JPH0276811A - Patch preparation and production thereof - Google Patents

Abstract

PURPOSE:To obtain a patch having excellent stability of medicinal component in a base and excellent release of the medicinal component of the base to the skin by adding the medicinal component to a hydrophilic (meth)acrylic acid alkyl ester copolymer as a base component. CONSTITUTION:1-40wt.% ionic unsaturated monomer (preferably unsaturated aliphatic sulfonic acid derivative) is blended with 2-30wt.% (meth)acrylate shown by the formula (R1 is H or CH3: R2 is H or 1-4C alkyl; n is 1-23), 0.05-1.0wt.% crosslinking component such as polyethylene glycol di(meth)acrylate, 10-80wt.% water-soluble polyhydric alcohol (preferably glycerin), 5-40wt.% water and 0.02-30wt.% medicinal component as base components, polymerized and crosslinked in the presence of a polymerization initiator to give the aimed patch. The polymerization and crosslinking are preferably carried out by ultraviolet-light irradiation in the presence of photopolymerization initiator.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention provides a patch preparation for external skin application, which has easy control of release of medicinal ingredients, alleviation of skin irritation, and excellent adhesion and peeling from the skin. and its manufacturing method.

[Conventional technology]

Conventionally known adhesive patches contain polymer compounds (synthetic rubbers such as natural rubber, styrene-butadiene rubber, polybutadiene rubber, polyisobutylene rubber, polyisoprene rubber, butyl rubber, and styrene-isoprene-styrene), tackifiers (e.g. Rosin, dehydrogenated rosin or ester,
terpene resins, petroleum resins such as 1,3-pentadiene), softeners (e.g. polybutene, liquid paraffin,
It is composed of base components such as processing oil, vegetable oil, naphthenic oil, etc.) and fillers (for example, calcium carbonate, zinc white, silicas, etc.) and medicinal components. Note that the tackifiers and softeners used in these base ingredients generally cause skin irritation (
Many substances have been suggested as causative agents of side effects such as skin irritation, redness, edema, etc.) and skin disorders (contact dermatitis, etc.).

On the other hand, regarding patch preparations based on acrylic polymers, for example, JP-A-62-126119;
2-21395, JP 61-187867, JP 61-1'26020, JP 60-5!1121
No. 0, JP-A-62-29516, JP-A-61-267
No. 510, etc., and these are formulated by synthesizing a polymer in a base by a solution polymerization method or an emulsion polymerization method, 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.

Additionally, since these bases are lipophilic acrylic polymers, their adhesion to the skin is too strong;
When removed from the skin, a portion of the stratum corneum is often damaged, causing irritation.

Furthermore, acrylic polymers synthesized by solution polymerization contain residual solvent and residual monomer, while acrylic polymers synthesized by emulsion polymerization contain surfactants. It may also be the cause.

[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) A patch that releases medicinal ingredients into the skin better than in the base.

(2) A patch with excellent stability of medicinal ingredients in the base.

(3) A patch that is easy to adhere to and peel off from the skin. In other words, a patch that can be easily attached to any part of the human body surface, can be easily peeled off, and can be adhered without losing its adhesive properties even after repeated application.

(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 a patch that satisfies the requirements (11 to (4)) for a patch.

[Means to solve the problem]

The present inventors have conducted extensive research to develop a patch that can satisfy the requirements (1) to (4) above, and have discovered a patch having the following formulation.

The invention of the present application relates to a patch characterized by containing a hydrophilic (meth)acrylic acid alkyl ester copolymer as a base component and a medicinal ingredient therein. Moreover, in the base component, a medicinal ingredient is blended with (meth)acrylic acid alkyl ester in the monomer state, a photoinitiator is added, and polymerization and crosslinking are performed by irradiation with radiation such as ultraviolet rays. It is to be formulated into a formulation.

The circumstances of the completion of the present invention will be explained below. The first component of the hydrophilic (meth)acrylic acid alkyl ester copolymer, which is the base component, imparts hydrophilicity and adhesive strength, is soluble in a mixture of water and polyhydric alcohol, and is capable of radical polymerization. The second component, which is (meth)acrylate, imparts hydrophilicity and cohesive force; The third component, which is a crosslinking component, constitutes the crosslinking portion of the first component and the second component. It is preferable that the polymer has a polymerizable functional group at both ends. This hydrophilic (meth)acrylic acid alkyl ester copolymer contains a water-soluble polyhydric alcohol and water, and the water-soluble polyhydric alcohols include ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol, and triethylene glycol. methylene glycol, dipropylene glycol,
Engineering.

2-butanediol, 1,3-butanediol, 1゜4
-Butanediol, 1,5-bentanediol, hexanediol, neopentyl glycol, dibromneopentyl glycol1. Examples include trimethylbentanediol, trimethylolethane, trimethylolpropane, pentaerythrol, dipentaerythrol, glycerin, diglycerin, and sorbitol, with glycerin being preferred.

The amount of water-soluble polyhydric alcohol used is 10 to 80% by weight, preferably 30 to 70% by weight of the total amount.

Water used with water-soluble polyhydric alcohol has a 5 to 40
% by weight, preferably 10-30% by weight. Electrolytes such as sodium chloride, calcium chloride, potassium chloride, lithium chloride, ammonium chloride, and magnesium chloride can also be used together with water.

Further, a solubilizing agent may be used to promote uniform dispersion of the medicinal ingredient in the base and to prevent recrystallization of the medicinal ingredient.

Examples of solubilizing agents include higher fatty acid esters such as isopropyl myristate, isopropyl palmitate, butyl stearate, hexyl laurate, myristyl myristate, decyl oleate, octyldodecyl myristate, hexyldecyl dimethyloctanoate, and polyoxyethylene. Examples include polyoxyethylene alkyl ethers such as lauryl ether and polyoxyethylene oleyl ether, polyoxyethylene alkylphenyl ethers such as polyoxyethylene nonylphenyl ether and polyoxyethylene octylphenyl ether, crotamiton, and liquid paraffin.

The ionic unsaturated monomer, which is the first component, needs to be soluble in a mixture of water-soluble polyhydric alcohol and water, and is preferably an anionic monomer. Its usage is
The amount is 1 to 40% by weight, or 7 to 30% by weight, based on the total amount. Preferred ionic unsaturated monomers include unsaturated aliphatic carboxylic acids or salts thereof such as acrylic acid, methacrylic acid, maleic acid, itaconic acid, and citraconic acid, methallylsulfonic acid, 2-sulfoethyl acrylate, and 2-sulfoethyl acrylate. - Radically polymerizable carbon-carbon double bonds such as unsaturated aliphatic sulfonic acids or salts thereof such as sulfoethyl methacrylate, 3-sulfopropyl acrylate, 3-sulfopropyl methacrylate, acrylamide-2-methylpropanesulfonic acid Among these, particularly preferred are ionic unsaturated monomers having 3-sulfopropyl (
Mention may be made of meth)acrylates or salts thereof. Cations that form salts include sodium, potassium, lithium, ammonium, etc., with sodium and potassium being preferred. These ionic unsaturated monomers may be used alone (or may be used in combination).

Next, the second component used in the present invention has the general formula (% formula % (
1) (In the formula, R1 is a hydrogen atom or a methyl group, R2 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and n is 1 to 23.)

Examples of the (meth)acrylate represented by general formula (1) 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 hetano (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 monomethacrylate, methoxy nonaethylene glycol monomethacrylate, etc. are particularly preferred.

One or more types of these (meth)acrylates are used. The amount used is 2 to 30% by weight, preferably 5 to 20% by weight, based on the total amount.

Next, as the third component, the crosslinking component, ethylene glycol di(meth)acrylate, diethylene glycol di(meth)acrylate, triethylene glycol di(
meth)acrylate, tetraethylene glycol di(meth)acrylate, nonaethylene glycol di(meth)acrylate
Polyethylene glycol di(meth)acrylate such as acrylate, polypropylene glycol di(meth)acrylate such as propylene glycol di(meth)acrylate, dipropylene glycol di(meth)acrylate, 1,3-butanediol di(meth)acrylate, etc. 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 In addition to polyhydric alcohol poly(meth)acrylates such as (meth)agerylate, polymer diol diacrylates such as polyester acrylate, polyurethane acrylate, and epoxy acrylate, alkoxysilylalkyl (meth)acrylates such as trimethoxysilylpropyl (meth)acrylate are also available. Can be used.

The amount used is 0.05 to 1.0% by weight based on the total amount,
Preferably it is 0.1 to 0.5% by weight.

When the amount of the third component used is 0.05% by weight or less, the crosslinking density of the wood-philic (meth)acrylic acid alkyl ester copolymer becomes significantly small, and the cohesive force of the base material becomes weak, resulting in a patch. Or, even if it is made into a patch preparation, its adhesion to the skin is unstable, and when it is removed, a part of the base is destroyed and remains on the skin. on the other hand,
The amount of the third component used is 1. When o exceeds % by weight, the crosslinking density of the hydrophilic (meth)acrylic acid alkyl ester copolymer increases significantly, resulting in decreased adhesion to the skin and spontaneous desorption during application. Furthermore, the release properties of the medicinal ingredients are significantly reduced and the amount remaining in the base increases, making it impossible to expect sufficient effects as a patch preparation.

To produce the patch according to the present invention, each of the above monomers, polyhydric alcohol, and water are mixed in a predetermined ratio, a predetermined amount of medicinal ingredient is added, and polymerization and crosslinking are carried out in the presence of a polymerization initiator. However, the polymerization and crosslinking method includes, for example, light, light, etc. in the presence of a photopolymerization initiator.
In particular, ordinary radical polymerization techniques are used, such as irradiation with ultraviolet rays, heating in the presence of a thermal polymerization initiator, and a combination of both. In the present invention, it is preferable to directly irradiate light, especially ultraviolet rays, in the presence of a photopolymerization initiator because polymerization and crosslinking are more quickly promoted.

Examples of photopolymerization initiators include benzoin, benzoin alkyl ethers such as benzoin isopropyl ether and benzoin isobutyl ether, benzophenones such as benzophenone and methyl-0-benzoyl benzoate, acetophenone, trichloroacetophenone, and pt-butyltrichloroacetophenone. , 2.2
- Acetophenones such as dimethoxy-2-phenylacetophenone and P-dimethylaminoacetophenone; xanthone, thioxanthone, 2-chloroxanthone, 2-
Thioxanthone such as isopropylthioxanthone,
Benzyl, 2-ethylanthraquinone, methylbenzoylformate, 2-hydroxy-1-phenylpropan-1-one, 2-hydroxy-4-isopropyl-2-
Methylpro2 Biophenone! -Hydroxycyclohexy, It/7° enyl ketone, tetramethylthiuram monosulf[ide, allyldiazonium salt, etc., and these are usually 0.05 to 1.0% by weight based on the total amount of monomers used. , preferably 0.1 to 0.
Used at 5% by weight.

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 of the light emitted from these light sources is 25 o = s. OO
mμ is suitable, more preferably 300 to 400 mμ
Light with a wavelength of 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-
These include t-butyl peroxide, di-t-amyl peroxide, dicumyl peroxide, t-butyl perbenzoate, etc., and these are usually used in an amount of 0.05 to 1% by weight based on the total amount of monomers used. %, preferably 0.1-0.5
% by weight used. The heating temperature is 50 to 90'C, preferably 60 to 80C, and heated for 0.5 to 6 hours, preferably 1 to 3 hours.

The patch preparation 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 is 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 in order to be uniformly dispersed in the base, and after being uniformly dispersed, these are mixed with an acrylic monomer, and the It is necessary to complete the polymerization and crosslinking by irradiating 9 with .

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 characteristic.

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

The medicinal ingredients contained in the patch preparation of the present invention include, for example, salicylic acid, methyl salicylate, glycylic acid salicylate, :]-)Lt, It
- Menthol, camphor, pepper oil, thymol, nicotinic acid benzyl ester, capsicum extract, kabsaicin, nonylic acid vanillylamide, flubinac, butyl flufenamate, piroxicam, indomethacin, ketoprofen, pranoprofen, feprazone, loxoprofen, anzenaf sodium, oxaprozin, Emorphazone, tiaprofen, fuenbufen, fentiazac, diclozenaf sodium, diflunisal, ibuprofenpiconol, hendazasoc, and sprofen, and their esters (i-forms), bubrenorphine hydrochloride, pentazocine, butorphanol tartrate, etc.

Central nervous system acting agents (sleep analgesics, anti-epileptic drugs, psychiatric drugs, etc.) include fluphenazine, thioridazine, diazepam, chlorpromazine, nitrazepam, estazolam, triazolam, nimetazepam, flunitrazepam, halocesazolam, flurazebam, clonazebam, proberidiazine, prochlorperazine, albrasillam,
Prazepam, flutazolam, mexazolam, oxazepam, oxazolam, cloxapram, lorazebam, fludiazepam, promazepam, prazepam, etc.

As diuretics, hydrothiazide, pendroflumethiazide, ethiazide, cyclopenthiazide, hydrochlorothiazide, penflutide, methyclothiazide, furosemide, metolazone, polythiazide, pendroflumethiazide, etc.

As antihypertensive agents, clonidine, altheroxirone,
Resinamine, dihydroergotoxin mesylate, reserpine, prazosin, captopril, pindolol, enalapril maleate, etc.

Coronary vasodilators include nitroglycerin, nitroglycol, isosorbitcinitrate, bapaverine hydrochloride, dipyridamole, efloxate, trimethacin, nicorandil, cinnarizine, nyridone, molsidomine, nifedipine, etc.

As an antitussive expectorant, codeine phosphate, dihydrocodeine phosphate, ephedrine hydrochloride, chlorprenaline hydrochloride, phenotyrol hydrobromide, salbutamol sulfate, dimemorphan phosphate, azelastine hydrochloride, clenbuterol hydrochloride, tulopterol hydrochloride, trimethoquinol hydrochloride, procaterol hydrochloride. , fromhexine hydrochloride, tranilast, tipepidine hibenzate, ketotifen fumarate, formotyol fumarate, pensproveline phosphate, glycyrrhetinic acid, etc.

As antihistamines, diphenhydramine hydrochloride, triprolidine hydrochloride, isothipendyl hydrochloride, promethacin hydrochloride, chlorpheniramine maleate, cyprohebutadine hydrochloride, lemastine fumarate, carbinoxamine maleate, dimethindene maleate, etc.

As antiarrhythmic agents, alprenolol, oxprenolol, bucumolol, bupranolol, pindolol,
Indenolol, carteolol, bucumolol, propranolol, timolol, etc.

Cardiotropes include digitalis, ubidecarenone, digoxin, methyldigoxin, destranoside, etc.

As a sex hormone agent, estradiol enanthate,
Estradiol cipinate, levonorgestrel, estradiol, etc.

As adrenocortical hormones, hydrocortisone acetate, hydrocortisone, prednisolone, triamcinolone acetonide, dexamethacin phosphate, methylprednisolone, gyclorisine acetate, methylprednisolone acetate, fluocinolone acetonide, dexamethacin acetate, dexamethacin, fluorometholone, beta-phosphate Metacin sodium, betamethacin, betamethacin valerate, beclomethasone propionate, fludroxycortide, hydrocortisone butyrate, betamethacin dipropionate, fluocinonide, clobetasol propionate, diflucortolone valerate, haldinonide, amcinonide, prednisolone valerate, etc.

Local anesthetics include lidocaine, ethyl aminobenzoate, propylene hydrochloride, dibucaine, propylene and the like.

These medicinal ingredients may be used alone or in combination of two or more as necessary, within the range of 0.02 to 30% by weight. In addition, if necessary, absorption enhancers may be added to increase the absorption of the medicinal ingredients, stabilizers may be added to maintain the stability of the medicinal ingredients, and excipients used in the manufacture of patches may also be added. It is included in the adhesive preparation of the present invention.

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

A solution of an ionic unsaturated monomer and a crosslinking component in polyhydric alcohol and/or water is mixed with a photopolymerization initiator added to methacrylate as a second component. Next, the medicinal ingredient was uniformly dispersed in polyhydric alcohol, the above mixture of acrylic monomers was added thereto, and the mixture was defoamed to obtain a uniform solution. Pour this solution onto a horizontally held polyester film to the desired thickness.
After nitrogen substitution, a patch preparation with desired adhesiveness was obtained by irradiating with ultraviolet rays.

(Example〕 The present invention will be specifically explained below using examples.

Example 1 10 parts of 1-hydroxycyclohexyl phenyl ketone (manufactured by Ciba Geigy, trade name Nilgacure 184) was added to 2
- It was dissolved in 2400 parts of hydroxyethyl methacrylate, and 35 parts of tetraethylene glycol dimethacrylate was further added and dissolved in this solution. (This solution is referred to as Solution A) Separately, 600 parts of sulfopropyl methacrylate potassium salt was dissolved under heating in 2450 parts of 55% saline solution, and 2800 parts of glycerin was further added to obtain a homogeneous solution. (This liquid is referred to as liquid B.) Also, 100 parts of ketoprofen was added to 1605 parts of propylene glycol, stirred thoroughly to obtain a uniform 4-dispersion liquid, which was added to 2445 parts of liquid A, and further 5850 parts of liquid B was added. A
It was added to the liquid and defoamed to obtain a homogeneous solution. Thickness 50-mm with a groove to prevent this liquid from flowing out around the liquid.
300I thick on PET film kept horizontally.
While keeping this in a nitrogen atmosphere, a 30W chemical lamp (Toshiba FL3O
After irradiating with ultraviolet rays for 5 minutes, the cured surface was covered with a release-treated PET film to prepare a patch.

Example 2 15 parts of 1-hydroxycyclohexylphenyl ketone (manufactured by Ciba Geigy, trade name Nilgacure 184) was added to 2
-Hydroxyethyl methacrylate)), and 50 parts of tetraethylene glycol dimethacrylate was further added and dissolved in this solution. (This solution is referred to as Solution A) Separately, 600 parts of sulfopropyl methacrylate potassium salt was dissolved under heating in 2450 parts of 55% saline solution, and 2800 parts of glycerin was further added to obtain a homogeneous solution. (This solution will be referred to as Solution B.) Also, add 100 parts of ketoprofen to 1585 parts of propylene glycol, stir thoroughly to obtain a uniform dispersion, add this to 2465 parts of Solution A, and further add 5850 parts of Solution B. A
It was added to the liquid and defoamed to obtain a homogeneous solution. Thickness 50-mm with a wall to prevent this liquid from flowing out around the liquid.
on a PET film kept horizontally with a thickness of 3001 mm.
It was poured to a depth of 1 m. While keeping this thing in a nitrogen atmosphere, use a 30W chemical lamp (Toshiba FL30).
After irradiating with ultraviolet rays for 5 minutes, the cured surface was covered with a release-treated PET film to prepare a patch.

Example 3 2-Methyl-[4-(methylthio)phenyl-2-morpholino-1-propanone 1 (l) was dissolved in 2400 parts of 2-hydroxyethyl methacrylate, and 35 parts of tetraethylene glycol dimethacrylate was added to this solution. and dissolved.

(This solution is referred to as Solution A) Separately, 600 parts of sulfopropyl methacrylate potassium salt was dissolved under heating in 2450 parts of 55% saline solution, and 2800 parts of glycerin was further added to obtain a uniform solution. (This liquid will be referred to as liquid B) Also, add 0717 parts of ketop to 1655 parts of propylene glycol.
Add 50 parts of liquid and stir thoroughly to obtain a uniform dispersion, add this to 2445 parts of liquid A, and then add 5850 parts of liquid B to A?
& was defoamed to obtain a homogeneous solution. A thickness of 50μ is provided to prevent this liquid from flowing out around the liquid.
The thickness of 300 mm is placed on the PET film held horizontally on the turtle.
Pour it so that it reaches a peak of μ. While keeping this thing in a nitrogen atmosphere, use a 30W chemical lamp (Toshiba FL30).
SBL) was placed under 15CIIIl and irradiated with ultraviolet rays for 30 seconds, and then the cured surface was covered with a release-treated PET film to prepare a patch.

Example 4 10 parts of 1-hydroxycyclohexyl phenyl ketone (manufactured by Ciba Geigy, trade name Nilgacure 184) was added to 2
- It was dissolved in 2,400 parts of hydroxyethyl methacrylate, and further, 40 parts of 1,3-butylene glycol dimethacrylate was added and dissolved in this solution. (This solution is referred to as Solution A) Separately, 600 parts of sulfopropyl methacrylate potassium salt was dissolved under heating in 2450 parts of 5% saline, and 2800 parts of glycerin was further added to obtain a homogeneous solution. (
(This solution is called Solution B.) Also, add 200 parts of ketoprofen to 1500 parts of propylene glycol, stir thoroughly to obtain a uniform dispersion, add this to 2450 parts of Solution A, and then add 5850 parts of Solution B to A.
It was added to the liquid and defoamed to obtain a homogeneous solution. Thickness 50-mm with a groove to prevent this liquid from flowing out around the liquid.
300μ thick on PET film kept horizontally.
It was poured into agriculture. While keeping this thing in a nitrogen atmosphere, use a 30W chemical lamp (Toshiba FL3QS).
After irradiating with ultraviolet rays for 5 minutes, the cured surface was covered with a release-treated PET film to prepare a patch.

Example 5 10 parts of 1-hydroxycyclohexylphenyl ketone (manufactured by Ciba Geigy, trade name Nilgacure 184) was added to 2
-Hydroxyethyl methacrylate)), and 35 parts of tetraethylene glycol dimethacrylate was further added and dissolved in this solution. (This solution is referred to as Solution A) Separately, 600 parts of sulfopropyl methacrylate potassium salt was dissolved under heating in 2450 parts of 5% saline, and 2800 parts of glycerin was further added to obtain a homogeneous solution. (This solution is referred to as Solution B.) Additionally, 100 parts of isosorbide nitrate was added to 1,605 parts of 1,3-butylene glycol, stirred thoroughly to obtain a uniform dispersion, and this was added to 2,445 parts of Solution A. B liquid 585
0 part was added to liquid A and defoamed to obtain a homogeneous solution. This liquid was poured to a thickness of 300 parts onto a horizontally held PET film having a thickness of 50 μm 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 (Toshiba FL30SBL) with a 15c1! After placing the patch on the bottom and irradiating it with ultraviolet rays for 5 minutes, the cured surface was covered with a release-treated PET film to prepare a patch.

Example 6 10 parts of 1-hydroxycyclohexylphenyl ketone (manufactured by Ciba Geigy, trade name Nilgacure 184) was added to 2
- It was dissolved in 2400 parts of hydroxyethyl methacrylate, and 35 parts of tetraethylene glycol dimethacrylate was further added and dissolved in this solution. (This solution is referred to as Solution A) Separately, 600 parts of sulfopropyl methacrylate potassium salt was dissolved under heating in 2450 parts of 5% saline, and 2800 parts of glycerin was further added to obtain a homogeneous solution. (This liquid will be referred to as liquid B.) Also, add 710 parts of Chronizi to 1605 parts of propylene glycol.
0 parts were added and sufficiently stirred to obtain a uniform dispersion, which was added to 2445 parts of liquid A, and further 5850 parts of liquid B was added to liquid A and defoamed to obtain a uniform solution. This liquid was poured to a thickness of 300 pl onto a 50-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 (Toshiba FL30SBL).
) and irradiated with ultraviolet rays for 5 minutes,
The cured surface was covered with a release-treated PET film to prepare a patch.

Example 7 10 parts of 1-hydroxycyclohexyl phenyl ketone (manufactured by Ciba Geigy, trade name Nilgacure 184) was dissolved in 2400 parts of 2-hydroxyethyl methacrylate, and 35 parts of tetraethylene glycol dimethacrylate was further added and dissolved in this solution. I let it happen. (This solution is referred to as Solution A) Separately, 600 parts of sulfopropyl methacrylate potassium salt was dissolved under heating in 2450 parts of 5% saline, and 2800 parts of glycerin was further added to obtain a homogeneous solution. (
(This solution is referred to as Solution B.) Additionally, 100 parts of propranolol hydrochloride was added to 1,605 parts of 1,3-butylene glycol, stirred thoroughly to obtain a uniform dispersion, and this was added to 2,445 parts of Solution A, and then liquid 5
850 parts were added to Solution A and defoamed to obtain a homogeneous solution. This liquid was poured to a thickness of 300μ onto a 1) ET film kept horizontally with a thickness of 50μ and provided with a hole to prevent the liquid from flowing out. While maintaining the nitrogen atmosphere, use a 30W chemical lamp (
The PET was placed under a 15 ct (FL30SBL manufactured by Toshiba), 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 8 10 parts of 1-hydroxycyclohexylphenyl ketone (manufactured by Ciba Geigy, trade name: Irgacure 184) was added to 2
- It was dissolved in 2400 parts of hydroxyethyl methacrylate, and 35 parts of tetraethylene glycol dimethacrylate was further added and dissolved in this solution. (This solution is referred to as Solution A.) Separately, 600 parts of sulfopropyl methacrylate potassium salt was dissolved under heating in 2,395 parts of pure water to obtain a homogeneous solution. (This solution is referred to as Solution B.) Additionally, 10 parts of estradiol was dissolved in 30 parts of crotamiton, 4520 parts of 1.3-butanediol was added thereto, and stirred thoroughly to obtain a uniform dispersion. A liquid 2445
Furthermore, 2995 parts of Solution B was added to Solution A, and defoamed to obtain a homogeneous solution.

This liquid was poured to a thickness of 300 mm onto a 50 mm thick PET film held horizontally and provided with a groove to prevent the liquid from flowing out. While maintaining the product in a nitrogen atmosphere, it was placed 15 cm under a 30 W chemical lamp (FL30SBL manufactured by Toshiba) and irradiated with ultraviolet rays for 5 minutes, and then the cured surface was covered with a release-treated PET film to form a patch.

Example 9 10 parts of 1-hydroxycyclohexyl phenyl ketone (manufactured by Ciba Geigy, trade name: Irgacure 184) was dissolved in 2400 parts of 2-hydroxyethyl methacrylate, and 35 parts of tetraethylene glycol dimethacrylate was further added to this solution. was added and dissolved. (This solution is A
Make it into a liquid. ') Separately, 600 parts of sulfopropyl methacrylate potassium salt was dissolved in 2395 parts of pure water under heating to obtain a homogeneous solution. (The boiling liquid is referred to as Solution B.) Also, dissolve 100 parts of estradiol in 300 parts of crotamiton, add 4520 parts of 1.3-butanediol, stir thoroughly to obtain a uniform dispersion, and add this. A liquid 24
45 parts of liquid, and further added 2995 parts of liquid B to liquid A,
A homogeneous solution was obtained by defoaming. This liquid was poured to a thickness of 300 mm onto a 50#l 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,
0W chemical lamp (Toshiba F'L30SBL) 1
After placing the sample under 5 cm and irradiating it with ultraviolet rays for 5 minutes, the cured surface was covered with a release-treated PET film to prepare a patch.

Example 10 20 parts of 1-hydroxycyclohexyl phenyl ketone (manufactured by Ciba Geigy, trade name: Irgacure 184) was dissolved in 2400 parts of 2-hydroxyethyl methacrylate, and 35 parts of tetraethylene glycol dimethacrylate was further added to this solution. was added and dissolved. (This solution is referred to as Solution A.) Separately, 600 parts of sulfopropyl methacrylate potassium salt was dissolved under heating in 2395 parts of pure water to obtain a homogeneous solution. (This liquid is called liquid B.) Also, crotamiton 1
Dissolve 50 parts of estradiol in 50 parts, add 1,
Add 4,350 parts of 3-butanediol, stir thoroughly to obtain a uniform dispersion, add this to 2,455 parts of Part A, and further add 2,995 parts of Part B to Part A, defoaming to form a uniform solution. I got it.

This liquid was poured to a thickness of 300 .mu.m onto a 50 .mu. thick PET film held horizontally and provided with a groove to prevent the liquid from flowing out. While maintaining this material in a nitrogen atmosphere, place it 15 cm below a 30W chemical lamp (FL30SBL manufactured by Toshiba) and expose it to 50% of ultraviolet rays.
After irradiation for a minute, the cured surface was covered with a release-treated PET film to prepare a patch.

Example 11 10 parts of ■-Hydroxycyclohexyl phenyl ketone (manufactured by Ciba Geigy, trade name: Irugaki Air 184) was added to 2
- It was dissolved in 2400 parts of hydroxyethyl methacrylate, and 35 parts of tetraethylene glycol dimethacrylate was further added and dissolved in this solution. (This solution is referred to as Solution A.) Separately, 600 parts of sulfopropyl methacrylate potassium salt was dissolved under heating in 2395 parts of pure water to obtain a homogeneous solution. (This liquid is called liquid B.) Also, crotamiton 50
200 parts of isosorbide nitrate was dissolved in 0 parts, and 1.
Add 3,860 parts of 3-butanediol, stir thoroughly to obtain a uniform dispersion, add this to 2,445 parts of Part A, and further add 2,995 parts of Part B to Part A, defoaming to obtain a uniform solution. Obtained. This liquid was poured to a thickness of 300 μl onto a 50 μm 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 Toshiba) while being kept in a nitrogen atmosphere, and after irradiating it with ultraviolet rays for 5 minutes, the cured surface was mold-released.
It was covered with T film to make a patch.

Example 12 10 parts of 1-hydroxycyclohexylphenyl ketone (manufactured by Ciba Geigy, trade name: Irgacure 184) was added to 2
-Hydroxyethyl methacrylate)), and 35 parts of tetraethylene glycol dimethacrylate was further added and dissolved in this solution. (This solution is referred to as Solution A.) Separately, 200 parts of sulfopropyl methacrylate potassium salt was dissolved under heating in 800 parts of pure water to obtain a homogeneous solution. (This solution is referred to as Solution B.) Additionally, 400 parts of isosorbide nitrate was dissolved in 500 parts of crotamiton, 5655 parts of 1.3-butanediol was added thereto, and the mixture was thoroughly stirred to obtain a uniform dispersion. A liquid 24
Further, 1000 parts of solution B was added to solution A and defoamed to obtain a uniform solution. This liquid was poured to a thickness of 300 μm onto a 50 μm-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,
0W chemical lamp (Toshiba FL30SBL) 15
After being placed under cs+ and irradiated 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 30 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 was carried out by a solution polymerization method to obtain a solution of a polymer with an intrinsic viscosity of 2.18 in a toluene solvent.Next, 0.9 part of ketoprofen was added as a medicinal ingredient to a solution of this polymer in ethyl acetate.
A homogeneous mixture was obtained by stirring.

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

Comparative Example 2 50 parts of methoxyethyl acrylate, 25 parts of isooctyl acrylate and 25 parts of butyl acrylate are charged into a polymerization reactor. Furthermore, 150 parts of water, 2 parts of an emulsifier, and 0.0 parts of ammonium persulfate as a polymerization initiator were added to this.
3 parts were added and polymerized by heating at a reaction temperature of 60 to 65°C for 4 hours under a nitrogen stream, and further aged at 80°C for 2 hours, resulting in a polymerization rate of 99.5% and a viscosity of 60 boids (BH type rotational viscometer 4R).
An emulsion copolymer of pn+) 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.

Comparative Example 3 ■-Hydroxycyclohexyl? 2 parts of 10 parts of enylketone (manufactured by Ciba Geigy, trade name: Irgacure 184)
- It was dissolved in 2400 parts of hydroxyethyl methacrylate, and 150 parts of tetraethylene glycol dimethacrylate was further added and dissolved in this solution. (This solution is referred to as Solution A) Separately, 600 parts of sulfopropyl methacrylate potassium salt was dissolved under heating in 2450 parts of 5% saline, and 2800 parts of glycerin was further added to obtain a homogeneous solution. (
(This solution is called Solution B.) Also, add 110 parts of ketoprofen to 1750 parts of propylene glycol, stir thoroughly to obtain a uniform dispersion, add this to 2450 parts of Solution A, and then add 5850 parts of Solution B to A.
It was added to the liquid and defoamed to obtain a homogeneous solution. Thickness 50-mm with a groove to prevent this liquid from flowing out around the liquid.
300-mm thick on PET film held horizontally.
I poured it so that it was. While keeping this thing in a nitrogen atmosphere, use a 30W chemical lamp (Toshiba FL30SB).
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.

Test Example 1 A release test sample for medicinal ingredients (sample of Examples 1 to 2 and Comparative Example 1.3) of 8.55 cd (diameter 3.3 cm) was weighed and placed in a release test cell. 150 1715M phosphate buffer as test solution
ml is added, fixed in a constant temperature bath at 37°C, and stirred at a constant speed using a magnetic stirrer. Accurately collect 3 ml of the test liquid from the release cell at regular intervals. Immediately add test solution 3+++1 pre-warmed to 37°C to the release cell.
Accurately refill and keep the fluid level constant. After completing the test, treat the sample with water to wash off the plaster, remove the support,
After drying at 100° C. for 1 hour and standing at room temperature, the weight is measured. Calculate the plaster weight from the difference in weight before and after. The test solution collected earlier is returned to room temperature and used as the sample solution.

Accurately take 1 ml of the sample solution and standard solution, add 5s+1 of the internal standard solution, filter through a 0.45 μ membrane filter, and then perform HPLC per 10 μl.
The results of this test, in which the medicinal ingredients were quantified using the method, are shown in Figure 1.

As is clear from FIG. 1, the patch of the present invention has significantly superior release properties compared to patches containing lipophilic acrylate as the main component in the base.

Moreover, by changing the crosslinking density of the acrylate in the base of the present invention, it is possible to arbitrarily control the release properties of the medicinal ingredient.

Furthermore, the release rate of the medicinal ingredient in the base is close to 100%, and the residual amount is extremely low. Furthermore, as is clear from ■ in Comparative Example 3, the content of tetraethylene glycol dimethacrylate, which is the third component and also the crosslinking component, is 1% by weight or more (Comparative Example 3 is 1% by weight).
(contains 48% by weight), the release property decreases, and after application 4%
Approximately 20% of the medicinal ingredients remain in the base even after 0 hours have passed.

Next, as is clear from FIGS. 2 and 3, the patch of the present invention has significantly superior release properties compared to commercially available products.

Test Example 2 Skin irritation test Six types of Examples 1, 2, 8, 10, and 11 and Comparative Example 1 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 12 Clear redness 12: Severe sensation The test results revealed that the patch of the present invention significantly reduces skin irritation.

Test Example 3 Adhesion Test Using seven types of Examples 1 to 4 and Comparative Examples 1 to 3, tack measurements and a sticking test on human skin were conducted. The tack measurement method (probe tack method) will be described 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 contact time was 0.1 seconds, and the contact pressure was 10
0 g/co! , the measurement was carried out under the conditions of a separation speed of 1.0 cm/sec.

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 of the invention]

As shown in Test Examples 1 to 3 above, the present invention has a remarkable drug release effect in release tests for medicinal ingredients. This allows the medicinal ingredients to be released more quickly than in the base, which greatly contributes to improving the immediate effectiveness, sustainability, and therapeutic effects of the drug.

In addition, in the skin irritation test, the incidence of skin irritation was extremely low, and the test results were better than expected. Although this problem of skin contact has been a particular problem with patch preparations, the patch preparation of the present invention hardly causes any skin contact and is extremely safe.

Also, in the adhesion test, it has excellent initial adhesion, with almost no peeling occurring 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 process is carried out at room temperature, it is now possible to use medicinal ingredients that previously had problems with heat treatment. It is a manufacturing method.

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

[Brief explanation of the drawing]

Figure 1 shows Examples 1 and 2 of the present invention and Comparative Examples 1.3.
The release test results are shown in a curve graph. In FIG. 1, ■ indicates the release curve of Example 1, ■ indicates the release curve of Example 2, ■ indicates the release curve of Comparative Example 1, and ■ indicates the release curve of Comparative Example 3. Figure 1 Release test

Claims (1)

[Claims] 1. As a base component, an ionic unsaturated monomer, a (meth)acrylate represented by (a) below, a crosslinking component, a water-soluble polyhydric alcohol, water and a medicinal ingredient are blended, A patch preparation that is polymerized and crosslinked in the presence of a polymerization initiator. (a) It is a (meth)acrylate represented by the following general formula. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R_1 is a hydrogen atom or a methyl group, R_2 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and n is an integer from 1 to 23.) 2 , 1 to 40% by weight of an ionic unsaturated monomer as a base component, and (meth)acrylate 2 represented by (a) below.
~30% by weight, crosslinking component 0.05-1.0% by weight, water-soluble polyhydric alcohol 10-80% by weight, water 5-40% by weight
and 0.02 to 30% by weight of a medicinal ingredient, and is polymerized and crosslinked in the presence of a polymerization initiator. (a) It is a (meth)acrylate represented by the following general formula. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R_1 is a hydrogen atom or a methyl group, R_2 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and n is an integer from 1 to 23.) 3 , a radically polymerizable ionic unsaturated monomer that is soluble in a mixture of a water-soluble polyhydric alcohol and water, a (meth)acrylate represented by the following general formula (a), a crosslinking component, and a water-soluble polyhydric monomer. A method for producing a patch preparation, which comprises irradiating a paste containing alcohol, water, and medicinal ingredients with ultraviolet rays in the presence of a photopolymerization initiator to polymerize and crosslink it. (a) It is a (meth)acrylate represented by the following general formula. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R_1 is a hydrogen atom or a methyl group, R_2 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and n is an integer from 1 to 23.)