution. (This solution is called Solution A.) Separately, add 89 parts of crotamiton to 1 part of ketochik.
A homogeneous dispersion liquid was obtained by dissolving 10 parts of the liquid, and this was added to liquid A and thoroughly stirred to defoam, and then a homogeneous solution was obtained. This liquid was poured to a thickness of 300 μm onto a 50 ts thick PET film held horizontally and provided with a groove to prevent the liquid from flowing out. While keeping this thing in a nitrogen atmosphere, use a 30W chemical lamp (F
L30SBL) was placed 15 cm below and irradiated with ultraviolet rays for 5 minutes, and then the cured surface was covered with a release-treated PET film to prepare a patch.

Example 7 Glucosylethyl methacrylate (manufactured by Nihon Sakka Co., Ltd.) 35
0 part was dissolved in 350 parts of water to make a homogeneous aqueous solution, and 2-hydroxy-1-phenylpropan-1-one (manufactured by Merck Japan, trade name: Darocure 1)16)
After adding 1 part of tetraethylene glycol dimethacrylate and uniformly dispersing it, 50 parts of tetraethylene glycol dimethacrylate was further added to this solution to obtain a uniform dispersion. (This liquid is called liquid A.) Separately, 100 parts of glycerin and 12 parts of propylene glycol
20 parts of ketoprofen was dissolved in 9 parts to obtain a uniform dispersion, which was added to Solution A and thoroughly stirred to defoam, and then a uniform solution was obtained. A horizontally held PET with a thickness of 50 mm with a groove to prevent this liquid from flowing around the liquid.
It was poured onto the film to a thickness of 300-
While maintaining this product in a nitrogen atmosphere, place it 15 cm below a 30W chemical lamp (FL30SBL manufactured by Nijima).
After irradiating with ultraviolet rays for 5 minutes, the cured surface was covered with a release-treated PET film to prepare a patch.

Example 8 Glucosylethyl methacrylate (manufactured by Nihon Sakka Co., Ltd.) 35
0 part was dissolved in 200 parts of water to make a homogeneous aqueous solution, and 2-hydroxy-1-phenylpropan-1-one (manufactured by Merck Japan, trade name: Darocure 1)16)
After adding 1 part of tetraethylene glycol dimethacrylate and uniformly dispersing it, 50 parts of tetraethylene glycol dimethacrylate was further added to this solution to obtain a uniform dispersion. (This solution is called Solution A.) Separately, add 70 parts of 2-hydroxyethyl methacrylate,
100 parts of polyethylene glycol and 99 parts of dipropylene glycol were added to obtain a homogeneous solution. (This solution is referred to as Solution B.) Additionally, 30 parts of isosorbide nitrate was added to 100 parts of crotamiton and stirred thoroughly to obtain a uniform dispersion.
This was added to 601 parts of liquid A, and further 269 parts of liquid B was added to liquid A and defoamed to obtain a uniform solution. This liquid was placed on a 50n thick horizontal PET film with a groove to prevent it from flowing out.
I poured it so that it was. While keeping this thing in a nitrogen atmosphere, use a 30W chemical lamp (FL30SB made in Japan).
After placing it 15 cm below L) and irradiating it with ultraviolet rays for 5 minutes,
The cured surface was covered with a release-treated PET film to prepare a patch.

Comparative Example 1 60 parts of 2-ethylhexyl acrylate and 37 parts of butyl methacrylate were charged into a polymerization reactor, and ethyl acetate was used as a solvent, the temperature was maintained at 60°C under a nitrogen stream, and azobisisobutyronitrile was used as a catalyst. Polymerization is carried out by a solution polymerization method, and the intrinsic viscosity in toluene solvent is 2.50.
A solution of the polymer was obtained.

Next, 1.0 part of ketoprofen as a medicinal ingredient was added to the ethyl acetate solution of this polymer and stirred to obtain a homogeneous mixture.

This solution was applied onto a PET film and dried by heating to obtain a patch preparation with a thickness of 300 nm.

Comparative Example 2 50 parts of methoxyethyl acrylate and 25 parts of isooctyl acrylate were charged into a polymerization reactor. Furthermore, 150 parts of water, 2 parts of an emulsifier, and 0.3 parts of ammonium persulfate as a polymerization initiator were added thereto, and the mixture was heated under a nitrogen stream. Polymerization was carried out by heating at a reaction temperature of 60 to 65°C for 4 hours, and further heated at 80°C for 2 hours, resulting in a polymerization rate of 99.5% and a viscosity of 60 poise (
An emulsion copolymer of BH type rotational viscometer (4rps+) was obtained.

Next, 1.0 part of ketoprofen was emulsified with an emulsifier and mixed with the above emulsified copolymer, and this was coated on a PET film and dried by heating to obtain a patch with a thickness of 300 mm.

Test Example 1 Skin irritation test Six types of Examples 1 to 4 and Comparative Examples 1 and 2 were applied to the upper backs of 30 healthy male adults for 48 hours. Thirty minutes and 24 hours after peeling, the degree of skin irritation of each person was determined.

Table 1 Skin irritation test The skin texture used as the criterion is as follows.

: No change ± : Slight redness + : Clear redness + 2 Severe sensation The above test results revealed that the patch of the present invention significantly reduces skin irritation.

Test Example 2 Tackiness Test Using eight types of Examples 1 to 3 and 5 to 7 and Comparative Example 1.2, tack measurements and a sticking test on human skin were conducted. The tank measurement method (probe tack method) will be explained below.

This method measures the force when a probe with a fixed cross-sectional area is brought into contact with the surface of the adhesive patch and pulled away in the vertical direction, and conditions such as contact time, contact pressure, and separation speed can be changed. In the case of this test, the measurement was carried out under the following conditions: contact times of o, i seconds and 10 seconds, contact pressure of 100 g/cd, and separation rate of 1.0 CIQ/second.

Table 2 Adhesive Properties As is clear from Table 2, the patch of the present invention has appropriate adhesiveness, easily adheres to the skin, and can be easily peeled off.

[Action/Effect]

In the skin irritation test of the present invention, the incidence of skin irritation was extremely low and the test results were better than expected. This problem of skin contact has been a particular problem for external patches, but the topical patch of the present invention is extremely safe with almost no skin contact.

Also, in the adhesion test, it has excellent initial adhesion, with almost no peeling observed during the process, and even if it does peel off, it can be easily reattached and the adhesive strength will not decrease. Moreover, it has good adhesion when peeled off, and can be easily peeled off without causing any pain when peeled off.

Furthermore, the production of the present invention is carried out through simple steps such as irradiation with ultraviolet rays, and is an economically advantageous method since it can be processed without complicated manufacturing steps.

Furthermore, since the manufacturing conditions are room temperature, it is now possible to easily use medicinal ingredients that previously had problems with heat treatment, which is a particularly significant advantage when manufacturing such pharmaceutical patches. This is a manufacturing method.

The external patch of the present invention obtained as described above is a pharmaceutical preparation that has excellent physical properties, adhesive properties, safety, and pain relief when used on the human body, and is useful in the pharmaceutical industry. It is.

Claims (5)

[Claims] (1) An external patch comprising a glycoside monomer represented by the following general formula (A) as a base component. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (A) (In the formula, R represents a hydrogen atom or a lower alkyl group.) (2) General formula (A) according to claim (1) as a base component
An external patch containing a glycoside monomer represented by the following, water, polyhydric alcohol, a medicinal ingredient, and/or a crosslinking component, which is polymerized and/or crosslinked in the presence of a polymerization initiator. (3) General formula (A) according to claim (1) as a base component
Glycoside monomer represented by (meth)acrylate,
An external patch containing water, a polyhydric alcohol, a medicinal ingredient, and/or a crosslinking component, which is polymerized and/or crosslinked in the presence of a polymerization initiator. (4) General formula (A) according to claim (1) as a base component
Glycoside monomer represented by (meth)acrylate,
Manufacture of an external patch characterized by polymerizing and/or crosslinking a paste obtained by blending water, polyhydric alcohol, medicinal ingredients, and/or crosslinking ingredients by irradiating it with ultraviolet rays in the presence of a polymerization initiator. Method. (5) An external patch, wherein the glycoside monomer according to claims (1) to (4) is glycosylethyl methacrylate.