JPH09301854A - Tape preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a tape preparation excellent in percutaneous absorption, mucous membrane-permeating property and attaching property and having low irritation to skin by adding a rubber component or other copolymer, a liquid component and a medicine to a specific copolymer. SOLUTION: This tape preparation is obtained by providing a tacky agent layer formed of (A) 100 pts.wt. copolymer comprising (i) 25-90wt.% (meth)acrylic acid alkyl ester having 4-18C alkyl, (ii) 0-70wt.% (meth)acrylic acid alkyl ester having <=3C alkyl and (iii) 2-40wt.% N-vinyl-2-pyrrolidone, (B) 1-100 pts.wt. copolymer of a rubber component or (meth)acrylic acid with methyl (meth) acrylate, (C) 1-100 pts.wt. liquid component (especially preferably isopropyl myristate or isopropyl palmitate) compatible with the component A and (D) a medicine on one side of a support. Furthermore, a material capable of percutaneously permeating a biomembrane is used as the component D.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a tape preparation, and more particularly to a tape preparation having excellent transdermal or transmucosal permeability and stickiness of a drug and low skin irritation.

[0002]

2. Description of the Related Art Tape preparations are applied to the skin and a predetermined amount of drug is permeated through the skin and administered into the body. At this time, the stratum corneum of the skin serves as a barrier layer to prevent the absorption of the drug when allowing the drug to penetrate the skin. Therefore, various absorption enhancers are used for permeating a predetermined amount of drug.

As the absorption accelerator, for example, lactic acid in JP-A-5-43457 and JP-A-5-1863 are disclosed.
No. 71 discloses polyoxyethylene alkyl ether phosphate and lauric acid diethanol diamide salt in addition to lactic acid. However, there is a problem in that the amount of these absorption enhancers such as lactic acid is limited because they tend to cause skin irritation.

Recently, from the tendency of reducing skin irritation, many methods have been adopted in which a liquid component such as a fatty acid ester is added to an adhesive to plasticize the adhesive layer to enhance drug release. . However, it is necessary to add a large amount of liquid component to the pressure-sensitive adhesive in order to obtain sufficient drug release, and as a result, there is a problem that the cohesive force of the pressure-sensitive adhesive layer is extremely reduced. This decrease in cohesive strength is caused by making the adhesive layer sticky when peeling the tape preparation from the skin, increasing the skin irritation by pulling on the skin, causing hair peeling, or the adhesive leaving the adhesive on the skin. It causes problems such as the rest.

On the other hand, Japanese Patent Application Laid-Open No. 6-23029 discloses a gel preparation containing a liquid component such as polyethylene glycol or isopropyl myristate for plasticizing an adhesive layer. However, if a large amount of liquid component is added to the pressure-sensitive adhesive, it is necessary to impart cohesive force to the pressure-sensitive adhesive by cross-linking, and therefore, a cross-linking step must be added.

[0006]

SUMMARY OF THE INVENTION In order to solve the above-mentioned drawbacks, the present invention provides a tape preparation having excellent transdermal or transmucosal permeability of a drug and adhesiveness and low skin irritation. To do.

[0007]

The tape preparation of the present invention comprises:
In a tape preparation having a pressure-sensitive adhesive layer containing a drug on one surface of a support, the pressure-sensitive adhesive layer comprises a (meth) acrylic acid alkyl ester having an alkyl group having 4 to 18 carbon atoms and an alkyl group having carbon number of Copolymer (A) consisting of 3 or less (meth) acrylic acid alkyl ester and N-vinyl-2-pyrrolidone, rubber component or copolymer (B), liquid component compatible with the copolymer (A) And formed from a drug.

The copolymer (A) used in the present invention is used as a pressure-sensitive adhesive base. The alkyl group has (meth) acrylic acid alkyl ester having 4 to 18 carbon atoms, and the alkyl group has carbon number. Containing 3 or less (meth) acrylic acid alkyl ester and N-vinyl-2-pyrrolidone as constituent components.

Examples of the (meth) acrylic acid alkyl ester having 4 to 18 carbon atoms in the alkyl group include butyl (meth) acrylate, hexyl (meth) acrylate, octyl (meth) acrylate and 2-ethylhexyl (meth). Examples thereof include acrylate, decyl (meth) acrylate, dodecyl (meth) acrylate, tridecyl (meth) acrylate and octadecyl (meth) acrylate. Of these, (meth) acrylic acid alkyl esters having an alkyl group with 4 to 8 carbon atoms are preferable because they have an excellent balance of adhesiveness and drug compatibility.

In the above copolymer (A), the content of the (meth) acrylic acid alkyl ester whose alkyl group has 4 to 18 carbon atoms is 25 to 90% by weight, preferably 30 to 80% by weight. is there. If it is less than 25% by weight, the adhesiveness of the adhesive base to the skin will be reduced, and if it exceeds 90% by weight, the polarity of the adhesive base will be low and the compatibility with a relatively highly polar drug will be poor. Solubility in the adhesive becomes low. That is, it becomes difficult to maintain a high release property and administer a fixed amount of a drug over a long period of time.

Examples of the (meth) acrylic acid alkyl ester having an alkyl group having 3 or less carbon atoms include methyl (meth) acrylate, ethyl (meth) acrylate and propyl (meth) acrylate. Of these, methyl acrylate and ethyl acrylate are particularly preferable because of their tackiness and easy availability.

In the above copolymer (A), the content of the (meth) acrylic acid alkyl ester whose alkyl group has 3 or less carbon atoms is 0 to 70% by weight, preferably 0 to
60% by weight. If it exceeds 70% by weight, the adhesiveness of the adhesive to the skin will deteriorate. The alkyl group has 3 carbon atoms
The following (meth) acrylic acid alkyl ester can suppress the decrease in polarity of the pressure-sensitive adhesive base, but may not be added depending on the balance with other components.

The above N-vinyl-2-pyrrolidone is used for imparting cohesive force to the pressure-sensitive adhesive base and increasing the polarity of the pressure-sensitive adhesive base. Also, unlike (meth) acrylic acid, since there is no acid at the terminal, it does not react with drugs or cause skin irritation. Also, the polarity of the adhesive base can be increased.

The content of N-vinyl-2-pyrrolidone is 2 to 40% by weight, preferably 5 to 30% by weight.
It is. If it is less than 2% by weight, the cohesiveness of the pressure-sensitive adhesive base will be reduced, and if it exceeds 40% by weight, the sticking property will be poor and the polarity of the pressure-sensitive adhesive base will be high, whereby the water resistance during sweating or bathing will be reduced.

The above-mentioned copolymer (A) contains a polyfunctional monomer in an amount of 0.005 to 0.005 based on the total amount of the monomers for the purpose of enhancing the cohesive force.
You may copolymerize in the range of 0.5 weight%. If the amount of the polyfunctional monomer added is less than 0.005% by weight, the effect of increasing the cohesive force of the pressure-sensitive adhesive base is insufficient, and if it exceeds 0.5% by weight, the pressure-sensitive adhesive base easily gels.

Examples of the polyfunctional monomer include, for example,
Examples thereof include 1,6-hexane glycol dimethacrylate, tetraethylene glycol diacrylate, trimethylolpropane triacrylate, divinylbenzene, divinyltoluene, and diallyl phthalate.

The above copolymer (A) is usually obtained by solution polymerization of the above monomers in the presence of a polymerization initiator. However, the polymerization form is not limited to this, and the polymerization reaction conditions are appropriately selected mainly depending on the type of the monomer. For example, in the case of carrying out solution polymerization, ethyl acetate or other general polymerization solvent is added to a predetermined amount of the above-mentioned monomer, and azobis type, peroxide type, etc. are added in a reactor equipped with a stirring device and a cooling device. 70 in a nitrogen atmosphere in the presence of a polymerization initiator
The reaction may be performed at a temperature of ~ 90 ° C for 8 to 40 hours. Further, the above-mentioned monomer and solvent may be added all at once, or may be added in appropriate divided portions. In addition, it is preferable that the polymerization initiator is appropriately added in portions according to the progress of the reaction.

As the azobis type polymerization initiator, 2,
2'-azobisisobutyronitrile, 1,1'-azobis (cyclohexane-1-carbonitrile), 2,2'-azobis (2,4-dimethylvaleronitrile), etc., and the above-mentioned peroxide system Examples of the polymerization initiator include lauroyl peroxide, benzoyl peroxide, di (t-butyl) peroxide and the like.

The adhesive base used in the present invention is formed by adding a rubber component or copolymer (B), a liquid component and a drug to the above copolymer (A).

The amount of the rubber component added is such that the copolymer (A)
It is 1 to 100 parts by weight, preferably 10 to 50 parts by weight, relative to 100 parts by weight. If the addition amount is less than 1 part by weight, the cohesive force is not sufficiently imparted, the adhesive layer becomes sticky, and when peeled from the skin, the skin is excessively stretched or peeled, resulting in increased skin irritation. It causes the adhesive residue on the skin. Further, when the amount added exceeds 100 parts by weight, the adhesive force to the skin is lowered and peeling easily occurs.

Examples of the rubber component include natural rubber and synthetic rubber, which may be used alone or in combination of two or more kinds. Examples of the synthetic rubber include polyisoprene rubber (IR), styrene-butadiene rubber (SBR), polyisobutylene (PIB), butyl rubber (IIR), polybutadiene rubber (BR), chloroprene rubber, acrylonitrile-butadiene rubber (NBR). Block copolymers such as styrene / isoprene block copolymer (SIS), styrene / butadiene block copolymer (SBS), styrene / ethylene / butylene block copolymer (SEBS); 2-chloroethyl vinyl ether / acrylic acid ester copolymer (ACM), Examples thereof include acrylic rubber such as acrylonitrile / acrylic acid ester copolymer (ANM),
These may be used alone or in combination of two or more.

Among the above synthetic rubbers, polyisoprene rubber (IR) and styrene-butadiene rubber (SB) are particularly preferable.
R), polyisobutylene (PIB), styrene / isoprene block copolymer (SIS), styrene / butadiene block copolymer (SBS), styrene / ethylene / butylene block copolymer (SEBS), 2-chloroethyl vinyl ether / acrylic acid ester copolymer (ACM) is preferred.

As the above copolymer (B), a copolymer of (meth) acrylic acid and methyl (meth) acrylate is used. If the proportion of (meth) acrylic acid in the copolymer (B) increases, the water resistance deteriorates.
The following is preferred.

The amount of the copolymer (B) added is 100% for the same reason as in the case of the rubber component.
1 to 100 parts by weight, preferably 1
0 to 50 parts by weight.

Commercially available products of the above copolymer (B) include:
Those having a (meth) acrylic acid content of 10 to 60% by weight are easily available, for example, "Eudragit L100" manufactured by Rohm Pharma [(meth) acrylic acid content of 38 to 52% by weight], "Eudragit S100".
[(Meth) acrylic acid content 25 to 34.5% by weight],
"Eudragit L-55" [(meth) acrylic acid content of 11.5 to 15.5% by weight] and the like can be mentioned, and these may be used alone or in combination of two or more kinds. The commercially available product has a particle size of 1 to 150 μm.

The above liquid component is compatible with the above copolymer (A) and is used for plasticizing the copolymer (A) which is an adhesive base. As the liquid component,
For example, cetyl octanoate, hexyl laurate, isopropyl myristate, octyldodecyl myristate, isopropyl palmitate, butyl stearate,
Fatty acid esters of monohydric alcohols such as octyl stearate, octyl hydroxystearate, ethyl oleate, decyl oleate, myristyl lactate; diisopropyl adipate, dioctyl adipate, diethyl sebacate, dioctyl sebacate, dioctyl succinate, etc. Basic acid esters; phthalic acid diesters such as diethyl phthalate, diheptyl phthalate, octyl phthalate; triethyl citrate, propylene glycol dicaprate, glyceryl trioctanoate, tri (octanoic acid / decanoic acid) glyceryl, medium chain fatty acid triglycerides, etc. Fatty acid esters of polyhydric alcohols and fatty acids corresponding to these fatty acid esters; polyhydric alcohols such as glycerin and diglycerin; alkylene glycols having 4 or more carbon atoms, polyethylene glycol , Polyalkylene glycol such as polypropylene glycol; polyalkyl alcohol; low molecular weight polymethyl vinyl ether: triacetin; liquid polysaccharide; liquid cationic surfactant such as alkyl trimethyl ammonium chloride having 12 or more carbon atoms; polyoxyethylene alkyl Nonionic surfactants such as ether, polyoxyethylene alkyl ester, fatty acid diethanolamide, sorbitan alkyl ester, sorbitan polyoxyethylene alkyl ester;
Amphoteric surfactants such as dimethyl betaine; liquid amino acids and the like can be mentioned, and these can be used alone or in combination of two or more kinds.

Among the above liquid components, isopropyl myristate, isopropyl palmitate, diethyl sebacate, diisopropyl adipate, medium-chain fatty acid triglyceride, polyethylene glycol, triacetin,
Triethyl citrate and the like are preferred.

The amount of the above liquid component added is the copolymer (A).
The amount is 1 to 100 parts by weight, preferably 5 to 70 parts by weight, and more preferably 10 to 60 parts by weight, relative to 100 parts by weight. If the amount added is less than 1 part by weight, the adhesive base cannot be sufficiently plasticized, so that sufficient drug release cannot be obtained. On the other hand, if the addition amount exceeds 100 parts by weight, the adhesive base material is excessively plasticized, so that the adhesive base material becomes sticky. This stickiness causes excessive skin tension when peeling the tape preparation from the skin and causes hair peeling, which increases skin irritation and causes adhesive residue on the skin.

The drug used in the present invention is not particularly limited as long as it can permeate the biological membrane transdermally, and examples thereof include the following. Examples of drugs include general anesthetics, local anesthetics, sleep / analgesics, antipyretic and anti-inflammatory analgesics,
Steroidal anti-inflammatory drug, excitatory / stimulant, sedative, neuropsychiatric agent, local anesthetic, skeletal muscle relaxant, autonomic nerve agent, antispasmodic, antiparkinson's disease, antihistamine, cardiotonic agent, arrhythmic agent, diuretic, blood pressure Depressant, vasoconstrictor, vasodilator, arteriosclerosis agent, respiratory stimulant, respiratory stimulant, antitussive expectorant, peptic ulcer treatment agent, choleretic agent, hormone agent, genitourinary and anal agent, parasitic Agents for skin diseases, emollients, vitamins, mineral agents, hemostatics, anticoagulants, agents for liver diseases, addictive agents, gout remedies, diabetic agents,
Examples include antineoplastic agents, radiopharmaceuticals, Chinese herbal medicines, antibiotics, chemotherapeutic agents, antiparasitic / antiprotozoal agents, and narcotics.

Antipyretic and anti-inflammatory analgesics include acetaminophenone, phenacetin, mefenamic acid, diclofenac sodium, flufenamic acid, aspirin, sodium salicylate, aminopyrine, alclofenac, ibuprofen, naproxen, flurbiprofen, ketoprofen, amphenac. Sodium, mepyrizole, indomethacin, pentazocine, piroxicam, etc .;
Examples of the steroidal anti-inflammatory agent include hydrocortisone, triamcinolone, dexamethasone, betamethasone, prednisolone and the like.

As the vasodilator, diltiazem hydrochloride,
Pentaerythritol tetranitrate, isosorbide dinitrate, trapidil, nicorandil, nitroglycerin, prenilamine lactate, molsidomine, nitrite amide, tolazoline hydrochloride, etc .; , Nadolol, metoprolol tartrate, azimaline, disopyramide, mexitylene hydrochloride, etc .;
As antihypertensives, ecarazine hydrochloride, indapamide,
Clonidine hydrochloride, bunitrolol hydrochloride, labetalol hydrochloride, captopril, guanabenz acetate, mebutamate,
Betanidine sulfate and the like are each mentioned.

Examples of the antitussive and expectorant include carbetapentane citrate, cloperastine, oxerazine tannate, clobutynol hydrochloride, clofedanol hydrochloride, noscapine hydrochloride, ephedrine hydrochloride, isoproterenol hydrochloride, chlorprenaline hydrochloride, methoxyphenamine hydrochloride. , Procaterol hydrochloride, tulobuterol hydrochloride, clenbuterol hydrochloride, ketotifen fumarate, etc .; anti-neoplastic agents include cyclophosphamide, fluorouracil, degafur, mitomycin C, procarbazine hydrochloride, doxyfluridine, ranimustine; local anesthetics include aminobenzoic fragrance Examples thereof include ethyl acid, tetracaine hydrochloride, procaine hydrochloride, dibucaine hydrochloride, oxybuprocaine hydrochloride, propitocaine hydrochloride and the like.

The hormonal agents include propylthiouracil, thiamazole, metenolone acetate, estradiol, estriol, progesterone, etc .; the antihistamines include diphenonehydramine hydrochloride, chlorpheniramine maleate, promethazine, cyproheptadine hydrochloride, diphenylpyraline hydrochloride. Etc .; as blood coagulation promoters, warfarin potassium, ticlopidine hydrochloride, etc .; as antispasmodics, methylatropine bromide, scopolamine, etc .;
As a general anesthetic, thiopental sodium, pentobarbital sodium, etc .; as a local anesthetic,
Ethyl aminobenzoate, tetracaine hydrochloride, procaine hydrochloride, dibucaine hydrochloride, oxybuprocaine hydrochloride, propito hydrochloride, etc .; hypnotic and analgesic agents such as bromvalerylurea, amobarbital, phenobarbital, etc .; antiepileptic agent such as phenytoin sodium; Examples of the stimulant / stimulant include methamphetamine hydrochloride and the like.

Examples of the antispasmodic agents include diphenidol hydrochloride, betahistine mesylate and the like; examples of the psychological agents include chlorpromazine hydrochloride, thioridazine, meprobamate, imipramine hydrochloride, chlordiazepoxide, diazepam and the like;
Skeletal muscle relaxants such as suxamethonium hydrochloride and eperisone hydrochloride; autonomic agents such as neostigmine bromide and bethanechol chloride; antiparkinson agents such as amantadine hydrochloride; diuretics hydroflumethiazide, isosorbide and furosemide Phenylephrine hydrochloride as a vasoconstrictor; lobeline hydrochloride, dimorpholamine, naloxone hydrochloride, etc. as respiratory stimulants; glycopyrronium bromide, proglumide, cetraxate hydrochloride, cimetidine, spizofuron, etc. as peptic ulcer therapeutics , Respectively.

As choleretic agents, ursodesoxycholic acid, osalmid, etc .; as urogenital and anal agents,
Hexamine, spartine, dinoprost, ritodrine hydrochloride, etc .; agents for parasitic skin diseases, such as salicylic acid, ciclopirox olamine, croconazole hydrochloride; emollients, such as urea; vitamins, such as calcitriol, thiamine hydrochloride; Sodium riboflavin phosphate, pyridoxine hydrochloride, nicotinamide, panthenol, ascorbic acid, and the like; inorganic preparations include calcium chloride, potassium iodide, and sodium iodide; and hemostatic agents include ethanesylate.

As agents for liver diseases, thiopronin, etc .; agents for addiction, cyanamide, etc .; agents for treating gout, colchicine, probenecid, sulfinpyrazone, etc .; agents for diabetes, tolbutamide, chlorpropamide, glyce. Sodium midine, glybuzol, buformin hydrochloride, insulin, etc .; As antibiotics, benzylpenicillin potassium, propicillin potassium, cloxacillin sodium, ampicillin sodium, bacampicillin hydrochloride, carbenicillin sodium, cephaloridine, cefoxitin sodium, erythromycin, chlorine Rumphenicol, tetracycline, kanamycin sulfate, cycloserine, etc .; chemotherapeutic agents, isoniaside, pyrazinamide, ethionamide, etc .; narcotics, morphine hydrochloride, phosphorus Codeine, cocaine hydrochloride, etc. pethidine hydrochloride may be mentioned, respectively.

The compounding amount of the above-mentioned drug varies depending on the kind of the drug and the purpose of use of the preparation, but when the amount is small, the sufficient medicinal effect of the drug cannot be obtained, and when the amount is large, the cohesive force and the adhesive force of the adhesive layer are lowered, Generally, 0.01 to 50% by weight in the pressure-sensitive adhesive layer is preferable because it becomes difficult to be compatible with each other.

The saturated solubility of the drug in the adhesive depends on the composition of the adhesive base, but by making the drug compatible in the adhesive layer at a concentration as close as possible to the saturated solubility to prevent crystal precipitation. , High drug release is obtained. In addition, the drug is present in the adhesive layer in a supersaturated state,
Even if crystals of the drug exist in a precipitated state, there is no particular problem. Further, the drug may be encapsulated or a drug storage layer may be provided.

If desired, a filler such as silicic acid anhydride may be added to the pressure-sensitive adhesive layer in order to further impart cohesive force.

As a method for uniformly mixing the above components, for example, a rotary stirring device such as a ball mill and a rotor mill; a rotary blade stirring device such as a propeller mixer, a disperxer, an ultra mixer, a paddle mixer and an anchor mixer; Examples thereof include a method of mixing using a kneading type stirring device such as a planetary mixer.

The support used in the present invention is preferably one which has flexibility and imparts self-supporting property to the tape preparation, and serves to prevent volatilization and migration of the drug in the pressure-sensitive adhesive layer. As a material for such a support,
For example, cellulose acetate, ethyl cellulose, polyethylene, polypropylene, polyvinyl chloride, vinyl acetate-
Vinyl chloride copolymer, ethylene-methyl acrylate copolymer, ethylene-vinyl acetate copolymer, ethylene-vinyl acetate-carbon monoxide copolymer, ethylene-butyl acrylate-carbon monoxide copolymer, polyvinylidene chloride,
Resin films of polyurethane, nylon, polyethylene terephthalate, polybutylene terephthalate and the like: aluminum sheets and the like can be mentioned, and these materials may be used as a single layer or as a laminate of two or more kinds. Further, materials other than the aluminum sheet may be used in the form of a woven fabric or a nonwoven fabric.

The above-mentioned support may be subjected to surface treatment such as corona treatment or plasma discharge treatment, or may be subjected to anchor coat treatment with an anchor agent, for the purpose of enhancing the adhesiveness to the adhesive layer. The thickness of the support is preferably 500 μm or less, more preferably 5 to 150 μm.

The tape preparation of the present invention is produced according to a usual method for producing an adhesive tape, and for example, a conventionally known method for producing an adhesive tape such as a solvent coating method, a hot melt coating method, an emulsion coating method can be used. However, the solvent coating method is particularly preferably used.

In the solvent coating method, the pressure-sensitive adhesive base was diluted with an appropriate solvent, and the rubber component or copolymer (B), liquid component, drug, and other additives were added to the solution to obtain the product. A tape preparation can be prepared by forming a pressure-sensitive adhesive layer on the support by applying the solution to the surface of the support and drying the solution to remove the solvent. Alternatively, the solution may be once coated on release paper, dried, and then transferred to a support to form an adhesive layer.

The thickness of the pressure-sensitive adhesive layer varies depending on the purpose of use, but if it becomes thin, the drug must be added at a high concentration,
As a result, the adhesive strength decreases, and when the thickness increases, the drug contained in the adhesive layer near the support does not sufficiently diffuse and the drug release amount decreases, so 10 to 200 μm is preferable.

This release paper may be stuck until the time of use for the purpose of protecting the pressure-sensitive adhesive layer. As the release paper, for example, a polyethylene terephthalate film treated with silicone is used, and the thickness thereof is 100.
0 μm or less, more preferably 30 to 200 μm
m.

The tape preparation obtained above is usually applied directly to the surface of the skin or mucous membrane for the purpose of transdermally or transmucosally administering the drug to the internal circulatory system. Further, the tape preparation may be applied to the skin or mucous membrane for the purpose of treating a diseased part of the skin or mucous membrane. Furthermore, after use, it can be easily peeled from the skin without feeling pain.

(Function) In the tape preparation of the present invention, the copolymer (A) is an adhesive base having a well-balanced drug release property and adhesiveness to the skin, and by further adding a liquid component. The copolymer (A) is plasticized, and the drug release property is dramatically improved. Further, although the cohesive force of the pressure-sensitive adhesive layer is reduced by the addition of the liquid component, the addition of the rubber component or the copolymer (B) gives a sufficient cohesive force. Generally, skin irritation increases when the adhesiveness to the skin is strong, but the plasticized pressure-sensitive adhesive layer has strong adhesiveness to the skin, and the skin is excessively stretched or peeled when peeled off. It causes high skin irritation. In addition, it causes unpleasant phenomena such as adhesive residue on the skin. However, in the present invention, by increasing the cohesive force by adding the rubber component or the copolymer (B), the adhesiveness to the skin becomes good and mild, and the skin irritation can be extremely reduced. Moreover, the adhesive residue on the skin can be prevented. With the above constitution, the tape preparation of the present invention is excellent in transdermal or transmucosal permeability of a drug, excellent in sticking property, and low in skin irritation.

[0049]

Next, embodiments of the present invention will be described. Preparation of copolymer (A-1) 200 parts by weight of ethyl acrylate, octyl acrylate 1
60 parts by weight, 40 parts by weight of N-vinyl-2-pyrrolidone and 400 parts by weight of ethyl acetate were supplied to a separable flask equipped with a stirrer and a reflux cooling device, and heated to 80 ° C. while stirring and purging with nitrogen. Then lauroyl peroxide 2
10 parts by weight of a solution prepared by dissolving 100 parts by weight of ethyl acetate in 100 parts by weight.
It divided | segmented and 1 was added to the separable flask, and superposition | polymerization was started. The remaining 9 was added at 1-hour intervals from the second hour after the start of the reaction, and after the addition of the entire amount was completed, the reaction was continued for another 2 hours.
In order to adjust the viscosity, 100 parts by weight of ethyl acetate was added 4 times every 2 hours after the reaction was started. After the reaction is complete, cool
Next, ethyl acetate was added to obtain an adhesive base solution having a solid content concentration of 31% by weight and a viscosity of 5.5 × 10 ⁴ cps (hereinafter referred to as adhesive base (A-1)).

(Example 1) The above adhesive base (A-1) 10
To 0 parts by weight (solid content), 30 parts by weight of a 5% by weight toluene solution of polyisoprene rubber (“Nipol IR-2200” manufactured by Nippon Zeon Co., Ltd.) as solid content, 40 parts by weight of isopropyl myristate and isosorbide nitrate as solid content. The content of the solution was 18% by weight, and the whole solution was uniformly stirred with a disper mixer to obtain an adhesive solution. This adhesive solution was dried on a silicone-treated surface of a polyethylene terephthalate film having a thickness of 35 μm so that the thickness after drying was 40 μm.
It was coated so as to have a thickness of m and dried in an oven at 60 ° C. for 30 minutes to form a pressure-sensitive adhesive layer. This pressure-sensitive adhesive layer was laminated on the polyethylene terephthalate side of a laminated film of polyethylene terephthalate and ethylene / vinyl acetate copolymer to obtain a tape preparation having a thickness of 60 μm.

(Example 2) 100 parts by weight (solid content) of the adhesive base (A-1) was added to a styrene-isoprene block copolymer ("Califlex TR1" manufactured by Shell Japan Co., Ltd.).
107 ") as a solid content, 5 parts by weight, 10 parts by weight of isopropyl myristate, and isosorbide dinitrate are added so as to be 18% by weight in the solid content to obtain an adhesive solution. From the solution, a tape preparation having an adhesive layer thickness of 60 μm was obtained in the same manner as in Example 1.

Example 3 100 parts by weight (solid content) of the adhesive base (A-1) was mixed with acrylic rubber (“N” manufactured by Nippon Zeon Co., Ltd.).
50 parts by weight of a 5% by weight toluene solution of ipol AR-31 ") as a solid content, isopropyl myristate 60
After adding 1 part by weight and indomethacin to 13.5% by weight in the solid content to obtain a pressure-sensitive adhesive solution, a tape preparation having a pressure-sensitive adhesive layer having a thickness of 80 μm was prepared in the same manner as in Example 1 from the pressure-sensitive adhesive solution. Obtained.

Example 4 Preparation of Copolymer (A-2) 302 parts by weight of 2-ethylhexyl acrylate, 98 parts by weight of N-vinyl-2-pyrrolidone and 400 parts by weight of ethyl acetate were added to a stirring device and a reflux cooling device. It was supplied to a separable flask equipped with the flask, and the temperature was raised to 80 ° C. while stirring and purging with nitrogen. Then, 2 parts by weight of lauroyl peroxide was added to 1 part of ethyl acetate.
The solution dissolved in 00 parts by weight was divided into 10 parts, and 1 was added to a separable flask to start polymerization. The remaining 9 was added at 1-hour intervals from the second hour after the start of the reaction, and after the addition of the total amount was completed, the reaction was continued for another 2 hours. In order to adjust the viscosity, 100 parts by weight of ethyl acetate was added 4 times every 2 hours after the reaction was started. After completion of the reaction, the mixture was cooled, and ethyl acetate was added to the mixture to give a solid concentration of 31% by weight and a viscosity of 1.1 × 10 ⁴ cps.
To obtain an adhesive base solution (hereinafter referred to as an adhesive base (A-2)).

To 100 parts by weight (solid content) of the adhesive base (A-2), 80 parts by weight of a 5% by weight toluene solution of styrene-butadiene rubber (“Nipol 1006” manufactured by Nippon Zeon Co., Ltd.) as a solid content, sebacic acid After 80 parts by weight of diethyl and 13.5% by weight of indomethacin were added to the solid content to obtain a pressure-sensitive adhesive solution, a tape having a pressure-sensitive adhesive layer having a thickness of 80 μm was prepared from this pressure-sensitive adhesive solution in the same manner as in Example 1. A formulation was obtained.

(Example 5) Preparation of copolymer (A-3) 260 parts by weight of ethyl acrylate, butyl acrylate 12
0 parts by weight, 20 parts by weight of N-vinyl-2-pyrrolidone and 400 parts by weight of ethyl acetate were supplied to a separable flask equipped with a stirrer and a reflux cooling device, and heated to 80 ° C while stirring and purging with nitrogen. Then, a solution prepared by dissolving 2 parts by weight of lauroyl peroxide in 100 parts by weight of ethyl acetate was divided into 10 parts, and 1 was added to a separable flask to start polymerization. The remaining 9 was added at 1-hour intervals from the second hour after the start of the reaction, and after the addition of the entire amount was completed, the reaction was continued for another 2 hours.
In order to adjust the viscosity, 100 parts by weight of ethyl acetate was added 4 times every 2 hours after the reaction was started. After the reaction is complete, cool
Next, ethyl acetate was added to obtain an adhesive base solution [hereinafter referred to as adhesive base (A-3)] having a solid content concentration of 31% by weight and a viscosity of 6.5 × 10 ⁴ cps.

100 parts by weight (solid content) of the adhesive base (A-3) was added to polyisobutylene (“VIS” manufactured by Exxon Chemical Co., Ltd.).
2 parts by weight of a 5% by weight toluene solution of TANEX MML-100 ") as a solid content, polyethylene glycol 5
Parts by weight and isosorbide dinitrate were added so as to be 18% by weight in the solid content to obtain a pressure-sensitive adhesive solution, and from this pressure-sensitive adhesive solution, a tape preparation having a pressure-sensitive adhesive layer having a thickness of 60 μm was obtained in the same manner as in Example 1. It was

Example 6 To 100 parts by weight (solid content) of the adhesive base (A-3), a 5% by weight toluene solution of polyisoprene rubber (“Nipol IR-2200” manufactured by Nippon Zeon Co., Ltd.) was used as a solid content. 10 parts by weight, 10 parts by weight of a 5% by weight toluene solution of styrene-isoprene block copolymer (“Califlex TR1107” manufactured by Shell Japan Co., Ltd.) as a solid content, 5 parts of acrylic rubber (“Nipol AR-31” manufactured by Zeon Corporation) 10% by weight of toluene solution as a solid content, polyethylene glycol 4
After 0 parts by weight and isosorbide dinitrate were added so as to be 18% by weight in the solid content to obtain a pressure-sensitive adhesive solution, from this pressure-sensitive adhesive solution, a tape preparation having a pressure-sensitive adhesive layer having a thickness of 60 μm was prepared in the same manner as in Example 1. Obtained.

(Comparative Example 1) 100 parts by weight (solid content) of the adhesive base (A-1) was mixed with isosorbide dinitrate alone in the solid content of 1 part.
A tape preparation having a pressure-sensitive adhesive layer having a thickness of 60 μm was obtained in the same manner as in Example 1 except that the amount was 8% by weight.

Comparative Example 2 Indomethacin alone was added to 100 parts by weight (solid content) of the adhesive base (A-1) in 1 of the solid content.
After adding so as to be 3.5% by weight to obtain an adhesive solution,
From this pressure-sensitive adhesive solution, a tape preparation having a pressure-sensitive adhesive layer having a thickness of 80 μm was obtained in the same manner as in Example 1.

(Comparative Example 3) To 100 parts by weight (solid content) of the adhesive base (A-1), a 5% by weight toluene solution of polyisoprene rubber ("Nipol IR-2200" manufactured by Nippon Zeon Co., Ltd.) was used as a solid content. 0.5 parts by weight, 40 parts by weight of isopropyl myristate and isosorbide dinitrate in solid content 1
After adding 8% by weight to obtain a pressure-sensitive adhesive solution, a tape preparation having a pressure-sensitive adhesive layer having a thickness of 60 μm was obtained from this pressure-sensitive adhesive solution in the same manner as in Example 1.

Comparative Example 4 100 parts by weight (solid content) of the adhesive base (A-1) was mixed with acrylic rubber (“N” manufactured by Nippon Zeon Co., Ltd.).
150 parts by weight of a 5% by weight toluene solution of ipol AR-31 ") as a solid content, isopropyl myristate 6
0 parts by weight and indomethacin in solid content 13.5% by weight
To obtain a pressure-sensitive adhesive solution, and then from this pressure-sensitive adhesive solution, in the same manner as in Example 1, the thickness of the pressure-sensitive adhesive layer was 80 μm.
A tape preparation of

(Comparative Example 5) 100 parts by weight of adhesive base (A-2) (-("Califlex TR" manufactured by Shell Japan Co., Ltd.
1107 ") as a solid content of a 5% by weight toluene solution.
After adding 0 parts by weight, 0.5 parts by weight of diethyl sebacate and isosorbide nitrate to 18% by weight in the solid content to obtain a pressure-sensitive adhesive solution, the pressure-sensitive adhesive solution was treated in the same manner as in Example 1. A tape preparation having an adhesive layer thickness of 60 μm was obtained.

(Comparative Example 6) 100 parts by weight of the adhesive base (A-3) was added to a styrene-isoprene block copolymer ("Califlex TR1107" manufactured by Shell Japan Co., Ltd.).
100 parts by weight of a 5 wt% toluene solution of
150 parts by weight of polyethylene glycol and isosorbide dinitrate were added so as to be 18% by weight in the solid content to obtain a pressure-sensitive adhesive solution, and a tape having a pressure-sensitive adhesive layer having a thickness of 60 μm was prepared from this pressure-sensitive adhesive solution in the same manner as in Example 1. A formulation was obtained.

The following performance evaluations were carried out on the tape preparations obtained in the above Examples and Comparative Examples, and the results are shown in Table 1. 1) Drug transfer test A test piece (10 cm ² ) of the tape preparation was attached to the dehaired back of a Japanese white rabbit, which was peeled off and collected after 24 hours. The unattached test piece and the recovered test piece were extracted with methanol, and the initial content and residual amount of the drug in the tape preparation were measured by high performance liquid chromatography, and the difference between the two was taken as the skin transfer amount. The same measurement was performed 5 times for each of the examples and comparative examples, and the average value is shown in the table.

2) Skin irritation test A test piece (10 cm ² ) of the tape preparation was attached to the dehaired back of a Japanese white rabbit and peeled off after 24 hours. Immediately after peeling and 1 hour after peeling, the erythema state of the skin was visually observed and evaluated according to the following criteria. The same evaluation was performed 5 times for each Example and Comparative Example, and the average value was used as the skin irritation index. <Standard> 0: No erythema was observed at all 1: Very slight erythema that was barely discernible was observed. 2: Clear erythema was observed. 3: Medium erythema was observed. 4: Strong deep red erythema was observed.

3) Skin Adhesion Test A test piece (10 cm ² ) of the tape preparation was attached to the dehaired back of a Japanese white rabbit for 24 hours, and the adhesion state of the test piece was visually observed and evaluated according to the following criteria. . The same evaluation was performed 5 times for each Example and Comparative Example, and the average value was used as the skin adhesion index. <Standard> 0: Peeled off within 24 hours. A considerable part (5 cm ² or more) was peeled off at 1:24 hours. A small portion (less than 5 cm ² ) was peeled off at 2:24 hours. It did not peel at all in 3:24 hours.

4) Cohesive Strength Sensory Evaluation A test piece (10 cm ² ) of the tape preparation was attached to the dehaired back of a Japanese white rabbit and peeled off after 24 hours. The "stickiness" of the test piece at the time of peeling was sensory-evaluated according to the following criteria. The same evaluation was performed 5 times for each example and comparative example, and the average value was used as the stickiness index. <Standard> 0: No stickiness (no adhesive residue on the skin). 1: Slightly sticky (there was slight adhesive residue on the skin). 2: It was quite sticky (there was considerable adhesive residue on the skin).

[0068]

[Table 1]

[0069]

[Table 2]

In all of the examples, a high drug transfer amount was exhibited, the adhesive strength to the skin was good, the tackiness layer was not sticky at all, and the skin irritation was low. On the other hand, Comparative Examples 1 and 2 did not contain the rubber component and the liquid component, and thus the drug transferability was low. In Comparative Example 3, the migration of the drug was increased by the addition of the liquid component, but since the amount of the rubber component added was small, the stickiness of the pressure-sensitive adhesive layer was not eliminated and the amount of adhesive residue on the skin was large. In addition, the skin was considerably pulled, so that the skin irritation was strong. In Comparative Example 4, since the addition amount of the rubber component was too large, the rooting force of the formulation was weakened,
It has come off during application. In Comparative Example 5, since the amount of the liquid component added was too small, a sufficient drug transfer amount could not be obtained. Further, in Comparative Example 6, since the amount of the liquid component added was too large, a sufficient cohesive force could not be obtained, the tackiness of the pressure-sensitive adhesive layer was large, and adhesive residue on the skin occurred. Furthermore, the skin was considerably stretched, and the skin irritation was strong.

Example 7 100 parts by weight (solid content) of the adhesive base (A-1) was mixed with (meth) acrylic acid-methyl (meth) acrylate copolymer (weight ratio 1: 1) (Rohm P
10% by weight of "eudragit L100" manufactured by Harma Co., (meth) acrylic acid content of 38 to 52% by weight)
After 30 parts by weight of the ethyl acetate dispersion as a solid content, 40 parts by weight of isopropyl myristate and isosorbide dinitrate were added so as to be 18% by weight in the solid content, a pressure-sensitive adhesive solution was obtained. A tape preparation having an adhesive layer thickness of 60 μm was obtained in the same manner as in 1.

Example 8 100 parts by weight (solid content) of the adhesive base (A-2) was added to (meth) acrylic acid-methyl (meth) acrylate copolymer (weight ratio 1: 2) (Rohm P.
"Eudragit S100" manufactured by Harma Co., 20 parts by weight of a 10% by weight acetone solution of (meth) acrylic acid content of 25 to 34.5% by weight as a solid content, 20 parts by weight of isopropyl myristate and isosorbide nitrate in the solid content. After adding 18% by weight to obtain a pressure-sensitive adhesive solution, a tape preparation having a pressure-sensitive adhesive layer having a thickness of 60 μm was obtained from this pressure-sensitive adhesive solution in the same manner as in Example 1.

(Example 9) 100 parts by weight (solid content) of the adhesive base (A-3) was added to (meth) acrylic acid-methyl (meth) acrylate copolymer (weight ratio 1: 6) (Rohm P
"Eudragit L100-55" manufactured by Harma,
(Meth) acrylic acid content 11.5 to 15.5% by weight)
40 parts by weight of 10% by weight acetone solution of
50 parts by weight of isopropyl myristate and isosorbide dinitrate were added so as to be 18% by weight in the solid content to obtain a pressure-sensitive adhesive solution. Then, from this pressure-sensitive adhesive solution, a pressure-sensitive adhesive layer having a thickness of 60 μm was prepared in the same manner as in Example 1. A tape formulation was obtained.

(Example 10) 100 parts by weight (solid content) of the adhesive base (A-1) was added to (meth) acrylic acid-methyl (meth) acrylate copolymer (weight ratio 1: 2) (Rohm P
"Eudragid S100" manufactured by Harma Co., 20 wt parts of 10 wt% acetone solution of (meth) acrylic acid content of 25 to 34.5 wt%) as solid content, 5 wt parts of diethyl sebacate and indomethacin in solid content of 1
After adding so as to be 3.5% by weight to obtain an adhesive solution,
From this pressure-sensitive adhesive solution, a tape preparation having a pressure-sensitive adhesive layer having a thickness of 80 μm was obtained in the same manner as in Example 1.

(Example 11) 100 parts by weight (solid content) of the adhesive base (A-1) was added to (meth) acrylic acid-methyl (meth) acrylate copolymer (weight ratio 1: 2) (Rohm P
"Eudragit S100" manufactured by Harma Co., a 10% by weight acetone solution of (meth) acrylic acid content 25 to 34.5% by weight) as a solid content of 70 parts by weight, polyethylene glycol 70 parts by weight and piroxicam in the solid content of 9 parts by weight. % To give a pressure-sensitive adhesive solution, and from this pressure-sensitive adhesive solution, a tape preparation having a pressure-sensitive adhesive layer having a thickness of 120 μm was obtained in the same manner as in Example 1.

Example 12 100 parts by weight (solid content) of the adhesive base (A-1) was added to (meth) acrylic acid-methyl (meth) acrylate copolymer (weight ratio 1: 2) (Rohm P
20 parts by weight of a 10% by weight acetone solution of "Eudragit S100" manufactured by Harma Co., (meth) acrylic acid content of 25 to 34.5% by weight as solid content, (meth)
Acrylic acid-methyl (meth) acrylate copolymer (weight ratio 1: 6) ("Eudragid L100-55" manufactured by Rohm Pharma, content of (meth) acrylic acid 1)
1.5 to 15.5% by weight) 10% by weight acetone solution as a solid content 20 parts by weight, polyethylene glycol 50
After adding 1 part by weight and isosbide nitrate so as to be 18% by weight in the solid content to obtain a pressure-sensitive adhesive solution, a pressure-sensitive adhesive layer tape preparation having a thickness of 60 μm was obtained from this pressure-sensitive adhesive solution in the same manner as in Example 1. It was

(Comparative Example 7) 100 parts by weight (solid content) of the adhesive base (A-1) was added to (meth) acrylic acid-methyl (meth) acrylate copolymer (weight ratio 1: 1) (Rohm P
10% by weight of "eudragit L100" manufactured by Harma Co., (meth) acrylic acid content of 38 to 52% by weight)
After adding 0.5 parts by weight of ethyl acetate dispersion as a solid content, 40 parts by weight of isopropyl myristate and isosorbide nitrate to 18% by weight in the solid content to obtain an adhesive solution, from this adhesive solution, A tape preparation having an adhesive layer thickness of 60 μm was obtained in the same manner as in Example 1.

Comparative Example 8 100 parts by weight (solid content) of the adhesive base (A-2) was added to (meth) acrylic acid-methyl (meth) acrylate copolymer (weight ratio 1: 2) (Rohm P
"Eudragid S100" manufactured by Harma Co., a 10 wt% acetone solution of (meth) acrylic acid content of 25 to 34.5 wt%) as a solid content of 150 parts by weight, isopropyl myristate 40 parts by weight, and isosuvide nitrate in the solid content. After the addition of 18% by weight to obtain a pressure-sensitive adhesive solution, a tape preparation having a pressure-sensitive adhesive layer having a thickness of 60 μm was obtained from this pressure-sensitive adhesive solution in the same manner as in Example 1.

(Comparative Example 9) 100 parts by weight (solid content) of the adhesive base (A-3) was added to (meth) acrylic acid-methyl (meth) acrylate copolymer (weight ratio 1: 6) (Rohm P
"Eudragit L100-55" manufactured by Harma,
(Meth) acrylic acid content 11.5 to 15.5% by weight)
40 parts by weight of 10% by weight acetone solution of
After 0.5 part by weight of isopropyl myristate and indomethacin were added so as to be 13.5% by weight in the solid content to obtain a pressure-sensitive adhesive solution, the pressure-sensitive adhesive layer was formed in the same manner as in Example 1 from the pressure-sensitive adhesive solution. A tape preparation having a thickness of 80 μm was obtained.

(Comparative Example 10) 100 parts by weight (solid content) of the adhesive base (A-3) was added to (meth) acrylic acid-methyl (meth) acrylate copolymer (weight ratio 1: 6) (Rohm P
"Eudragit L100-55" manufactured by Harma,
(Meth) acrylic acid content 11.5 to 15.5% by weight)
Of 10% by weight acetone solution as a solid content, 150 parts by weight of isopropyl myristate, and indomethacin to 13.5% by weight in the solid content to obtain a pressure-sensitive adhesive solution. A tape preparation having an adhesive layer thickness of 80 μm was obtained in the same manner as in Example 1.

Comparative Example 11 100 parts by weight of the adhesive base (A-1) was mixed with (meth) acrylic acid-methyl (meth) acrylate copolymer (weight ratio 1: 2) (Rohm Pharma).
"Eudragit S100" (manufactured by Eudragit S100), a (meth) acrylic acid content of 25 to 34.5% by weight) of 10% by weight in acetone was added as solid content, and 30 parts by weight of piroxicam was added so as to be 9% by weight in the solid content. After obtaining the adhesive solution,
From this pressure-sensitive adhesive solution, a tape preparation having a pressure-sensitive adhesive layer having a thickness of 120 μm was obtained in the same manner as in Example 1.

The tape formulations obtained in Examples 7 to 12 and Comparative Examples 7 to 11 were subjected to the same performance evaluation as in Example 1 and the results are shown in Table 4.

[0083]

[Table 3]

[0084]

[Table 4]

In Examples 7 to 12, all showed a high drug transfer amount, had good adhesion to the skin, had no sticky adhesive layer, and had low skin irritation. On the other hand, in Comparative Example 7, although the drug transferability is increased by the addition of the liquid component, the addition amount of the copolymer (B) is small,
The tackiness of the adhesive layer was not eliminated, and the amount of adhesive residue on the skin was large. In addition, the skin was considerably pulled, so that the skin irritation was strong. In Comparative Example 8, since the amount of the copolymer (B) added was too large, the adhesive strength of the preparation was weakened and peeled off during application. In Comparative Example 9, since the amount of the liquid component added was too small, a sufficient amount of drug transfer could not be obtained. Also,
In Comparative Example 10, since the amount of the liquid component added was too large, sufficient cohesive force could not be obtained, the tackiness of the pressure-sensitive adhesive layer was large, and adhesive residue on the skin was generated. The skin was considerably stretched, and the skin irritation was great. In Comparative Example 11, since the liquid component was not added, a sufficient drug transfer amount could not be obtained.

[0086]

The structure of the tape preparation of the present invention is as described above, the release of the drug and the stickability to the skin are well balanced, and the skin irritation is small. Further, since the tape preparation of the present invention uses an excellent adhesive base, it shows high solubility even for a drug having a relatively high polarity and can be applied to various drugs.

Claims (1)

[Claims] 1. A tape preparation having a pressure-sensitive adhesive layer containing a drug provided on one side of a support, wherein the pressure-sensitive adhesive layer comprises a (meth) acrylic acid alkyl ester having an alkyl group with 4 to 18 carbon atoms. 100 parts by weight of a copolymer (A) composed of 90% by weight, 0 to 70% by weight of a (meth) acrylic acid alkyl ester having an alkyl group having 3 or less carbon atoms, and 2 to 40% by weight of N-vinyl-2-pyrrolidone, From a rubber component or 1 to 100 parts by weight of a copolymer (B) of (meth) acrylic acid and methyl (meth) acrylate, 1 to 100 parts by weight of a liquid component compatible with the copolymer (A), and a drug A tape preparation characterized by being formed.