JP2503095B2 - Patch - Google Patents

Description

TECHNICAL FIELD The present invention relates to a patch for transdermal administration or transmucosal administration of a drug. More specifically, it relates to a patch having excellent transdermal absorbability of a drug and being less irritating to the patch.

(Prior Art) In order to obtain a drug effect systemically or locally, a transdermal patch is used to absorb a drug (physiologically active substance) through the skin. This transdermal administration method has many advantages over the conventional tendency administration method. For example, when a drug is orally administered, the drug absorbed in the intestine is circulated to the liver and metabolized, so that a considerable amount of the drug is decomposed before its drug effect is exerted. On the other hand, in the transdermal administration method, the absorbed drug does not pass through the liver during the initial circulation in the body. Therefore, the medicinal effect is not greatly reduced by metabolism in the liver. Oral administration of a drug may cause gastrointestinal disorders, but transdermal administration does not cause such a problem. Furthermore, by controlling the absorbability of the drug, it becomes possible to reduce side effects caused by the drug being absorbed in large amounts in a short time. If a constant blood concentration can be maintained over a long period of time, the number of drug administrations can be reduced.

However, the transdermal administration method has some problems. For example, even when a drug is administered using a transdermal patch, the drug often does not easily penetrate the skin, resulting in a low bioavailability. In particular, there is a stratum corneum on the surface of the skin, and this stratum corneum has a barrier function that prevents foreign substances from entering the body, so in many cases a sufficient amount of drug capable of exerting a pharmacological effect is not absorbed through the skin. .
Therefore, a preparation containing an absorption enhancer in order to weaken the barrier function of the stratum corneum and absorb a sufficient amount of the drug has been produced. However, in general, an auxiliary agent having a large absorption promoting effect is not preferable because it has a large irritation to the skin.

As a percutaneous absorption preparation, a patch in which a pressure-sensitive adhesive layer containing a drug is provided on one surface of a support is widely used. Such patches often cause mechanical irritation by pulling on the skin during peeling, and often cause skin irritation such as a rash because they are applied to the skin for a long time.

As a means for solving such a problem, a pressure-sensitive adhesive having a low adhesive strength is used for the pressure-sensitive adhesive layer, and silicic acid anhydride is further added. Such patches have little mechanical irritation or skin irritation at the time of peeling. However, when the pressure-sensitive adhesive layer containing a large amount of silicic acid anhydride is to be formed by the solvent coating method, the thixotropy of the pressure-sensitive adhesive layer solution coated on the support becomes large, which makes smooth coating difficult. Become.

(Problems to be Solved by the Invention) The present invention is to solve the above-mentioned conventional problems, and an object thereof is to provide a patch that effectively releases a drug and can be absorbed through the skin. It is in.

Another object of the present invention is to provide a patch which has low skin irritation, can be applied to the skin surface without peeling for a long time, and can be easily peeled from the skin surface. .

Still another object of the present invention is to provide a patch which can easily form a pressure-sensitive adhesive layer by a solvent coating method.

(Means for Solving the Problems) The patch of the present invention is a patch in which a pressure-sensitive adhesive layer is provided on one surface of a flexible support, and the pressure-sensitive adhesive layer is a pressure-sensitive adhesive base or the pressure-sensitive adhesive group. A compound having a plasticizing effect on the agent, silicic acid anhydride, a drug, and a water-absorbing filler, and the content of silicic acid anhydride in the pressure-sensitive adhesive layer is 4 to 20% by weight,
The water-absorbing filler has a property of absorbing water and swelling, and not substantially swelling by the drug, thereby achieving the above object.

Examples of the adhesive base used in the patch of the present invention include acrylic adhesives, rubber adhesives, silicone adhesives, polyvinyl ether adhesives, polyurethane adhesives and the like. In particular, an acrylic adhesive or a rubber adhesive is preferably used.

As an acrylic adhesive, because of its adhesive physical properties,
In particular, a (co) polymer of (meth) acrylic acid alkyl ester obtained from an aliphatic alcohol having 4 to 18 carbon atoms and (meth) acrylic acid and / or the above (meth) acrylic acid alkyl ester and other functionalities A copolymer with a monomer is preferably used.

Examples of the (meth) acrylic acid ester include butyl acrylate, isobutyl acrylate, hexyl acrylate, octyl acrylate, 2-ethylhexyl acrylate, isooctyl acrylate, decyl acrylate, isodecyl acrylate, lauryl acrylate, acrylic acid. Stearyl, methyl methacrylate, ethyl methacrylate,
There are butyl methacrylate, isobutyl methacrylate, 2-ethylhexyl methacrylate, isooctyl methacrylate, decyl methacrylate, isodecyl methacrylate, lauryl methacrylate, stearyl methacrylate and the like.

Examples of the other functional monomer include a monomer having a hydroxyl group, a monomer having a carboxyl group, a monomer having an amide group, a monomer having an amino group, and the like. Examples of the monomer having a hydroxyl group include hydroxyalkyl (meth) acrylates such as 2-hydroxyethyl (meth) acrylate and hydroxypropyl (meth) acrylate. Examples of the monomer having a carboxyl group include α, β such as acrylic acid and methacrylic acid.
Unsaturated carboxylic acids; maleic acid monoalkyl esters such as butyl maleate; maleic acid; fumaric acid; crotonic acid. Maleic anhydride can also be used as it can form a copolymer similar to maleic acid. Examples of the amide group-containing monomer include alkyl (meth) acrylamides such as acrylamide, dimethyl acrylamide, and diethyl acrylamide; alkyl ether methylol (meth) acrylamides such as butoxymethyl acrylamide and ethoxymethyl acrylamide; diacetone acrylamide; vinylpyrrolidone. Examples of the monomer having an amino group include dimethylamino acrylate. In addition to the above, vinyl acetate, styrene, α-methylstyrene, vinyl chloride, acrylonitrile, ethylene, propylene, butadiene, etc. may also be used.

The acrylic pressure-sensitive adhesive can be obtained by copolymerizing the above-mentioned monomers by a commonly known method. The copolymer component preferably contains 50% by weight or more of the above-mentioned (meth) acrylic acid alkyl ester.

As the rubber-based pressure-sensitive adhesive, natural rubber, synthetic isoprene rubber, polyisobutylene, polyisoprene, polybutadiene, styrene-butadiene copolymer, styrene-isoprene copolymer, styrene-isoprene-styrene block copolymer and the like are used.

As the silicone resin adhesive, silicone rubber such as polyorganosiloxane is used.

In the above-mentioned pressure-sensitive adhesive, if necessary, various compounding agents, for example, tackifiers such as rosin resin, polyterpene resin, coumarone-indene resin, petroleum resin, terpene phenol resin; liquid polybutene, mineral oil, lanolin, liquid isobutylene. , Softening agents such as liquid polyacrylate; fillers;
Antiaging agents and the like are added.

A compound (plasticizer) having a plasticizing action on the above-mentioned adhesive base is added to the adhesive layer of the patch of the present invention.
Such a compound adjusts the viscosity of the pressure-sensitive adhesive layer and promotes transdermal or transmucosal absorbability of the compounded drug.

Examples of the plasticizer used in the patch of the present invention include compounds such as esters, ethers, hydrocarbons, alcohols and amides, and fatty acid esters are particularly preferably used. Examples of such compounds include cetyl octanoate, hexyl laurate, isopropyl myristate, octyldodecyl myristate, isopropyl palmitate, octyl palmitate, butyl stearate, octyl stearate, octyl hydroxystearate, isotridecyl isononanoate. , Monooleic alcohol fatty acid ester such as ethyl oleate, decyl oleate, mink oil fatty acid ethyl, myristyl lactate; dibasic acid ester such as diisopropyl adipate, dioctyl adipate, diethyl sebacate, dioctyl succinate; propylene glycol dicaprate , Glyceryl trioctanoate, glyceryl tri (octanoic acid / decanoic acid), glyceryl tripalmitate, sobitanolate,
Polyhydric alcohol fatty acid ester such as neutral fatty acid oil and fat;
Animal and vegetable oils such as olive oil, safflower oil, coconut oil fatty acid triglyceride and cottonseed oil; hydrocarbons such as squalane, α-olefin oligomer, liquid paraffin and wax; cetanol, behenyl alcohol, 2-hexyldecanol, 2-octyldecanol, oleyl alcohol, etc. Alcohols; ethers such as polyoxyethylene lauryl ether and polyoxyethylene oleyl ether; amide compounds such as oleic acid amide and lauric acid monoethanolamide; dimethyl polysiloxane,
There are silicones such as methylphenyl polysiloxane.

The compounding amount of the plasticizer depends on the type and polarity of the plasticizer, the type and polarity of the adhesive base, the molecular weight, and the like. Usually, relative to 100 parts by weight of the adhesive base, 1 to 300 parts by weight,
It is preferably 3 to 100 parts by weight. If it exceeds 300 parts by weight, the cohesive force of the adhesive layer will be insufficient.

Further, silicic acid anhydride is added to the pressure-sensitive adhesive layer of the patch of the present invention for the purpose of improving the cohesive force of the pressure-sensitive adhesive layer. As the silicic acid anhydride, fine particles having a particle size of about 0.01 to about 100 μm are used. The content of such silicic acid anhydride is adjusted depending on the type and amount of the drug to be incorporated, the type and composition of the adhesive base, the type and amount of the plasticizer, etc.
It is blended in a proportion of ~ 20% by weight. If it is less than 4% by weight, the effect of improving the cohesive force is small, and if it exceeds 20% by weight, the tackiness of the pressure-sensitive adhesive layer is lost. When silicic acid anhydride is blended in an appropriate amount, the patch layer has cohesive force to the extent that adhesive residue does not occur when peeled off, at the same time it is soft and fits well on the skin, and does not peel off with weak adhesive force. It shows good stickiness. Further, mechanical irritation caused by pulling the skin during application and peeling can be reduced.

The silicic acid anhydride is generally a hydrophilic one having a hydroxyl group on the surface, but there is also a hydrophobic silicic acid anhydride whose surface is covered with a dimethylsilanol group. Such hydrophobic silicic acid anhydride is obtained by treating the surface of silicic acid anhydride particles having a hydroxyl group on the surface with dimethyldichlorosilane. In the present invention, as the silicic acid anhydride, a mixture of hydrophilic silicic acid anhydride and hydrophobic silicic acid anhydride can be used. The preferred blending ratio of the hydrophilic silicic acid and the hydrophobic silicic acid is 20 to 80% by weight of the hydrophilic silicic acid and 80 to 20% by weight of the hydrophobic silicic acid based on the total amount of the silicic acid anhydride. It is a ratio. When the hydrophobic silicic acid anhydride content is less than 20% by weight and the hydrophilic silicic acid anhydride content is more than 80% by weight, the thixotropic property of the adhesive base solution becomes large, and the adhesive layer is formed on the support pair by the solvent coating method. Becomes difficult to do. Furthermore, the pressure-sensitive adhesive layer easily absorbs moisture, and the patch is easily peeled off by sweating. On the other hand, if the hydrophobic silicic acid anhydride exceeds 80% by weight, the cohesive force of the pressure-sensitive adhesive layer cannot be increased.

The drug (physiologically active substance) used in the patch of the present invention is not particularly limited as long as it is a drug that can penetrate a biological membrane by transdermal administration or transmucosal administration. For example, antipyretic anti-inflammatory analgesics, steroidal anti-inflammatory agents, vasodilators, hypertensive / arrhythmic agents, antihypertensive agents, antitussive agents, antitumor agents,
Local anesthetic, hormone, asthma / nasal allergy treatment,
Examples thereof include antihistamines, anticoagulants, antispasmodics, cerebral circulation / metabolic agents, antidepressants / anxiety agents, vitamin D preparations, oral hypoglycemic agents, antiulcer agents, hypnotics, antibiotics and the like.

Antipyretic and anti-inflammatory analgesics include indomethacin, salicylic acid, aspirin, acetaminophen, diclofenac sodium, ibuprofen, sulindac, naproxen, furifenamate, ibufenac, fenbufen, alclofenac, phenylbutazone, mehenamic acid, bendazac, piroxicam, flur Examples include biprofen, pentazocine, buprenorphine hydrochloride, butorphanol tartrate.

Hydrocortisone, as a steroidal anti-inflammatory drug,
Prodnisolone, fluocinolone acetonide, fludoxycortide, methylprednisolone, hydrocortisone acetate, triamcinolone acetonide, dexamethasone,
Hetamethasone acetate, diflucortron valerate, propionclohetazole, fluocinonide, etc.

Vasodilators include diltiazem, verapamil, pentaerythritol tetranitrate, dipyridamole, isosorbide dinitrate, nifedipine, nitroglycerin.

Examples of agents for hypertension / arrhythmia include propanolol, atenolol, pindolol, quinidine sulfate, azmarin,
Examples include alprenolol hydrochloride, metoprolol tartrate, nadolol, timolol maleate, and disopyramide.

As hypotensive agents, clonidine hydrochloride, captoril,
Examples include prazosin hydrochloride, benbutolol sulfate, guanabenz acetate, guanfacine hydrochloride, guanabenz acetate, punazosin hydrochloride, ellanapril maleate, arotinolol hydrochloride, and bunitrolol hydrochloride.

As the antitussive agent, procaterol hydrochloride, terbutaline sulfate, fenoterol hydrobromide, tulobuterol hydrochloride, ambroxol hydrochloride, pirbuterol hydrochloride,
Examples include mabuterol hydrochloride, clenbuterol hydrochloride, trimethoquinol hydrochloride, formoterol fumarate.

Anti-tumor agents include 5-fluorouracil, 1- (2
-Tetrahydrofuryl) -5-fluorouracil, mitomycin C and the like.

Local anesthetics include benzocaine, procaine, lidocaine, tetracaine and the like.

The hormonal agents include steroid hormones such as estrogen, estradiol, testosterone, progesterone and prostaglandins; peptide hormones such as insulin.

Asthma / nasal allergy treatment agents include ketotifen fumarate, azelastine hydrochloride, sodium cromoglycate and the like. Antihistamines include cycloheptazine hydrochloride, diphenhydramine hydrochloride, fenbenzamine,
There is mequitazine. Anticoagulants include heparin and the like. Antispasmodics include scopolamine, clofluperol, and the like. Cerebral circulatory metabolism improvers include pinpocetine, flunarizine hydrochloride, nicardipine hydrochloride, brovincamine fumarate, dihydroergotoxine mesylate,
Examples include ifenprodil tartrate and isoxuprine hydrochloride. Examples of antidepressant / anxiolytic agents include maprotiline hydrochloride, etizolam, diazepam, bromazepam, amitriptyline hydrochloride, and mianserin hydrochloride. Examples of vitamin D agents include α-calcidol and ergocasiferol. Oral hypoglycemic agents include glibenclamide,
There is gliclazide. Antiulcer agents include grepobride malate, famotidine, glycopyrronium bromide and the like. Examples of sleeping pills include phenobarbital and amobarbital. Antibiotics include tetracycline and chloramphenicol.

The blending amount of these drugs varies depending on the type of drug, the purpose of use of the patch, etc., but is usually 0.1 to 40 in the adhesive layer.
% By weight.

The water-absorbing filler used in the patch of the present invention is a compound capable of absorbing water and swelling (usually a polymer), and has a low affinity with the adhesive base and the drug contained therein,
It can be dispersed in the adhesive base in the form of fine particles. By containing such a filler in the pressure-sensitive adhesive layer, the drug release property and the coatability of the pressure-sensitive adhesive layer solution can be significantly improved. As such a water-absorbing filler, cross-linked polyvinyl pyrrolidone, crystalline cellulose, cross-linked carboxymethyl cellulose, cross-linked hydroxyalkyl cellulose (for example, cross-linked hydroxypropyl cellulose),
Examples include cross-linked polyvinyl alcohol. In particular, crosslinked polyvinylpyrrolidone is preferably used.

The crosslinked polyvinylpyrrolidone is obtained by copolymerizing N-vinyl-2-pyrrolidone and a polyfunctional monomer. Examples of the polyfunctional monomer used include di (meth) acrylates such as hexamethylene glycol di (meth) acrylate, ethylene glycol di (meth) acrylate, and triethylene glycol di (meth) acrylate; trimethylolpropane tri ( Tri (meth) acrylates such as (meth) acrylate; and tetra (meth) acrylates such as pentaerythritol tetra (meth) acrylate; polyallyl compounds such as diethylene glycol bisallyl carbonate, triallyl glycerin, triallyl cyanurate; ethylene bismaleimide, etc. A polymaleimide compound or the like is used. Alternatively, divinylbenzene, methylenebisacrylamide, ethylidenebisvinylpyrrolidone, divinylketone, butadiene, isoprene and the like can be used.

The amount of the polyfunctional monomer to be copolymerized is preferably 0.1 to 10 mol% based on the total amount of the monomers. If it is less than 0.1 mol%, the resulting crosslinked polyvinylpyrrolidone will dissolve in the adhesive base or swell excessively, making it difficult to maintain the particle structure in the adhesive base. When the amount of the polyfunctional monomer exceeds 10 mol%, the obtained crosslinked polyvinylpyrrolidone hardly absorbs water and the drug release property of the pressure-sensitive adhesive layer cannot be enhanced.

Suitable examples of commercially available cross-linked polyvinylpyrrolidone include Kollidon CL (manufactured by BASF), Polyplasdone XL (GAF
Manufactured by U.S.A.
No. 0, 3933766, 3689439, 4139688 and
No. 4180633.

Such a water-absorbing filler is blended in the pressure-sensitive adhesive layer in a proportion of 0.5 to 20% by weight. If it is less than 0.5% by weight, the effect of promoting drug release cannot be obtained, and the effect of lowering the thixotropic property of the pressure-sensitive adhesive layer solution is also small. If it exceeds 20% by weight, the adhesive strength of the pressure-sensitive adhesive layer is reduced, and good sticking properties cannot be obtained.

As the support used for the patch of the present invention, a support usually used for patches is used. As the material for such a support, polyolefin, cellulose acetate,
Examples include ethyl cellulose, polyethylene terephthalate, plasticized vinyl acetate-vinyl chloride copolymer, nylon, ethylene-vinyl acetate copolymer, plasticized polyvinyl chloride, polyurethane, polyvinylidene chloride, and aluminum. These materials are flexible, breathable, water vapor permeable,
It is selected according to the required properties such as drug impermeability, moisture retention, and appearance. And, for example, it is used as a single layer sheet or a laminate of two or more sheets. Materials other than aluminum may be used as a woven or nonwoven fabric.

The patch of the present invention can be produced according to a usual method for producing an adhesive tape. For example, various coating methods such as a solvent coating method, a hot melt coating method, an electron beam curing method and an emulsion coating method are adopted. In particular, the solvent coating method is preferably used. To form the adhesive layer by the solvent coating method, for example,
Dilute the adhesive base with an appropriate solvent, add plasticizer, silicic acid anhydride, drug, and water-absorbing filler, and if necessary, compounding ingredients, mix evenly, and support the resulting solution. Apply on body surface and dry. For coating, a coater such as a roll coater or a blade coater is used. Instead of directly applying the solution to the surface of the support, the solution may be applied onto a release paper coated with a silicone resin or the like, dried and then brought into close contact with the support. Such release paper is used to protect the surface of the pressure-sensitive adhesive layer of the patch until use. Even in coating methods other than the solvent coating method, it is recommended to dispose a release paper for protecting the surface of the pressure-sensitive adhesive layer after forming the pressure-sensitive adhesive layer. The thickness of the pressure-sensitive adhesive layer varies depending on the use, but is usually 30 to 2000 μm. If it is less than 30 μm, the required amount of drug cannot be contained and the adhesiveness is insufficient. When it exceeds 2000 μm, the drug contained in the pressure-sensitive adhesive layer near the support does not sufficiently diffuse, and the drug release property decreases.

(Action) The patch of the present invention is configured as described above, and since the adhesive layer contains a compound having a plasticizing action on the adhesive base, the adhesive force of the adhesive base is relatively low. . Therefore, skin irritation is low and skin irritation is unlikely to occur. Furthermore, the body surface is not peeled off when the patch is peeled off. Since the pressure-sensitive adhesive layer is flexible, it adheres to the surface of the skin and can follow the expansion and contraction of the skin even though it has a low adhesive force, so that it does not easily peel off.

Generally, when a compound having a plasticizing action is added to the pressure-sensitive adhesive base, the cohesive force of the pressure-sensitive adhesive base is reduced, and the composition of the pressure-sensitive adhesive layer sticks out to the outside of the support or when the patch is peeled off. Moreover, the adhesive composition may remain on the skin. However, in the patch of the present invention, the cohesive force does not decrease due to the silicic acid anhydride contained in the pressure-sensitive adhesive layer. Furthermore, in the patch of the present invention, due to the effect of the plasticizer in the pressure-sensitive adhesive layer, the pressure-sensitive adhesive base is in a swollen state, and the viscosity of the pressure-sensitive adhesive is low. The silicic acid anhydride contained in the pressure-sensitive adhesive layer suppresses the fluidity of the pressure-sensitive adhesive layer while maintaining the swelling state of the pressure-sensitive adhesive base. Therefore,
Even though the pressure-sensitive adhesive layer has a good cohesive force, it can easily diffuse and move through the drug or the pressure-sensitive adhesive base, and is effectively released and percutaneously absorbed.

Furthermore, since the patch of the present invention contains a water-absorbing filler in the adhesive layer, the drug is released more effectively. Although the detailed mechanism is not clear, it is considered as follows. The water-absorptive filler has a property that it does not substantially swell with a drug and absorbs water to swell. Therefore, when the patch of the present invention is applied to the skin surface, the water-absorptive filler absorbs moisture or sweat evaporated from the skin surface and swells, and acts to remove the drug from the adhesive layer. By the action of this water-absorbent filler, the drug is effectively released from the adhesive layer and administered into the blood through the skin or mucous membrane.

(Example) Hereinafter, the present invention will be described with reference to Examples.

Example 1 Dodecyl methacrylate 2286 g, 2-ethylhexyl methacrylate 14256 g, 2-ethylhexyl acrylate 1656
g, hexanediol dimethacrylate 2.3 g, and ethyl acetate 8500 g were placed in a 40 polymerization machine and heated to 80 ° C. Next, a solution prepared by dissolving 16 g of lauroyl peroxide in 1500 g of cyclohexane was added to this mixed solution over 6 hours and polymerized to obtain an adhesive solution having a weight average molecular weight of 1.0x10 ⁶ and a solid content of 58%.

To this adhesive solution, isopropyl myristate, hydrophilic silicic acid anhydride (Aerosil A-200), a 10% ethyl acetate solution of isosorbide dinitrate and crosslinked polyvinylpyrrolidone (Colidone CL) were added. Then, the mixture was uniformly mixed with a dissolver to prepare an ethyl acetate dispersion having a nonvolatile content of about 30%. This dispersion was applied onto polyester release paper so that the thickness after drying would be 100 μm, and dried at 60 ° C. for 30 minutes to form an adhesive layer. A polyester / EVA laminate film was attached to this to obtain the patch of the present invention.

Adhesive 50.3% by weight Isopropyl myristate 7.3% by weight Aerosil A-200 9.3% by weight Isosorbide dinitrate 22.2% by weight Kollidon CL 10.9% by weight Example 2 Using the adhesive solution prepared in Example 1, the ratio after drying was as follows: A pressure-sensitive adhesive layer dispersion liquid was prepared so as to have the composition shown in, and the patch of the present invention was obtained in the same manner as in Example 1. This adhesive layer dispersion has a smaller amount of cross-linked polyvinylpyrrolidone (Kolidone CL) than in Example 1.

Adhesive 52.2% by weight Isopropyl myristate 7.6% by weight Aerosil A-200 9.0% by weight Isosorbide dinitrate 23.6% by weight Kollidon CL 7.6% by weight Comparative Example 1 Using the adhesive solution prepared in Example 1, the ratio after drying was as follows. A pressure-sensitive adhesive layer dispersion liquid was prepared so as to have the composition shown in, and a patch was obtained in the same manner as in Example 1. This adhesive layer dispersion does not use crosslinked polyvinylpyrrolidone (Kolidone CL).

Adhesive 59.3% by weight Isopropyl myristate 8.0% by weight Aerosil A-200 12.0% by weight Isosorbide dinitrate 20.7% by weight Comparative Example 2 Using the adhesive solution prepared in Example 1, the ratio after drying is the composition shown below. Thus, the pressure-sensitive adhesive layer dispersion was prepared and a patch was obtained in the same manner as in Example 1. This adhesive layer dispersion does not use hydrophilic silicic anhydride (Aerosil A-200).

Adhesive 50.8% by weight Isopropyl myristate 8.3% by weight Isosorbide dinitrate 25.6% by weight Kollidon CL 15.3% by weight Experimental Example 1 Regarding the patches obtained in the above Example 1, Example 2, Comparative Example 1 and Comparative Example 2, The releasability, the holding power of the patch, the patchability and the coatability of the pressure-sensitive adhesive layer dispersion were evaluated.
Table 1 shows the results. The methods for evaluating the releasability, holding power, stickiness and coatability are as follows.

Release test: Nude mouse skin permeability test was performed. The skin removed from the back of a nude mouse was fixed to a Franz diffusion cell, and a patch of 3.14 cm ² was attached to the upper side of the skin.
The diffusion cell was kept at a constant temperature of 37 ° C, and a 20% polyethylene glycol (PEG) aqueous solution was used as a receptor solution. The amount of drug transferred to the receptor solution under the skin after 24 hours (mg / c
m ² ) was measured by high performance liquid chromatography (HPLC) to evaluate the release property of the drug from the patch.

Holding power test: Measured according to the JIS Z0237 adhesive tape / adhesive sheet test method. The patch was cut into a rectangle of 25 mm x 50 mm to prepare a test piece. Stick the upper 25 mm x 25 mm part of this test piece on a stainless steel test plate, apply a load of 1 kg to the other end of the test piece, leave it in an oven at 40 ° C, The time (minutes) from peeling to falling was measured, and the value was used as the holding power. The longer the time before falling, the greater the holding force and the greater the cohesive force. When the holding power is large, adhesive residue is less likely to occur when the patch is applied.

Adhesion test: Cut the patch to a size of 15 mm × 15 mm,
The test piece was used. Attach this test piece to the chest of the subject and
The peeling of the test piece after a lapse of time and the degree of adhesive residue when the test piece was peeled off were observed.

Coatability test: Using a comma coater with a dryer capable of continuous coating, it was investigated whether or not continuous coating could be performed to a certain thickness with a smooth surface condition.

As can be seen from Table 1, the patches (Example 1 and Example 2) of the present invention containing cross-linked polyvinylpyrrolidone and hydrophilic silicic anhydride (Aerosil A-200) have releasability, holding power, patchability and Excellent coatability. On the other hand, the patch of Comparative Example 1 containing no cross-linked polyvinylpyrrolidone was not sufficient in releasability and holding power, and the applicability of the pressure-sensitive adhesive layer solution when preparing the patch was poor. The patch of Comparative Example 2 containing cross-linked polyvinylpyrrolidone but not containing silicic acid improved the release property as compared with the patch of Comparative Example 1, but was inferior in holding power and patchability. An adhesive residue was produced when peeled off. further,
From a comparison between Example 1 and Example 2, it can be seen that the larger the blended amount of crosslinked polyvinylpyrrolidone, the higher the releasability and the holding power.

Example 3 80 g of 2-ethylhexyl acrylate, 2 methacrylic acid
-Ethylhexyl (60 g), butyl acrylate (60 g) and ethyl acetate (130 g) were placed in a polymerization machine and heated to 60 ° C. Then
A solution prepared by dissolving 0.5 g of lauroyl peroxide in 50 g of cyclohexane was added over 6 hours and polymerized to obtain a pressure-sensitive adhesive solution having a weight average molecular weight of 6.5 × 10 ⁵ and a solid content of 54%.

To this adhesive solution, isopropyl myristate, hydrophilic silicic acid anhydride (Aerosil A-200), indomethacin and crosslinked polyvinylpyrrolidone (Colidon CL) were added so that the ratio after drying would be the composition shown below, and the mixture was dissolved with a dissolver. The mixture was uniformly mixed to prepare an ethyl acetate dispersion liquid having a nonvolatile content of about 30%. The thickness of this dispersion is 50 μm after drying.
Coated on polyester release paper at 60 ℃
It was dried for 30 minutes to form an adhesive layer. A polyethylene film was attached to this to obtain the patch of the present invention.

Adhesive 56 wt% Isopropyl myristate 20 wt% Aerosil A-200 5 wt% Indomethacin 8 wt% Kollidon CL 11 wt% Comparative Example 3 Using the adhesive solution prepared in Example 3 and indomethacin, the ratio after drying was A pressure-sensitive adhesive layer liquid was prepared so as to have the composition shown below, and a patch was obtained in the same manner as in Example 3. This pressure-sensitive adhesive layer liquid does not contain isopropyl myristate, silicic acid anhydride and crosslinked polyvinylpyrrolidone.

Adhesive of Example 3 92% by weight Indomethacin 8% by weight Comparative Example 4 Using the adhesive solution prepared in Example 3, an adhesive layer dispersion liquid was prepared so that the ratio after drying would be the composition shown below. A patch was obtained in the same manner as in Example 3. This pressure-sensitive adhesive layer dispersion liquid is the same as in Example 3 except that the crosslinked polyvinylpyrrolidone was not used.

Adhesive of Example 3 67% by weight Isopropyl myristate 20% by weight Aerosil A-200 5% by weight Indomethacin 8% by weight Example 2 About the patches obtained in the above Example 3, Comparative Example 3 and Comparative Example 4, the drug was used. The releasability and the adhesive patch holding power were evaluated. The test method is the same as in Experimental Example 1 above. However,
In the present Example, the results of the drug release test were used to show the amount of indomethacin released (0.014 mg / c) obtained with the patch of Comparative Example 3.
It was shown as a relative value when m ² ) was defined as the release rate of 100. The test results are shown in Table 2.

As can be seen from Table 2, isopropyl myristate,
The patch of Comparative Example 3 containing no silicic acid anhydride and cross-linked polyvinylpyrrolidone had sufficient holding power, but was inferior in drug release property to other patches. In the patch of Comparative Example 4 in which the patch of Comparative Example 3 was mixed with isopropyl myristate and silicic acid anhydride, the drug release was improved but the holding power was decreased. On the other hand, the patch of the present invention (Example 3) had high drug release and excellent retention.

Example 4 Styrene-isoprene-styrene block copolymer (SIS), liquid paraffin, alicyclic saturated hydrocarbon resin (trade name Alcon P, manufactured by Arakawa Chemical Co., Ltd.), glycol salicylate, crystalline cellulose and Aerosil A-200 were used. The pressure-sensitive adhesive layer block was prepared by adding the ingredients so as to have the composition shown below and uniformly mixing at 140 ° C. The pressure-sensitive adhesive layer block was coated with a hot melt coater to a thickness of 100 μm.
It was coated on polyester release paper at 120 ° C. so as to have m, to form an adhesive layer. A soft polyvinyl chloride film was attached to this to obtain the patch of the present invention.

SIS 30 wt% Liquid paraffin 22 wt% Alicyclic saturated hydrocarbon resin 24 wt% Glycol salicylate 8 wt% Crystalline cellulose 9 wt% Aerosil A-200 5 wt% Comparative Example 5 A pressure-sensitive adhesive layer block having the composition shown below is prepared. A patch was prepared in the same manner as in Example 4. This adhesive layer block does not use crystalline cellulose.

SIS 40% by weight Liquid paraffin 21% by weight Alicyclic saturated hydrocarbon resin 31% by weight Glycolic salicylate 8% by weight Experimental Example 3 Drug release and patchability of the patches obtained in Example 4 and Comparative Example 5 above. And the skin irritation was evaluated. Table 3 shows the results. The test method is the same as in Experimental Example 1 above.

As can be seen from Table 3, the patch of Comparative Example 5 containing no crystalline cellulose was inferior in the drug release property and the patch property, and some adhesive residue was generated when the patch was peeled off. On the other hand, the patch of the present invention of Example 4 containing crystalline cellulose was excellent in releasability and patchability.

(Effect of the Invention) Thus, the patch of the present invention can effectively percutaneously or transmucosally absorb various drugs. The patch of the present invention is
Especially when absorbing water, the drug releasing effect is great.
Therefore, the patch of the present invention, when administered to the skin, absorbs water evaporated from the skin surface, sweat, etc., and effectively releases the drug. Furthermore, the patch of the present invention has extremely low skin irritation and can be applied to the skin surface without peeling off for a long time. Furthermore, this patch is
The adhesive composition does not remain on the skin when the patch is peeled off. Since the patch of the present invention has a small thixotropic property in the pressure-sensitive adhesive layer solution, the pressure-sensitive adhesive layer can be easily formed by the solvent coating method.

Claims (1)

(57) [Claims] 1. A patch having a pressure-sensitive adhesive layer provided on one surface of a flexible support, the pressure-sensitive adhesive layer being a pressure-sensitive adhesive base, and a compound having a plasticizing action on the pressure-sensitive adhesive base, It contains silicic anhydride, a drug, and a water-absorbing filler, and the content of silicic acid anhydride in the pressure-sensitive adhesive layer is 4 to 20% by weight, and the water-absorbing filler absorbs water and swells. An adhesive patch having the property of not substantially swelling with the drug.