JPH0413617A - Patch - Google Patents

Abstract

PURPOSE:To obtain a patch capable of percutaneously absorbing a drug effectively, by forming a tacky agent layer containing a drug, a water absorbing filler and a tacky base on one side of a substrate. CONSTITUTION:0.1-30wt.% drug except eperisone, triperisone and salts thereof is blended with 0.5-20wt.% water absorbing filler (e.g. crosslinked polyvinylpyrrolidone), a tacky base and optionally a compound (e.g. isopropyl myristate) having plasticizing action on the tacky base to form a tacky agent layer. One side of a substrate is coated with the tacky agent layer having about 300-2,000mum thickness to give the objective patch. Since releasing effect of drug is high especially when the patch absorbs water, in the case of skin administration, the patch absorbs water, sweating, etc., vaporizing from the skin surface and the drug is percutaneously absorbed efficiently.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a patch used for transdermal or transmucosal administration of drugs. In particular, it relates to a patch that can effectively absorb drugs through the skin.

(Prior Art) Drugs (physiologically active substances) are absorbed through the skin using transdermal absorption preparations.

This transdermal administration method has the following advantages over conventional oral administration methods. For example, when a drug is orally administered, the drug is absorbed in the intestines and metabolized in the liver, resulting in a significant amount of the drug being degraded before it can exert its medicinal effect in the affected area. Furthermore, because a large amount of the drug is absorbed in a short period of time, side effects are likely to occur.

On the other hand, in transdermal administration, unlike the above-mentioned oral administration, the absorbed drug reaches the affected area without being broken down by metabolism in the liver. Furthermore, transdermal administration does not cause the same gastrointestinal disorders that occur with oral administration. Furthermore, if a constant drug release rate can be maintained over a long period of time, the number of drug administrations can be reduced.

However, even if a drug is administered using a transdermal absorption preparation, it is difficult for the drug to penetrate the skin, and a sufficient amount of the drug cannot be administered in many cases. For example, the stratum corneum on the skin surface has a barrier function to prevent foreign substances from entering the body, so a sufficient amount of a drug to exert its medicinal effect is not absorbed through the skin. - Strategically, attempts have been made to increase the transdermal absorption of drugs by adding absorption enhancers that have the function of weakening the barrier function of the stratum corneum to formulations. However, in general, absorption enhancers that have a large absorption promoting effect are
Patch preparations using such absorption enhancers are highly irritating to mucous membranes, and their uses are limited.

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

(Means for Solving the Problems) The patch of the present invention is a patch having an adhesive layer provided on one side of a support, and the adhesive layer does not contain eperisone, triperisone, or salts thereof. drugs, water-absorbing fillers,
and an adhesive base, the water-absorbing filler absorbs water and swells, and has the property of not being substantially swollen by the drug, thereby achieving the above object.

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

The drug used in the patch of the present invention is not particularly limited as long as it can permeate biological membranes by transdermal or transmucosal administration. For example, antipyretic and antiinflammatory analgesics, steroidal anti-inflammatory agents, vasodilators, antihypertensive/arrhythmia agents, antihypertensive agents, antitussive expectorants, antitumor agents, local anesthetics, hormonal agents, agents for treating sighs and nasal allergies, These include antihistamines, anticoagulants, antispasmodics, agents for improving cerebral circulation and metabolism, antidepressants and antianxiety agents, vitamin D preparations, oral hypoglycemic agents, antiulcer agents, sleeping pills, and antibiotics.

Antipyretic and antiinflammatory analgesics include indomethacin, salicylic acid, aspirin, acetaminophen, diclofenac sodium, ibuprofen, sulindac, naproxen, ketoprofen, flufenamic acid, ibufenac, fenbufen, alclofenac, phenylbutacin, mehenamic acid, pendazac, piroxicam, These include flurbiprofen, pentazocine, fullenorphine hydrochloride, and butorphanol tartrate.

Steroid anti-inflammatory agents include hydrocortisone, prednisolone, fluocinolone acetonide, fludoxycortide, methylprednisolone, hydrocortisone acetate, triamcinolone acetonide, dexamethacin, hetamethasone acetate, diflucortolone valerate, propion clohetasol, Examples include fluocinonide. Vasodilators include diltiazem, verapamil, pentaerythritol tetraborate, diviridamol, insorbide nitrate,
These include nifedipine and nitroglycerin.

Agents for hypertension and arrhythmia include propanolol, atenolol, pindolol, quinidine sulfate, ajmaline, alprenolol hydrochloride, metoprolol tartrate, nadolol, timolol maleate, and zimpyramide.

Antihypertensive drugs include clonidine hydrochloride, cabtril,
These include prazosin hydrochloride, penbutrol sulfate, guanabenz acetate, guanfacine hydrochloride, guanabenz acetate, bunazone hydrochloride, elanafuril maleate, arotinolol hydrochloride, and bunitrol hydrochloride.

Antitussive expectorants include procaterol hydrochloride, terbutaline sulfate, fetchmir hydrobromide, tulobuterol hydrochloride, amproxol hydrochloride, vilbutyol hydrochloride, mabuterol hydrochloride, clenbuterol hydrochloride, trimetoquinol hydrochloride, formotyol fumarate, etc. be.

Antitumor agents include 5-fluorouracil, 1-(2-
Examples include (tetrahydrofuryl)-5-fluorouracil and mitomycin C.

Local anesthetics include pensicaine, prophylaxis, lidocaine, and tetrahydro.

Examples of hormonal agents include steroid hormones such as estrogen, estradiol, testosterone, progesterone, and prostaglandin; and peptide hormones such as Inswan.

Asthma/nasal allergy treatment agents include ketotifen fumarate, azelastine hydrochloride, and sodium cromoglycate. Antihistamines include cycloheptadine hydrochloride, diphenhydramine hydrochloride, fenbenzamine, and mequitazine.

Anticoagulants include heparin, antispasmodics include
These include sufpolamine and clofluverol. Cerebral circulation and metabolism improving agents include vinpocetine, flunarizine hydrochloride,
These include nicardipine hydrochloride, provincamine fumarate, dihydroergotoxine mesylate, ifenbrodil tartrate, and inksprin hydrochloride. Examples of antidepressant/anxiolytics include maprotiline hydrochloride, ethidium, diazepam, promazepam, amitributyline hydrochloride, mianserin hydrochloride, and the like. Examples of vitamin D agents include α-calcidol and ergocasiferol.

Oral hypoglycemic agents include glibenclamide, gliclacit, and the like. Anti-ulcer agents include grepobride malate, famotidine, and glycopyrronium bromide. Sleeping pills include phenobarbital and amobarbital.

Antibiotics include tetracycline and chloramphenicol.

The blending amount of these drugs varies depending on the type of drug and the purpose of use of the preparation, but usually 0.1 to 30
It is contained in a proportion of % by weight.

The water-absorbing filler used in the present invention is a compound (usually a polymer) that can absorb water and swell. It can be dispersed in the form of fine particles. Such water-absorbing fillers include cross-linked polyvinylpyrrolidone, crystalline cellulose, cross-linked carboxymethyl cellulose, cross-linked hydroxyalkyl cellulose (eg, cross-linked hydroxypropyl cellulose), cross-linked 11-polyvinyl alcohol, and the like. Particularly preferred is crosslinked polyvinylpyrrolidone.

The crosslinked polyvinylpyrrolidone is prepared by copolymerizing N-vinyl-2-pyrrolidone and a polyfunctional monomer. Polyfunctional monomers used in copolymerization include hexamethylene glycol di(meth)acrylate, ethylene glycol di(meth)acrylate, triethylene glycol di(meth)acrylate, tetraethylene glycol di(meth)acrylate, and polyethylene glycol di(meth)acrylate. Di(meth)acrylates such as di(meth)acrylate; Tri(meth)acrylates such as trimethylolbronoacrylate; Tetra(meth)acrylates such as tetramethylolmethanetetraacrylate; Di(meth)acrylates such as diethylene glycolbis Boria 1-nor compounds such as allyl carbonate, triallylglycerin, and triallyl cyanurate; poly-1-maleimide compounds such as ethylene bismaleimide, and the like are used. A certain ζ1 is a cyclic acid amide compound such as N, N-divinylimidazolitone, N, N'-divinyl hydropyrimideinone, N-vinyl-3-ethylidene-pyrrolidone, divinylbenzene, N, N'- Methylenebisacrylamide, ethylidenebisvinylpyrrolidone, divinylketone, butadiene, isoprene, and the like may also be used. The amount of the polyfunctional monomer to be copolymerized is preferably 0.1 to 20% by weight, particularly preferably 0.5 to 10% by weight, based on the amount of vinylpyrrolidone monomer. The amount of polyfunctional monomer is 0.1
If the amount is less than % by weight, the obtained crosslinked polyvinylpyrrolidone will dissolve in the adhesive base or swell extremely, making it difficult to maintain its particle structure in the adhesive layer.

If the amount of the polyfunctional monomer exceeds 20% by weight, the resulting crosslinked polyvinylpyrrolidone hardly swells in water, making it impossible to enhance the drug release properties of the adhesive layer.

Further, as another method for preparing crosslinked polyvinylpyrrolidone, it can be obtained by heat treating soluble non-crosslinked polyvinylpyrrolidone with thionyl chloride, phosphorus trichloride, phosphorus pentachloride, etc. in an organic solvent.

Suitable examples of commercially available crosslinked polyvinylpyrrolidone include Koliton CLR (manufactured by BASF) and Polyplaston XLR (manufactured by GAF). Methods for producing these compounds are described in U.S. Pat.
No. 33766, No. 3689439, No. 4139688
No. 4180633.

The water-absorbing filler has the property of absorbing water and swelling appropriately. When this filler is added to one adhesive layer, the filler absorbs moisture or sweat that evaporates from the skin surface and swells. As a result, the release of the drug from the adhesive layer is improved.

The water-absorbing filler is blended into the adhesive layer in a proportion of 0.5 to 20% by weight. If the amount of the water-absorbing filler is less than 0.5% by weight, the effect of promoting drug release cannot be obtained. If it exceeds 20% by weight, the adhesiveness of the patch will decrease and good adhesion will not be obtained.

(Hereinafter, blank spaces) As the adhesive base used in the patch of the present invention, acrylic adhesive, rubber adhesive, silicone adhesive, etc. are used. In consideration of adhesive properties and cost, acrylic adhesives and rubber adhesives are preferably used.

From the viewpoint of adhesive properties, acrylic adhesives are particularly suitable for polymers or copolymers of (meth)acrylic acid alkyl esters obtained from aliphatic alcohols having 4 to 18 carbon atoms and (meth)acrylic acid. A combination or a copolymer of the above-mentioned (meth)acrylic acid alkyl ester and other functional monomers is preferably used.

(Meth)acrylic acid alkyl esters include butyl acrylate, isobutyl acrylate, hexyl acrylate, octyl acrylate, 2-ethylhexyl acrylate, inoctyl acrylate, decyl acrylate, indecyl acrylate, and acrylic acid. lauryl acid, stearyl acrylate, methyl methacrylate, ethyl methacrylate,
Butyl methacrylate, isobutyl methacrylate, 2-ethylhexyl methacrylate, isooctyl methacrylate, decyl methacrylate, indecyl methacrylate, lauryl methacrylate, stear 1-nor methacrylate, and the like are used.

Examples of the above-mentioned other functional monomers include monomers having a hydroxyl group, monomers having a carboxyl group, monomers having an amide group, and monomers having an amino group. Examples of monomers having a hydroxyl group include 2-hydroxyethyl (meth)acrylate, hydroxypropyl (
There are meta)acrylates, etc. Examples of monomers having a carboxyl group include α such as acrylic acid and methacrylic acid.

β-unsaturated carboxylic acids; maleic acid monoalkyl esters such as butyl maleate; maleic acid, fumaric acid; crotonic acid, and the like. Maleic anhydride can also be used since it can form copolymers similar to maleic acid. Monomers having an amide group include acrylamide, alkyl ether methylol (meth)acrylamide such as dimethylacrylamide and diethylacrylamide; alkyl ether methylol (meth)acrylamide such as butoxymethylacrylamide and nidoxymethylacrylamide; diaseptone acrylamide; vinylpyrrolidone and so on.

Examples of monomers having amide 7 groups include diethylamine 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 is obtained by copolymerizing the above monomers using a commonly known method. The copolymerization component includes the above (meth)acrylic acid alkyl ester, which accounts for 5% of the total copolymerization component.
It is preferable that the content is 0% by weight or more.

As the rubber adhesive, natural rubber, synthetic isoprene rubber, polyisobutylene, polyisoprene, polybutadiene, styrene-butadiene copolymer, styrene-isoprene copolymer, styrene-isoprene-styrene block copolymer, etc. are used. .

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

Various compounding agents may be added to the adhesive base as necessary. Such compounding agents include, for example, tackifiers such as rosin resins, polyterpene resins, chroman-indene resins, petroleum resins, and terpene phenol resins; liquid polybutene, mineral oil, lanolin, liquid imbutylene, and liquid polyacrylates. Softeners such as fillers; anti-aging agents, etc.

The adhesive layer of the patch of the present invention may optionally contain a compound (plasticizer) that has a plasticizing effect on the adhesive base.
is added. Such compounds adjust the viscosity of the adhesive layer and promote transdermal or transmucosal absorption of the formulated drug. Further, such compounds need to be safe for the human body.

Examples of the compound having a plasticizing effect include the compounds shown below. For example, cetyl octoate, hexyl laurate, isopropyl myristate, octyldodecyl myristate, isopropyl palmitate, octyl palmitate, butyl stearate, octyl stearate, octyl hydroxystearate, intridecyl isononanoate, ethyl oleate, oleic acid. -hydric alcohol fatty acid esters such as decyl, ethyl mink oil fatty acid, and myristyl lactate; dibasic acid esters such as diisopropyl adibate, dioctyl adipate, diethyl sebacate, and dioctyl succinate; propylene glycol cicaprate, glyceryl trioctanoate, Polyhydric alcohol fatty acid esters such as glyceryl tri(octanoate/decanoate), glyceryl tripalmitate, nbitan oleate, and neutral fatty acid oil; Animal and vegetable oils such as olive oil, safflower oil, coconut oil fatty acid triglyceride, and cottonseed oil; Squalane, α- Olefin oligomers Hydrocarbons such as liquid paraffin and wax; cetanol,
Alcohols such as behenyl alcohol, 2-hexyldecanol, 2-octyldecanol, oleyl alcohol; ethers such as polyoxyethylene lauryl ether, polio-ox diethylene oleyl ether; amide compounds such as oleic acid amide and lauric acid monoethanolamide; There are silicones such as dimethylpolysiloxane and methylphenylpolysiloxane.

The amount of the compound that promotes plasticizing action varies depending on the type and polarity of this compound, the type, polarity, and molecular weight of the adhesive base. Usually, 3 parts by weight for 100 parts by weight of the above adhesive base.
00 parts by weight or less, preferably 3 to 200 parts by weight. If it exceeds 300 parts by weight, the cohesive force of the adhesive layer will be insufficient.

As the support used in these patches, any of the supports commonly used in patches can be used. Examples of materials for 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, There are aluminum, etc. These materials are used as a single layer sheet or a laminate of two or more sheets. Alternatively, materials other than aluminum may be used as woven or non-woven fabrics.

The adhesive patch of the present invention can be manufactured according to a conventional adhesive tape manufacturing method. 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 may be used. In particular, a solvent coating method can be suitably used.

In the solvent coating method, the above-mentioned adhesive base is diluted with an appropriate solvent, and the above-mentioned drug, water-absorbing filler, and, if necessary, a compound having a plasticizing effect are added to the obtained adhesive base. The patch is prepared by applying the solution to the surface of the support and drying to remove the solvent. Alternatively, it is also possible to apply this solution onto a release paper, dry it, and then transfer it to a support. The thickness of the adhesive layer thus formed on the support varies depending on the purpose of use, but is usually within the range of about 30 μm to about 2000 μm. If the diameter is less than 30 μm, the desired amount of drug cannot be contained per unit area of the patch. If it exceeds 20 (1 (Ium), it will be 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 will not be used effectively.Adhesive layer A release paper may be applied over the layer to protect this layer until use.

(Function) When the patch of the present invention prepared as described above is applied to the surface of the skin or mucous membrane, the drug contained therein is easily absorbed into the blood through the skin or mucous membrane. Although the detailed mechanism is not clear, it is thought to be as follows.

The water-absorbing filler blended into the adhesive layer has the property of absorbing water and swelling, and not being substantially swollen by the drug. Therefore, when the patch of the present invention is applied to the skin surface, the water-absorbing filler absorbs moisture such as sweat, swells, and works to expel the drug from the adhesive layer. Due to the action of the filler, the drug is effectively released from the adhesive layer and administered into the blood through the skin or mucous membranes.

(Example) The present invention will be described below with reference to Examples.

Preparation of support patch (A) patch: Decyl methacrylate (DM) 22
86g, hexyl methacrylate (HM) 142
56g, Oxil to Acrylic Acid (HA) 1656
g, and 8500 g of ethyl acetate were placed in a 401 polymerization machine and heated to 80°C.

Next, 16 g of lauroyl peroxide was added to this reaction solution.
A solution dissolved in 1500 g of beef sun was added to the Cyclo over 6 hours and polymerized, resulting in a polymerization average molecular weight of 1.
．． 05
(manufactured by SF) and tenopropyl myristate, as shown in Table 1.
The mixture was added so as to have the composition shown in Figure 1, and mixed uniformly using a Daysilver to prepare an ethyl acetate dispersion containing about 30% non-volatile components. This was coated on polyester release paper so that the thickness after drying was 100 μm, and dried at 60° C. for 30 minutes to form an adhesive layer. This was laminated with a polyester/EVA laminate film to form a patch.

(B) Performance evaluation of patch: A release test was conducted on the patch obtained in section (A). The results are shown in Table 1 together with the results of Comparative Examples 1 and 2 below. The method for the above release test is as follows.

Release test: A nude mouse skin permeation test was conducted. The excised skin from the back of a nude mouse was fixed in a Franz diffusion cell, and a patch of 3.14 cm 2 was attached to the surface of the skin. After 24 hours, the amount of drug (mg/cm2) transferred to the Sebuter solution on the back side of the skin was measured by HPLC. The diffusion cell is kept at a constant temperature of 37°C, and the reservoir liquid is kept at a constant temperature of 20°C.
% polyethylene glycol aqueous solution was used.

Village! ``Shiny 1'' A patch was prepared and evaluated in the same manner as in Example 1, except that the components having the composition shown in Table 1 were used.

Point 1 L1 2-ethylhexyl acrylate 80g 1 2-ethylhexyl methacrylate 60g 1 Butyl acrylate 60
g and 130 g of ethyl acetate were put into an IL polymerization machine,
Heated to 60°C. Next, a solution of 0.5 g of lauroyl peroxide dissolved in 50 g of cyclohexane was added to this reaction solution over 6 hours, and polymerization was carried out.
A pressure-sensitive adhesive solution with a weight average molecular weight of 6.5×10′ and a solid content of 54% was obtained.

Indomethacin, cross-linked polyvinylpyrrolidone (Koriton CL), and isopropyl myristate were added to this adhesive solution so that the composition was as shown in Table 2.
The mixture was mixed uniformly using a day silver to prepare an ethyl acetate dispersion with a non-volatile composition of about 30%.

This was coated on a polyester release paper so that the thickness after drying would be 50 .mu.so and dried at 60.degree. C. for 30 minutes to form an adhesive layer. This was laminated with a polyethylene film to form a patch. The same evaluation as in Example 1 was performed using this patch, and the results are shown in Table 2 together with the results of Comparative Examples 3 and 4 described below.

A patch was prepared and evaluated in the same manner as in Example 2 using the ingredients having the composition shown in Table 2.

(The following is a blank space) Actual patch was prepared in the same manner as in Example 1, except that crystalline cellulose was used instead of cross-linked polyvinylvirolidone and an adhesive layer having the composition shown in Table 3 was formed. Table 3 shows the evaluation results of this patch.

(Leaving space below) Large W tip The procedure was the same as in Example 1 except that the 10% nitrate insorbide ethyl acetate solution was replaced with a 10% nitroglycerin ethyl acetate solution and the composition of the adhesive layer was changed as shown in Table 4. A patch was prepared and evaluated. The results are shown in Table 4 together with the results of Comparative Example 5 below.

A patch was prepared and evaluated in the same manner as in Example 4, except that the ingredients having the composition shown in Table 4 were used.

(Hereinafter in the margin) (Effects of the Invention) The patch of the present invention can thus effectively absorb various drugs such as insorbide nitrate and indomethacin transdermally or transmucosally. The patch of the present invention has a large drug release effect, especially when it absorbs water. therefore,
When the patch of the present invention is administered to the skin, it absorbs moisture 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 effect to the adhesive base.

that's all

Claims (1)

[Scope of Claims] 1. A patch having an adhesive layer provided on one side of a support, wherein the adhesive layer contains a drug other than eperisone, triperisone, and their salts, a water-absorbing filler, and A patch comprising an adhesive base, wherein the water-absorbing filler absorbs water and swells, and has a property of not being substantially swollen by the drug. 2. The adhesive patch according to claim 1, wherein the adhesive layer further contains a compound having a plasticizing effect on the adhesive base.