JPH0798744B2 - Patch - Google Patents

Description

TECHNICAL FIELD The present invention relates to a patch for transdermal administration or transmucosal administration of a drug. In particular, it relates to a patch that can effectively percutaneously absorb a drug.

(Prior Art) A drug (physiologically active substance) is absorbed through the skin using a transdermal preparation. This transdermal administration method has the following advantages over the conventional oral administration method. For example, when a drug is orally administered, the drug absorbed in the intestine is metabolized in the liver, so that a considerable amount of the drug is decomposed before it exerts a medicinal effect in the affected area. In addition, since the drug is absorbed in a large amount in a short time, side effects are likely to occur.

On the other hand, in transdermal administration, unlike the above oral administration, the absorbed drug reaches the affected area without being decomposed by metabolism in the liver. Furthermore, for transdermal administration,
It is unlikely to cause gastrointestinal disorders as seen with oral administration. By adjusting the release amount of the drug by transdermal administration, it is possible to reduce side effects caused by, for example, a large amount of the drug being absorbed in a short time. Furthermore, if a constant drug release rate can be maintained over a long period of time, the frequency of drug administration can be reduced.

However, even if a drug is administered using a percutaneously absorbable preparation, it is difficult for the drug to penetrate the skin, and it is often impossible to administer a sufficient amount of the drug. For example, the stratum corneum on the surface of the skin has a barrier function for preventing the invasion of foreign substances into the body, so that a sufficient amount of the drug capable of exerting a medicinal effect is not absorbed through the skin. In general, attempts have been made to increase the transdermal absorbability of a drug by adding an absorption enhancer having a function of weakening the barrier function of the stratum corneum to the preparation. However, generally, an absorption enhancer having a large absorption promoting effect is highly irritating to the skin or mucous membranes, and the patch using such an absorption promoting agent has limited applications.

(Problems to be Solved by the Invention) The present invention is to solve the above-mentioned conventional problems, and an object of the present invention is to efficiently release a drug and to effectively deliver the drug through the skin or mucous membranes to the body. It is to provide a patch that can be absorbed by the skin.

(Means for Solving the Problems) The patch of the present invention is a patch having an adhesive layer provided on one surface of a support, and the adhesive layer excludes eperisone, triperizone and salts thereof. Drug, water absorbent filler,
And an adhesive base, and the water-absorbing filler has a property of absorbing water and swelling, and not substantially swelling by the drug, thereby achieving the above object.

According to a preferred embodiment, in the patch of the present invention, the pressure-sensitive adhesive layer further contains a compound having a plasticizing effect on the pressure-sensitive adhesive base.

The drug 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 and antiphlogistic analgesics, steroidal anti-inflammatory agents, vasodilators, hypertensive / arrhythmic agents, antihypertensive agents, antitussive agents, antitumor agents, local anesthetics, hormonal agents, sigh / nasal allergy treatment agents Antihistamines, anticoagulants, antispasmodics, cerebral circulation / metabolic agents, antidepressants / anxiolytics, vitamin D preparations, oral hypoglycemic agents, antiulcer agents, hypnotics, antibiotics, etc.

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

Steroid anti-inflammatory agents include hydrocortisone, prednisolone, fluocinolone acetonide, fludoxycortide, methylprednisolone, hydrocortisone acetate, triamcinolone acetonide, dexamethasone, hetamethasone acetate, diflucortron valerate, propionclohetazole, fluocinonide. and so on. As vasodilators, diltiazem, verapamil, pentaerythritol tetranitrate, dipyridamole, isosorbide nitrate,
Examples include nifedipine and nitroglycerin.

Examples of the antihypertensive / arrhythmic agent include propanolol, atenolol, pindolol, quinidine sulfate, ajmaline, alprenolol hydrochloride, metoprolol tartrate, nadolol, timolol maleate, and disopyramide.

Examples of the antihypertensive agent include clonidine hydrochloride, captoril, prazosin hydrochloride, benbutrol sulfate, guanabenz acetate, guanfacine hydrochloride, guanabenz acetate, punazosin hydrochloride, ellanapril maleate, arotinolol hydrochloride, and bunitrolol hydrochloride.

Examples of antitussive agents include procaterol hydrochloride, tempbutaline sulfate, fenoterol hydrobromide, tulobuterol hydrochloride, ambroxol hydrochloride, pirbuterol hydrochloride, mabuterol hydrochloride, clenbuterol hydrochloride, trimetoquinol hydrochloride, formoterol fumarate.

Anti-tumor agents include 5-fluorouracil and 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 fumaric acid, ketotifen, azelastine hydrochloride, sodium cromoglycate, and the like. Antihistamines include cycloheptazine hydrochloride, diphenhydramine hydrochloride, fenbenzamine,
There is mequitazine.

As anticoagulants, heparin, etc., as antispasmodics,
Examples include scopolamine and clofluperol. Cerebral circulation metabolism improvers include pinpocetine, flunarizine hydrochloride,
Examples include nicardipine hydrochloride, brovincamin fumarate, dihydroergotoxine mesylate, ifenprodil tartrate, and isoxuprine hydrochloride. Examples of the antidepressant / anxiolytic agents include maprotiline hydrochloride, etizolam, diazepam, bromazepam, amitriptyline hydrochloride, mianserin hydrochloride and the like. Examples of vitamin D agents include α-calcidol and ergocasiferol. Oral hypoglycemic agents include glibenclamide, gliclazide and the like. Anti-ulcer agents include grepobride malate,
Examples include famotidine and glycopyrronium bromide. 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 the drug, the purpose of use of the preparation, etc., but is usually contained in the adhesive layer in a proportion of 0.1 to 30% by weight.

The water-absorbent filler used in the present invention is a compound (usually a polymer) capable of absorbing water and swelling, and has a low affinity with the adhesive base and the drug contained therein, which is a medium in the adhesive base. Can be dispersed in the form of fine particles. Examples of such water absorbent fillers include crosslinked polyvinylpyrrolidone, crystalline cellulose, crosslinked carboxymethyl cellulose, crosslinked hydroxyalkyl cellulose (eg, crosslinked hydroxypropyl cellulose), crosslinked polyvinyl alcohol, and the like. Crosslinked polyvinylpyrrolidone is particularly preferable.

The crosslinked polyvinylpyrrolidone is prepared by copolymerizing N-vinyl-2-pyrrolidone and a polyfunctional monomer. As the polyfunctional monomer used for the copolymerization, hexamethylene glycol di (meth) acrylate, ethylene glycol di (meth) acrylate, triethylene glycol di (meth) acrylate, tetraethylene glycol di (meth) acrylate, polyethylene glycol Di (meth) acrylates such as di (meth) acrylate
Acrylates; tri (meth) acrylates such as trimethylolpropane triacrylate; tetra (meth) acrylates such as tetramethylolmethane tetraacrylate; polyallyl compounds such as diethylene glycol bisallyl carbonate, triallyl glycerin, triallyl cyanurate; ethylene bismaleimide, etc. The polymaleimide compound and the like are used. Alternatively, N,
N'-divinylimidazolidone, N, N'-divinylhexahydropyrimidinone, N-vinyl-3-ethylidene-
Cyclic acid amide compounds such as pyrrolidone, divinylbenzene,
N, N'-methylenebisacrylamide, ethylidenebisvinylpyrrolidone, divinylketone, butadiene, isoprene and the like can also be used. The amount of polyfunctional monomer to be copolymerized is 0.1 with respect to the amount of vinylpyrrolidone monomer.
It is preferably ˜20% by weight, particularly preferably 0.5 to 10% by weight. The amount of polyfunctional monomer
If it is less than 0.1% by weight, the resulting crosslinked polyvinylpyrrolidone will dissolve in the adhesive base or swell excessively and it will be difficult to maintain its particle structure in the adhesive layer. When the amount of the polyfunctional monomer exceeds 20% by weight, the resulting crosslinked polyvinylpyrrolidone hardly swells in water, and the drug release property of the adhesive layer cannot be enhanced.

As another method for preparing crosslinked polyvinylpyrrolidone, it can be obtained by subjecting soluble non-crosslinked polyvinylpyrrolidone to heat treatment with thionyl chloride, phosphorous trichloride, phosphorous pentachloride or the like in an organic solvent.

Suitable examples of commercially available cross-linked polyvinylpyrrolidone include Kollidon CL ^R (manufactured by BASF) and polyplasdone X.
L ^R (manufactured by GAF). Methods for producing these compounds are described in U.S. Pat.Nos. 3,759,880, 3,933,766 and 3,689,439.
Nos. 4139688 and 4180633.

The water absorbent filler has a property of absorbing water and swelling appropriately. When this filler is added to the adhesive layer,
The filler absorbs moisture or sweat evaporated from the skin surface and swells. As a result, the release property of the drug from the pressure-sensitive adhesive layer is improved. The water-absorbent filler is 0 in the adhesive layer.
It is mixed in a ratio of 5 to 20% by weight. Water-absorbent filler is 0.5
If it is less than wt%, the effect of promoting drug release cannot be obtained. If it exceeds 20% by weight, the adhesiveness of the patch will decrease, and good patchability cannot be obtained.

As the adhesive base used in the patch of the present invention, an acrylic adhesive, a rubber adhesive, a silicone adhesive or the like is used. Considering the adhesive physical properties and costs, acrylic adhesives and rubber adhesives are preferably used.

The acrylic pressure-sensitive adhesive is particularly a polymer or copolymer of an alkyl (meth) acrylate obtained from an aliphatic alcohol having 4 to 18 carbon atoms and (meth) acrylic acid from the viewpoint of the adhesive physical properties. A combination or a copolymer of the above-mentioned (meth) acrylic acid alkyl ester and another functional monomer is preferably used.

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

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

The acrylic pressure-sensitive adhesive can be obtained by copolymerizing the above-mentioned monomers by a commonly known method. As the copolymerization component, the above (meth) acrylic acid alkyl ester is 50% of the total copolymerization component.
It is preferable that the content is at least wt%.

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

Silicone rubber such as polyorganosiloxane is used as the silicone adhesive. In addition to these adhesives, polyvinyl ether adhesives and polyurethane adhesives can be used.

Various compounding agents may be added to the above-mentioned pressure-sensitive adhesive base, if necessary. Examples of such compounding agents include tackifiers such as rosin resins, polyterpene resins, chroman-indene resins, petroleum resins, terpene phenol resins; liquid polybutene, mineral oil, lanolin, liquid isobutylene, liquid polyacrylates, etc. Softeners; fillers; antiaging agents and the like.

In the pressure-sensitive adhesive layer of the patch of the invention, a compound having a plasticizing action on the pressure-sensitive adhesive base (plasticizer), if necessary.
Is added. Such a compound adjusts the viscosity of the pressure-sensitive adhesive layer and promotes transdermal or transmucosal absorbability of the compounded drug. And such a compound needs to be safe for the human body.

Examples of the compound having a plasticizing action include the compounds shown below. For example, cetyl octanoate, hexyl laurate, isopropyl myristate, octyldodecyl myristate, isopropyl palmitate, octyl palmitate, butyl stearate, octyl stearate, octyl hydroxystearate, isotridecyl isononanoate, ethyl oleate, oleic acid. Monohydric alcohol fatty acid esters such as decyl, mink oil fatty acid ethyl, myristyl lactate; dibasic acid esters such as diisopropyl adipate, dioctyl adipate, diethyl sebacate, dioctyl succinate; propylene glycol dicaprate, glyceryl trioctanoate, tri ( Octanoic acid / decanoic acid) glycerin, glyceryl tripalmitate, sovitan oleate, polyhydric alcohol fatty acid esters such as neutral fatty acid oils and fats; Leave oil, safflower oil, coconut oil fatty acid triglyceride, animal and vegetable oils such as cottonseed oil; squalane, alpha-olefin oligomers,
Hydrocarbons such as liquid paraffin and wax; cetanol, behenyl alcohol, 2-hexyldecanol, 2
Alcohols such as octyldecanol and oleyl alcohol; ethers such as polyoxyethylene lauryl ether and polyoxyethylene oleyl ether; amide compounds such as oleic acid amide and lauric acid monoethanolamide; dimethyl polysiloxane, methylphenyl polysiloxane, etc. There is silicone.

The compounding amount of the compound having a plasticizing action depends on the type and polarity of the compound, the type of adhesive base, the polarity and the molecular weight. Usually, it is 300 parts by weight or less, preferably 3 to 200 parts by weight, relative to 100 parts by weight of the above adhesive base. If it exceeds 300 parts by weight, the cohesive force of the adhesive layer will be insufficient.

As the support used for these patches, any of the supports usually used for patches can be used. Examples of the material of the support include cellulose acetate, ethyl cellulose, polyethylene terephthalate, plasticized vinyl acetate-vinyl chloride copolymer, nylon, ethylene-vinyl acetate copolymer, plasticized polyvinyl chloride, polyurethane, polyvinylidene chloride, Aluminum etc. These materials are used as a single layer sheet or a laminated body of two or more sheets. Alternatively, materials other than aluminum can be used as woven or non-woven fabrics.

The patch of the present invention can be produced according to a usual method for producing an adhesive tape. For example, various known coating methods such as a solvent coating method, a hot melt coating method, an electron beam curing method and an emulsion coating method can be used. In particular, the solvent coating method can be preferably used. In the solvent coating method, the above-mentioned adhesive base was diluted with a suitable solvent, to which the above-mentioned drug, water-absorbing filler, and, if necessary, a compound having a plasticizing action were added to obtain The patch is prepared by applying the solution to the surface of the support and drying the solution to remove the solvent. Alternatively, it is also possible to apply this solution on a release paper, dry it, and then transfer it to a support. The thickness of the pressure-sensitive adhesive layer thus formed on the support varies depending on the purpose of use, but is usually in the range of about 30 μm to about 2000 μm. If it is less than 30 μm, the desired amount of drug cannot be contained per unit area of the patch. When it exceeds 2000 μm, it becomes difficult for the drug contained in the adhesive layer near the support to reach the skin surface due to diffusion, and the drug in the adhesive layer is not effectively used. On the adhesive layer,
Release paper may be applied until use for the purpose of protecting this layer.

(Operation) When the patch of the present invention prepared as described above is applied to the surface of skin or mucous membrane, the contained drug is easily absorbed into blood through the skin or mucous membrane. Although the detailed mechanism is not clear, it is considered as follows.
The water-absorbing filler compounded in the pressure-sensitive adhesive layer has the property of absorbing water and swelling, and not substantially swelling by the drug. Therefore, in the patch of the present invention, when it is applied to the surface of the skin, the water-absorbing filler absorbs water such as sweat and swells, and acts to remove the drug from the adhesive layer. By the action of this water-absorbing 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 (A) Preparation of patch: decyl methacrylate (DM) 2286
g, hexyl methacrylate (HM) 14256 g, hexyl acrylate (HA) 1656 g, and ethyl acetate 8500 g were placed in a 40 l polymerization machine and heated to 80 ° C. Then, in this reaction solution,
A solution prepared by dissolving 16 g of lauroyl peroxide in 1500 g of cyclohexane was added over 6 hours and polymerized to obtain an adhesive solution having a polymerization average molecular weight of 1.05 × 10 ⁶ and a solid content of 58%.

To this adhesive solution, 10% ethyl isosorbide nitrate acetate solution, cross-linked polyvinylpyrrolidone (Kolidone CL, manufactured by BASF) and isopropyl myristate were added to the composition shown in Table 1 and uniformly mixed with a dissolver. Then, an ethyl acetate dispersion having a nonvolatile content of about 30% was prepared. This was coated on 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 give a patch.

(B) Performance evaluation of patch: The patch obtained in section (A) was subjected to a release test. The results are shown in Table 1 together with the results of Comparative Examples 1 and 2 below. The method of the release test is 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 skin surface side. 2
The amount of drug (mg / cm ² ) transferred to the receptor solution on the back surface of the skin after 4 hours was measured by HPLC. The diffusion cell was kept at a constant temperature of 37 ° C, and a 20% polyethylene glycol aqueous solution was used as the receptor solution.

Comparative Examples 1 and 2 A patch was prepared and evaluated in the same manner as in Example 1 except that the components having the compositions shown in Table 1 were used.

Example 2 80 g of 2-ethylhexyl acrylate, 2-methacrylic acid
60 g of ethylhexyl, 60 g of butyl acrylate and 130 g of ethyl acetate were placed in a polymerization machine of 1 and heated to 60 ° C. Next, a solution prepared by dissolving 0.5 g of lauroyl peroxide in 50 g of cyclohexane was added to this reaction solution over 6 hours, and the mixture was polymerized to obtain an adhesive solution having a weight average molecular weight of 6.5 × 10 ⁵ and a solid content of 54%. Obtained.

To this adhesive solution, indomethacin, cross-linked polyvinylpyrrolidone (Kolidone CL), and isopropyl myristate were added so as to have the composition shown in Table 2, and uniformly mixed with a dissolver to prepare ethyl acetate containing about 30% of non-volatile components. A dispersion was prepared. This was applied onto polyester release paper so that the thickness after drying would be 50 μm, and dried at 60 ° C. for 30 minutes to form an adhesive layer. A polyethylene film was attached to this to give a patch. The same evaluation as in Example 1 was carried out using this patch, and the results are shown in Table 2 together with the results of Comparative Examples 3 to 4 described later.

Comparative Examples 3 to 4 A patch was prepared and evaluated in the same manner as in Example 2 except that the components having the compositions shown in Table 2 were used.

Example 3 A patch was prepared in the same manner as in Example 1 except that crystalline cellulose was used instead of the crosslinked polyvinylpyrrolidone to form an adhesive layer having the composition shown in Table 3. Table 3 shows the evaluation results of this patch.

Example 4 A patch was prepared in the same manner as in Example 1 except that the 10% ethyl isosorbide nitrate acetate solution was replaced with a 10% nitroglycerin ethyl acetate solution and the composition of the adhesive layer was as shown in Table 4. Prepared and evaluated. The results are shown in Table 4 together with the results of Comparative Example 5 below.

Comparative Example 5 A patch was prepared and evaluated in the same manner as in Example 4 except that the components having the compositions shown in Table 4 were used.

(Effect of the Invention) As described above, the patch of the present invention can effectively percutaneously or transmucosally absorb various drugs such as isosorbide nitrate and indomethacin. The patch of the present invention has a great drug releasing effect particularly when it absorbs water. Therefore,
The patch of the present invention, when administered to the skin, absorbs water or sweat that evaporates from the skin surface and effectively releases the drug. Furthermore, in the adhesive layer of the patch of the present invention,
A high drug release effect can be obtained by adding a compound having a plasticizing action to the adhesive base.

Claims (2)

[Claims] 1. A patch having a pressure-sensitive adhesive layer provided on one surface of a support, wherein the pressure-sensitive adhesive layer is a drug except eperisone, triperizone and salts thereof, a water-absorbing filler, and a pressure-sensitive adhesive base. An adhesive patch containing the water-absorbent filler, which has a property of absorbing water and swelling and not substantially swelling by the drug. 2. The patch according to claim 1, wherein the pressure-sensitive adhesive layer further contains a compound having a plasticizing action on the pressure-sensitive adhesive base.