JPH0592919A - Tape formulation - Google Patents

Abstract

(57) [Summary] [Purpose] A transdermal tape preparation that exhibits a rapid release of the drug when applied to the skin due to the compatibility of the drug with the adhesive and exhibits effective release properties within a predetermined time. provide. [Structure] A tape preparation having a pressure-sensitive adhesive layer comprising a pressure-sensitive adhesive containing a drug in a compatible state on a support, wherein the pressure-sensitive adhesive has an alkyl group having 4 to 18 carbon atoms (meth).
25 to 50% by weight of acrylic acid alkyl ester, 20 to 70% by weight of alkyl group (meth) acrylic acid alkyl ester having 2 or less carbon atoms, and 2 to 4 of vinylpyrrolidone.
A tape preparation characterized in that it is a copolymer obtained by polymerization at a ratio of 0% by weight.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a percutaneous absorption preparation which is applied to a biological membrane such as skin or mucous membrane to administer a required drug through the biological membrane to the internal circulation system. The present invention relates to a tape preparation which is particularly preferably used for a drug having a relatively high polarity.

[0002]

2. Description of the Related Art A drug is contained in a pressure-sensitive adhesive in a compatible state, the pressure-sensitive adhesive is supported in layers on a support, and the pressure-sensitive adhesive layer is attached to the skin to transfer the drug to the body. Transdermal administration methods for administration are known. As described above, the main advantage of the administration method using the transdermal preparation is that it is possible to maintain a constant effective blood concentration for a long period of time, and thus it is expected that the duration of drug action and the reduction of side effects will be reduced. It can reduce the frequency of drug administration and improve patient compliance. Since the first pass effect in the liver can be avoided, the burden on the liver can be reduced.

The conditions required for such a transdermal preparation are as follows: Make sure that the drug product adheres to the skin for a certain period of time under any circumstances.

[0004] After the preparation is applied to the skin, it must be in intimate contact with the skin for 24 hours or 48 hours to absorb the required amount of drug. Further, it is necessary that the preparation adheres to the skin and does not peel off even when sweating or taking a bath.

2. Adhesives have a moderate compatibility with drugs,
Do not interact with the drug.

In order to release a large amount of the drug from the pressure-sensitive adhesive layer in a predetermined time, the drug needs to be contained in the pressure-sensitive adhesive at a high concentration, and the drug is dissolved in the pressure-sensitive adhesive. Desirable to be present. For that purpose, it is necessary that the drug and the component constituting the adhesive have high compatibility. Further, it is necessary that the interaction between the drug and the constituent component of the adhesive is not strong in the compatible state. For example, when the interaction between acid and base is strong, the release of the drug from the adhesive layer may be reduced.

3. There is little skin irritation caused by applying an adhesive to the skin.

A problem with tape formulations is the side effect of skin irritation. While the tape preparation is being applied to the skin, the adhesive layer is in contact with the skin surface, which prevents the normal functioning of the skin in that part, that is, secretion, metabolism and expansion and contraction. It is always stimulated by the adhesive layer. As a result, erythema develops, and in severe cases, scab formation and edema formation, which may continue for several days after tape peeling. It is important to minimize such side effects.

4. After peeling the adhesive from the skin, the adhesive should not remain on the skin surface.

Conventionally, based on the above points 1 to 4, the following transdermal preparations have been proposed, for example.

First, Japanese Patent Publication No. 54-16566 discloses that
A tape preparation in which a storage layer encapsulating a drug is formed on an adhesive layer is described.

Generally, the diffusion rate of a drug from the pressure-sensitive adhesive layer to the outside is high when the drug is compatible with the pressure-sensitive adhesive layer. When a drug is present in an encapsulating storage layer, or when the drug is present in a powdered or crystallized form, the rate of diffusion from the storage layer, powder or crystals to the adjacent adhesive is rate limiting. Sometimes. In such cases, the release of the drug from the base is often lower than when the drug is compatible with the adhesive. Further, encapsulation is technically difficult from the viewpoint of manufacturing the tape preparation, and the cost is high. Therefore, the formulation in which the drug is compatible with the adhesive layer is superior to the encapsulated formulation.

JP-A-57-116011 discloses that isosorbide dinitrate (ISDN) or pentaerythritol tetranitrate (PETN) is used as a drug, and the glass transition temperature
There is described a tape preparation containing a polymer having pressure-sensitive adhesive property at room temperature of 70 ° C to -10 ° C.

In this preparation, a drug is dissolved in a polymer of the pressure-sensitive adhesive layer, and a (meth) acryl having an alkyl group having an average carbon number of 4 or more is used as an acrylic copolymer suitable as a constituent component of the pressure-sensitive adhesive layer. At least 50 acid alkyl esters
A polymer obtained by including it in a weight percentage is mentioned. But,
In this preparation, the compounding ratio of the (meth) acrylic acid alkyl ester having 4 or more carbon atoms in the alkyl group is 5 as described above.
This acrylic copolymer has a low polarity as a pressure-sensitive adhesive because it is considerably large at 0% by weight or more. for that reason,
The solubility of ISDN, which is a drug having relatively high polarity, in the adhesive is not high. Further, even if a relatively highly polar monomer is used as the monomer to be copolymerized with this (meth) acrylic acid alkyl ester, the polarity can be changed to some extent, but the content of the low polar monomer is large. There is a limit to increase the polarity within the range where the tackiness is good.

JP-A-59-199628 discloses that an acrylic copolymer suitable for compatibilizing a drug in a pressure-sensitive adhesive layer and a constituent component of the pressure-sensitive adhesive layer is (meth) acrylic acid alkyl ester and vinyl. It is a copolymer of pyrrolidone, and it is described that the content of vinylpyrrolidone is preferably in the range of 1 to 60% by weight.

Further, in JP-A-61-100520, an acrylic copolymer suitable as a constituent component of the pressure-sensitive adhesive layer is 45 mol% or more of 2-ethylhexyl acrylate and 20 to 55 mol% of vinylpyrrolidone. A (meth) acrylic acid ester having an alkyl group having 3 to 12 carbon atoms and a homopolymer Tg of -40 ° C or lower of 35 mol% or less, and a polyfunctional monomer of 0.005 to 0.5 based on the total weight of the monomer
A tape preparation in which the drug is ISDN, which is a copolymer contained in a weight percentage, is described.

However, in these preparations, since vinylpyrrolidone has extremely high hydrophilicity, a large amount of the compound may cause a problem in water resistance of the pressure-sensitive adhesive during perspiration.

In Japanese Patent Laid-Open No. 58-134020, an acrylic ester 85 having an alkyl group with 4 to 10 carbon atoms is disclosed.
~ 99 wt% and acrylic acid or methacrylic acid 1-15
Disclosed is a base layer containing a copolymer of 100% by weight and ISDN as a drug.

However, since an acid such as acrylic acid or methacrylic acid is used as a copolymerization component in this preparation, cohesive force of the pressure-sensitive adhesive is imparted, but on the other hand, such acid may cause skin irritation. Not preferred as a formulation. Further, depending on the drug, the above-mentioned acid may adversely affect the release property or stability of the drug due to the interaction with the acid.

Further, the following has been proposed as a tape preparation intended to improve the drug release to the skin by adding a specific absorption enhancer.

In JP-A-58-79918, an acrylic adhesive is blended with indomethacin and at least one selected from the group of polyoxyethylene alkyl ethers and polyoxyethylene alkylphenyl ethers as an absorption promoter. Anti-inflammatory analgesic tape formulations are described.

Japanese Patent Publication No. 62-502965 discloses a pressure-sensitive adhesive containing 20 to 45% by weight of nitroglycerin in an acrylic polymer containing an alkyl (meth) acrylate whose alkyl group has 4 to 10 carbon atoms. 1 to 30 fatty acid esters having 16 to 24 carbon atoms as a skin penetration enhancer
% By weight, and 0.2 to 5 glycerin monolaurate
Adhesive coating materials containing weight percent are described.

JP-A-2-233617 describes a percutaneous absorption preparation containing estradiol as a drug and lactic acid as an absorption promoter in an adhesive base.

The absorption enhancer has the function of improving either or both of the release of the drug from the adhesive layer and the transdermal absorbability of the drug. As the absorption enhancer, it is necessary to select the optimum one in consideration of the target drug. However,
As a result of incorporating an absorption enhancer into the adhesive, the adhesiveness should not be reduced or the skin irritation should not be increased. Generally, when an absorption enhancer is added to an adhesive, phase separation and bleed-out tend to occur over time, which causes problems with the stability of the adhesive over time, and the adhesive tends to peel off due to perspiration during skin application. .. Therefore, it is necessary to select the optimum adhesive in consideration of the target drug and the absorption promoter to be blended.

The object of the present invention is to provide a transdermal administration type tape preparation in which a drug is promptly released when it is applied to the skin by the compatibility of the drug with the adhesive and the drug is effectively released within a predetermined time. To provide.

[0026]

The present invention is to maintain a high release property for a drug having a relatively high polarity for a long time, to have good adhesiveness and to adhere to the skin for a long time, and to prevent sweating after application to the skin. A pressure-sensitive adhesive that sufficiently satisfies the conditions such as being relatively water-resistant even when taking a bath, having low skin irritation, and having good temporal stability even when an absorption promoter is added As a result of repeated researches, it was completed with the finding that a pressure-sensitive adhesive made of a specific acrylic copolymer can meet the above-mentioned demand.

That is, the tape preparation according to the present invention is
In a tape preparation in which an adhesive layer made of an adhesive containing a drug in a compatible state is held on a support, the adhesive is
An alkyl group having 4 to 18 carbon atoms (meth) acrylic acid alkyl ester is 25 to 50% by weight, an alkyl group having 2 or less carbon atoms (meth) acrylic acid alkyl ester is 20 to 70% by weight, and vinylpyrrolidone is 2 ~ 40% by weight
It is characterized in that it is a copolymer obtained by polymerization at a ratio of.

In the tape preparation according to the present invention, a typical example of the drug is isosorbide dinitrate, and its concentration in the adhesive layer is preferably 8 to 40% by weight, more preferably 1%.
It is in the range of 0 to 30% by weight.

An absorption promoter may be further contained in the pressure-sensitive adhesive layer. A typical example of an absorption enhancer is lactic acid,
The concentration of lactic acid in the pressure-sensitive adhesive layer may be preferably in the range of 0.1 to 10% by weight, more preferably 0.5 to 5% by weight.

In addition to the absorption enhancer, the pressure-sensitive adhesive layer may further contain an adhesiveness improver for sweating. A typical example of an agent for improving stickiness during sweating is diethyl sebacate, and the concentration of diethyl sebacate in the adhesive layer is preferably 0.1 to 15% by weight, more preferably 0.5 to 12% by weight. It is a range.

The copolymer of the tape preparation according to the present invention is
0.005 to 0.5 of all monomers in addition to the above monomers
It may be a copolymer obtained by adding a polyfunctional monomer in an amount of 0.01% by weight, more preferably 0.01 to 0.2% by weight, and polymerizing these monomers. The addition of the polyfunctional monomer causes only slight cross-linking between the resulting polymers, which increases the internal cohesive strength of the adhesive.
Therefore, the so-called adhesive residue phenomenon at the time of tape peeling is eliminated irrespective of the property of the applied skin and the amount of perspiration. Moreover, the addition of this polyfunctional monomer has no effect on drug release and skin irritation.

The constituents and production method of the tape preparation according to the present invention will be described in detail below. a) Adhesive The adhesive that is the main constituent of the adhesive layer of the tape preparation of the present invention is an alkyl group having a carbon number of 4 to 18 and a (meth) acrylic acid alkyl ester having a carbon number of 25 to 50% by weight and an alkyl group having a carbon number of It is a copolymer obtained by polymerizing 2 or less (meth) acrylic acid alkyl ester in a proportion of 20 to 70% by weight and vinylpyrrolidone in a proportion of 2 to 40% by weight. The (meth) acrylic acid alkyl ester having 4 to 18 carbon atoms of the alkyl group, which is the first monomer constituting the copolymer, is contained in the range of 25 to 50% by weight.

If the content of the first monomer exceeds 50% by weight, the polarity of the pressure-sensitive adhesive becomes low and the compatibility with a drug having a relatively high polarity is not so good. Has a low solubility. Therefore, it becomes difficult to maintain a high release property and administer a fixed amount of a drug for a long time. In addition, for a formulation with a high concentration of dissolved drug, a formulation with a low concentration of dissolved drug increases the formulation area when the same amount of drug is contained, or when the area is the same,
It is necessary to increase the thickness of the adhesive layer. When the preparation area is large, the skin irritation is high, which is not preferable for use.
If the pressure-sensitive adhesive layer is thick, it is disadvantageous in terms of drug release and manufacturing cost.

When the content of the first monomer is less than 25% by weight, the adhesiveness of the pressure-sensitive adhesive to the skin is lowered and the reliability of drug administration is lowered, which is not preferable.

A more preferable range of the first monomer content is 3
It is 0 to 45% by weight.

Examples of the first monomer include butyl acrylate, butyl methacrylate, hexyl acrylate, hexyl methacrylate, octyl acrylate, octyl methacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate, dodecyl. Examples thereof include acrylate, dodecyl methacrylate, tridecyl acrylate, tridecyl methacrylate, octadecyl acrylate, octadecyl methacrylate and the like. Among them, the alkyl group has 4 carbon atoms
.About.8 alkyl acrylates, that is, butyl acrylate, hexyl acrylate, octyl acrylate, 2-ethylhexyl acrylate, etc. are preferable from the viewpoint of the balance between adhesiveness and drug compatibility.

The (meth) acrylic acid alkyl ester having 2 or less carbon atoms in the alkyl group which is the second monomer constituting the above copolymer is contained in the range of 20 to 70% by weight. When the content of the second monomer exceeds 70% by weight, the adhesiveness of the pressure-sensitive adhesive to the skin is reduced and the reliability of drug administration is reduced, which is not preferable. On the contrary, when the content of the second monomer is less than 20% by weight, the polarity of the pressure-sensitive adhesive decreases and the solubility of a drug having a relatively high polarity decreases, which makes it difficult to maintain high release from the preparation. ..

A more preferable range of the content of the second monomer is 30 to 60% by weight.

The second monomer may be methyl acrylate, methyl methacrylate, ethyl acrylate,
It is ethyl methacrylate. Among them, methyl acrylate and ethyl acrylate are preferable because of good adhesiveness and easy availability.

The third monomer constituting the above-mentioned copolymer, vinylpyrrolidone, is contained in the range of 2 to 40% by weight, and generally, methacrylic acid or a methacrylic acid often used as a constituent monomer for imparting cohesive force to the pressure-sensitive adhesive. Unlike acrylic acid, it imparts cohesive force, but since there is no acid at the end, it does not cause a reaction with a drug or cause skin irritation.

When the content of vinylpyrrolidone is less than 2% by weight, the cohesive force of the pressure-sensitive adhesive decreases, so when the preparation is applied to the skin and peeled off after a predetermined time, a part of the pressure-sensitive adhesive remains on the skin, There is a high possibility that phenomena unfavorable to the formulation will occur. On the other hand, when the content of vinylpyrrolidone exceeds 40% by weight, the sticking property is deteriorated and the polarity of the pressure-sensitive adhesive becomes extremely high, and the water resistance during sweating or bathing decreases.

A more preferable range of the vinylpyrrolidone content is 5 to 30% by weight.

Further, it was obtained that the total content of the (meth) acrylic acid alkyl ester having a carbon number of the alkyl group of 2 or less, that is, the second monomer, and the vinylpyrrolidone, that is, the third monomer was 50% by weight or more. The polarity of the copolymer becomes high, the solubility of the drug having relatively high polarity becomes high, and high release of the drug from the base material can be obtained for a long time.
Therefore, in a preferred mode of carrying out the present invention, the polymer constituting the pressure-sensitive adhesive comprises a (meth) acrylic acid alkyl ester (second monomer) having an alkyl group having 2 or less carbon atoms and vinylpyrrolidone (third monomer). Combined content is 50
2% by weight of (meth) acrylic acid alkyl ester (first monomer) having 4 or more carbon atoms in the alkyl group
By copolymerizing 5 to 50% by weight, 20 to 70% by weight of the second monomer, and 2 to 40% by weight of the third monomer, the polarity is high, the sticking property is excellent, and the absorption promoter is retained. An excellent pressure-sensitive adhesive having good water resistance can be obtained.

The polyfunctional monomer, which is an optional additional component of the above copolymer, may be contained in a proportion of 0.005 to 0.5% by weight based on the total weight of the monomers. In the present pressure-sensitive adhesive, an adhesive residue phenomenon may occur depending on the content and molecular weight of vinylpyrrolidone, but the addition of the polyfunctional monomer eliminates the adhesive residue phenomenon by crosslinking between the produced polymers.

If the amount of the polyfunctional monomer added is less than 0.005% by weight, the effect of improving the internal cohesive force due to crosslinking is insufficient. On the contrary, if the amount added exceeds 0.5% by weight, the adhesive tends to gel due to crosslinking.

A more preferable range of the polyfunctional monomer is 0.01 to 0.2% by weight.

Examples of such polyfunctional monomers include, but are not limited to, di (meth) acrylate, tri (meth) acrylate, tetra (meth) acrylate and the like. More specifically, di (meth) acrylate obtained by combining polymethylene glycols such as hexamethylene glycol and octamethylene glycol with (meth) acrylic acid; polyalkylene glycols such as polyethylene glycol and polypropylene glycol Di (meth) acrylate obtained by combining with (meth) acrylic acid; tri (meth) acrylate such as trimethylolpropane tri (meth) acrylate or glycerin tri (meth) acrylate; and pentaerythritol tetra (meth) acrylate. The tetra (meth) acrylate of is exemplified. You may use these polyfunctional monomers in combination of 2 or more types.

The adhesive is prepared, for example, by solution polymerization. That is, a (meth) acrylic acid alkyl ester having an alkyl group having 4 to 18 carbon atoms and an alkyl group having 2 or less carbon atoms (meth) acryl are provided in a reactor equipped with a stirrer and a cooling solvent reflux device. Acid alkyl ester, vinylpyrrolidone, and a predetermined amount of a polyfunctional monomer as required, and ethyl acetate or other general polymerization solvent are added, preferably under a nitrogen gas atmosphere at a high temperature, for example, It is subjected to a radical polymerization reaction at a temperature of about 80 ° C. for 8 to 40 hours. The monomers and the solvent are charged into the reactor all at once or appropriately divided.

The catalyst (polymerization initiator) is appropriately divided and used for the reaction according to the progress of the reaction. As the polymerization initiator, azobis type, peroxide type and the like are used, but they are not limited. Examples of the azobis-based initiator include 2,2′-azobisisobutyronitrile (AIB
N); 1,1'-azobis (cyclohexane-1-carbonitrile); 2,2'-azobis- (2,4-dimethylvaleronitrile) and the like.

Examples of peroxide type initiators include benzoyl peroxide (BPO); lauroyl peroxide (LPO); ditertiary butyl peroxide and the like. By this polymerization reaction, a copolymer is usually obtained with a solid content of 15 to 70% by weight. Gel Permeation Chromatog
The weight average molecular weight in terms of styrene by raphy (GPC) is 100,000 to 2,000,000. The residual monomer content is 4% by weight or less based on the total weight of each solid content.

B) Drug The drug (physiologically active substance) used in the percutaneous absorption preparation of the present invention is not particularly limited as long as it can permeate a biological membrane transdermally.

Examples of drugs include general anesthetics, hypnotics / sedatives, antiepileptics, antipyretic and analgesic / antiinflammatory agents, steroidal anti-inflammatory agents, stimulants / stimulants, sedatives, neuropsychiatric agents, local anesthetics, Skeletal muscle relaxant, autonomic nerve agent, antispasmodic, antiparkinsonian, antihistamine, cardiotonic agent, arrhythmic agent, diuretic, antihypertensive agent, vasoconstrictor, vasodilator, arteriosclerotic agent, respiratory stimulant, antitussive expectorant Agents, peptic ulcer treatment agents, choleretic agents, hormone agents, genitourinary and anal agents, parasitic skin disease agents, emollients, vitamins, mineral agents, hemostatic agents, anticoagulants, liver diseases Agents, addictive agents, therapeutic agents for gout, antidiabetic agents, antineoplastic agents, radiopharmaceuticals, Kampo preparations, antibiotics, chemotherapeutic agents, antiparasitic / antiprotozoal agents, narcotics, etc.

Representative examples of each drug are shown below.

Examples of the antipyretic analgesic and anti-inflammatory agent are acetaminophen, phenacetin, mefenamic acid, diclofenac sodium, flufenamic acid, aspirin, sodium salicylate, aminopyrine, alclofenac, ibuprofen, naproxen, flurbiprofen, ketoprofen, amphenac sodium. , Mepyrizole,
Examples include indomethacin, pentazocine, piroxicam and the like.

Examples of steroidal anti-inflammatory agents include hydrocortisone, triamcinolone, dexamethasone, betamethasone, prednisolone and the like.

As a vasodilator, diltiazem hydrochloride,
Examples include pentaerythritol tetranitrate, isosorbide dinitrate, trazipyr, nicorandil, nitroglycerin, prenylamine lactate, molsidomine, amyl nitrite, and trazoline hydrochloride.

Examples of the antiarrhythmic agents include procainamide hydrochloride, lidocaine hydrochloride, propranolol hydrochloride, alprenolol hydrochloride, atenolol, nadolol, metoprolol tartrate, azimarin, disopyramide, mexiletine hydrochloride and the like.

Examples of the antihypertensive agent include ecarazine hydrochloride, indapamide, clonidine hydrochloride, bunitrolol hydrochloride, labetalol hydrochloride, captopril, guanabenz acetate, mebutamate, betanidine sulfate and the like.

Examples of the antitussive and expectorant include carbetapentane citrate, cloperastine, oxerazine tannate, clobutinol hydrochloride, clofedanol hydrochloride, noscapine hydrochloride, ephedrine hydrochloride, isoproterenol hydrochloride, chlorprenaline hydrochloride, methoxyphenamine hydrochloride. , Procaterol hydrochloride, tulobuterol hydrochloride, clenbuterol hydrochloride, ketotifen fumarate, etc. are exemplified.

Examples of the anti-neoplastic agents include cyclophosphamide, fluorouracil, degafur, mitomycin C, procarbazine hydrochloride, doxyfluridine, ranimustine and the like.

Examples of the local anesthetic include ethyl aminobenzoate, tetracaine hydrochloride, procaine hydrochloride, dibucaine hydrochloride, oxybuprocaine hydrochloride, propitocaine hydrochloride and the like.

Examples of the hormone agent include propylthiouracil, thiamazole, metenolone acetate, estradiol, estriol, progesterone and the like.

Examples of the antihistamine include diphenhydramine hydrochloride, chlorpheniramine maleate, promethazine, cyproheptadine hydrochloride, diphenylpyraline hydrochloride and the like.

Examples of the blood coagulation inhibitor include warfarin potassium, ticlopidine hydrochloride and the like.

Antispasmodics include methylatropine bromide,
Scopolamine etc. are illustrated.

Examples of general anesthetics include thiopental sodium and pentobarbital sodium.

Examples of the hypnotic / sedative agents include bromowarenyl urea, amobarbital, phenobarbital and the like.

Examples of antiepileptic agents include phenytoin sodium.

Examples of the stimulant / stimulant include methamphetamine hydrochloride and the like.

Examples of the antispasmodic agents include difendol hydrochloride, betahistine mesylate and the like.

Examples of the psychiatric agents include chlorpromazine hydrochloride, thioridazine, meprobamate, imipramine hydrochloride, chlordiazepoxide, diazepam and the like. Examples of the skeletal muscle relaxant include suxamethonium hydrochloride, eperisone hydrochloride and the like.

Examples of agents for autonomic nerves include neostigmine bromide and bethanechol chloride.

Examples of anti-Parkinson's agents include amantadine hydrochloride and the like.

As diuretics, hydroflumethiazide,
Examples thereof include isosorbide and furosemide.

Examples of the vasoconstrictor include phenylephrine hydrochloride and the like.

Examples of respiratory stimulants include lobeline hydrochloride, dimorphoramine, naloxone hydrochloride and the like.

Examples of the therapeutic agent for peptic ulcer include glycopyrronium bromide, proglumide, cetraxate hydrochloride, cimetidine, spizofron and the like.

Illustrative choleretic agents include ursodesoxycholic acid and osalmid. Examples of the urogenital and anal agents include hexamine, sparteine, dinoprost, ritodrine hydrochloride and the like.

Examples of the agent for parasitic skin disease include salicylic acid, ciclopirox olamine, croconazole hydrochloride and the like.

Examples of emollients include urea.

As the vitamin preparation, calcitriol,
Examples thereof include thiamine hydrochloride, riboflavin sodium phosphate, pyridoxine hydrochloride, nicotinic acid amide, panthenol and ascorbic acid.

Examples of the inorganic preparation include calcium chloride, potassium iodide, sodium iodide and the like.

Examples of hemostatic agents include ethanesylate and the like.

Examples of the liver disease agent include thiopronin.

Examples of the addictive drug include cinnamide and the like.

Examples of the therapeutic agent for gout include colchicine, probenecid, sulfinpyrazone and the like.

Examples of the antidiabetic agents include tolbutamide, chlorpropamide, glymidine sodium, glybsol,
Examples include buformin hydrochloride, insulin and the like.

Antibiotics include benzylpenicillin potassium, propicillin potassium, cloxacillin sodium, ampicillin sodium, bacampicillin hydrochloride,
Carbenicillin sodium, cephaloridine, cefoxitin sodium, erythromycin, chloramphenicol, tetracycline, kanamycin sulfate, cycloserine and the like are exemplified.

Examples of the chemotherapeutic agent include isoniazid, pyrazinamide, ethionamide and the like.

Examples of narcotics include morphine hydrochloride, codeine phosphate, cocaine hydrochloride, pethidine hydrochloride and the like.

Of the above-mentioned drugs, particularly preferred for application to the present pressure-sensitive adhesive is a drug having a high compatibility with the pressure-sensitive adhesive and having a relatively high polarity, particularly isosorbide dinitrate (ISDN). The content of ISDN in the pressure-sensitive adhesive layer is 8 to 40% by weight, more preferably 10 to 30% by weight.

The amount of the above-mentioned drug compounded in the pressure-sensitive adhesive is appropriately determined depending on the composition of the copolymerizable monomer, and is preferably in the range of 2 to 40% by weight. The saturated solubility of the drug in the adhesive varies depending on the copolymerization monomer composition. High release of the drug is obtained by compatibilizing the drug in the adhesive at a concentration as close as possible to its saturation solubility and preventing crystal precipitation. When the drug crystals precipitate,
Usually, the tackiness decreases. However, even if drug crystals are deposited in the application of the tape preparation of the present adhesive, there is no particular problem.

C) Absorption promoter and other compounds In the tape preparation according to the present invention, an absorption promoter may be added to the pressure-sensitive adhesive layer.

Examples of absorption promoters include fatty acid esters, polyhydric alcohols, higher alcohols, organic acids, surfactants, hydrocarbons and the like.

Specific examples of the absorption enhancer include the following.

As the fatty acid ester, monoesters of isopropyl myristate, isopropyl palmitate, octyldodecyl myristate, octyl palmitate, butyl stearate, octyl hydroxystearate, octyl stearate, ethyl oleate, decyl oleate and the like: adipine Examples thereof include diesters of acid diisopropyl, diethyl sebacate, dioctyl adipate and dioctyl succinate: triesters such as triethyl citrate.

As the polyhydric alcohol fatty acid ester,
Examples include propylene glycol dicaprate, glyceryl trioctanoate, sorbitan oleate, glyceryl tripalmitate, and neutral fatty acid oils and fats.

Examples of the polyhydric alcohol include propylene glycol and polyethylene glycol.

Examples of higher alcohols include cetanol, behenyl alcohol, oleyl alcohol and the like.

As the organic acid, lactic acid, propionic acid, cinnamic acid, nicotinic acid, phthalic acid, oxalic acid, fumaric acid,
Maleic acid, succinic acid, tartaric acid, citric acid and the like are exemplified, and further lauric acid, myristic acid, palmitic acid,
Examples thereof include fatty acids such as stearic acid and oleic acid.

Examples of the surfactant include nonionic surfactants such as polyoxyethylene sorbitan monolaurate, polyoxyethylene glyceryl monooleate, polyoxyethylene monostearate, polyoxyethylene lauryl ether and polyoxyethylene oleylamine:
Anionic surfactants such as lauroyl sarcosine, triethanolamine lauryl sulfate, sodium lauryl phosphate and sodium polyoxyethylene lauryl ether phosphate: amphoteric surfactants such as lecithin are exemplified.

Examples of the hydrocarbon include liquid paraffin, squalane, squalene and the like.

Lactic acid is preferred when ISDN is used as the drug. The preferable blending amount of lactic acid is in the range of 0.1 to 10% by weight in the pressure-sensitive adhesive layer. This blending amount is 0.1
If it is less than wt%, the absorption promoting action is insufficient. Further, if the blending amount exceeds 10% by weight, the irritation of the sticking part is slightly increased and the tackiness is reduced. A particularly preferable amount of lactic acid is in the range of 0.5 to 5% by weight.

By using lactic acid as an absorption enhancer, it is possible to absorb sufficient drug through the skin to develop the desired drug effect, and at the same time, the transdermal absorbability is increased and the application area is reduced. It is possible to reduce skin irritation.

In order to further improve the transdermal absorbability of the drug, it is of course possible to use another absorption promoter in addition to lactic acid.

Further, in the tape preparation according to the present invention, an adhesiveness improving agent at the time of sweating may be blended in the pressure-sensitive adhesive layer in some cases. When applied in a sweaty condition such as during the summer or when exercising, the supply of water from the skin surface to the adhesive layer is significant, and in a sense, the adhesive surface becomes more severe than when it is bathed, causing the tape preparation to peel off. It will be easier. As the adhesiveness improver used in such a case, diester or triester is preferable, and specific examples thereof include diethyl sebacate, diisopropyl adipate, triacetin, tributyrin, and medium chain fatty acid triglyceride. A particularly preferable adhesiveness improver is diethyl sebacate, and the preferable amount of diethyl sebacate to be compounded is 0.1 to 15% by weight in the pressure-sensitive adhesive layer. This blending amount is 0.1
If it is less than wt%, the effect of improving the sticking property at the time of sweating is insufficient, and if it exceeds 15 wt%, diethyl sebacate cannot be retained in the pressure-sensitive adhesive layer and the tackiness is lowered. A particularly preferable compounding amount of diethyl sebacate is in the range of 0.5 to 12% by weight.

Although the detailed mechanism of action of the above diester or triester is not certain, it is considered as follows.

When the above-mentioned diester or triester is used as an agent for improving stickiness during sweating, it softens the base to improve stickiness and, at the same time, imparts some hydrophilicity to the base to enhance sweat absorption. , This prevents peeling off when sweating. As a result, the tape preparation does not peel off even when it is applied in a state accompanied by remarkable sweating such as in the summer or during exercise. In addition, this substance can be expected to have some absorption promoting effect.

Further, in the pressure-sensitive adhesive layer, a stabilizer for increasing the stability of the drug, a tackifier for adjusting the tackiness,
You may mix | blend a softener, a filler, etc. Examples of the tackifier include rosin-based resins, terpene-based resins, petroleum resins, coumarone-indene resins, terpene-phenol resins, and the like, and preferably rosin-based resins such as hydrogenated rosin esters are used. When a tackifier is used, it is contained in the pressure-sensitive adhesive layer in an amount of 45% by weight or less, preferably 5% by weight.
~ 20 wt%, add as needed.

D) Support As a support of the present tape preparation, a support that is flexible but has a function of imparting self-supporting property to the tape preparation and preventing volatilization and migration of the drug in the adhesive layer is used. It As the material of the support, cellulose acetate, ethyl cellulose,
Examples thereof include polyethylene terephthalate, plasticized vinyl acetate-vinyl chloride copolymer, nylon, ethylene-vinyl acetate copolymer, plasticized polyvinyl chloride, polyurethane, polyethylene, polyvinylidene chloride and aluminum. These materials are used, for example, as a single layer sheet or film or a laminate of two or more sheets. Materials other than aluminum may be used as woven or non-woven fabrics. As the support, one made of a material having conformability to the skin surface is preferably used, and a laminate film of polyethylene terephthalate and ethylene-vinyl acetate copolymer is particularly preferable. The thickness of the support is 500 μm or less, preferably 5 to 100 μm.

Further, in order to improve the adhesion between the support and the adhesive layer, the support may be subjected to corona treatment, plasma discharge treatment, or an anchor coating agent.

E) Release Paper The tape preparation is usually provided with a release paper on its surface for protection in order to protect the surface of the adhesive layer until use. As the release paper, polyethylene terephthalate film treated with silicon is often used, but the release paper is not limited thereto. The thickness of the release paper is 1000 μm or less, preferably 30 to 200 μm.

F) Preparation Method As a method for producing the tape preparation according to the present invention, a usual method for producing an adhesive tape can be applied. A typical example thereof is a solvent coating method, and in addition to this, a hot melt coating method, an electron beam curing emulsion coating method and the like are used.

To produce the tape preparation according to the present invention by a solvent coating method, for example, an adhesive base, a drug and an absorption promoter, and, if necessary, other compounding ingredients are dissolved or dispersed in an appropriate solvent, The obtained solution or dispersion is directly applied on the surface of the support and dried to form a patch layer having a thickness of 10 to 200 μm. Further, this solution or dispersion may be coated on a protective release paper and the adhesive layer obtained after drying may be adhered to the support. The thickness of the patch layer varies depending on the purpose of use, but is usually in the range of 10 to 200 μm. If the thickness is less than 10 μm, the required amount of drug cannot be contained and the adhesiveness is insufficient. When the thickness exceeds 200 μm, the drug contained in the patch layer near the support does not sufficiently diffuse, and the drug release property decreases.

[0115]

EFFECTS OF THE INVENTION According to the tape preparation of the present invention, the adhesive has good compatibility with a drug having a relatively high polarity, the solubility of the drug in the adhesive is high, and the drug contained in the adhesive is high. Since the amount is large, the effective release property is maintained for a long time after applying the adhesive to the skin.

Further, despite having a high solubility for a drug having a relatively high polarity, the adhesiveness is also good,
The water resistance of the adhesive when sweating or bathing is also good.

Furthermore, the skin irritation, which is a problem of the tape preparation, is extremely small.

In one form of the tape preparation according to the present invention, ISDN is used as a drug and lactic acid is contained as an absorption enhancer. Therefore, a sufficient amount of ISDN is absorbed through the skin to exert the desired drug effect. It is possible to reduce the skin irritation caused by the absorption enhancer.

In another form of the tape preparation according to the present invention, since diethyl sebacate is contained as a sticking property improving agent at the time of sweating, the tape preparation may peel even in a state accompanied by remarkable sweating. It can be attached for a long period of time.

[0120]

EXAMPLES Next, in order to specifically explain the present invention, examples showing one example of the present invention and some comparative examples showing a comparison therewith are given, and the performance test results of the obtained preparations are given. Indicates.

Preparation of Tape Formulation Example 1 40% by weight of 2-ethylhexyl acrylate (80 g)
Then, 35% by weight (70 g) of methyl acrylate and 25% by weight (50 g) of vinylpyrrolidone were charged in a separable flask, and 200 g of ethyl acetate was added so that the initial monomer concentration in the polymerization was 50% by weight. This solution was heated to 80 ° C. under a nitrogen atmosphere, 1 g of lauroyl peroxide as a polymerization initiator was dissolved in 100 ml of ethyl acetate, and the whole amount of the solution was sequentially added in small amounts and the polymerization reaction was carried out for 32 hours. It was

The produced polymer was taken out from the separable flask, and the tetrahydrofuran solution of piroxicam as a drug was adjusted so that the solid content (the total weight of the polymer and piroxicam after evaporation and removal of ethyl acetate and tetrahydrofuran) was 25% by weight. Further, piroxicam was added so that the concentration in the solid content of the mixture would be 6% by weight (the amount of piroxicam to the polymer was blended with piroxicam and set to the upper limit amount at which crystals did not precipitate when left standing for a long period of time. ).

This solution was siliconized to a thickness of 35 μm.
Of polyethylene terephthalate (PET) film on 1 side and dried at 60 ° C. for 30 minutes to give a thickness of 170
A μm pressure-sensitive adhesive layer was formed. Then, a support made of a PET film having a thickness of 10 μm was stuck on the pressure-sensitive adhesive layer.

An area of 10 cm ² was obtained for the layered product thus obtained.
A tape preparation containing 10 mg of piroxicam in each preparation was prepared.

Example 2 40% by weight of 2-ethylhexyl acrylate (80 g)
35% by weight (70 g) of methyl acrylate and 25% by weight (50 g) of vinylpyrrolidone were polymerized in the same manner as in Example 1 to obtain a polymer. Using a solution of ISDN in ethyl acetate as a drug, this was mixed with the polymer in the same manner as in Example 1 to prepare a tape preparation. However, IS
The concentration of DN in the solid content was 30% by weight, and the thickness of the adhesive layer after drying was 33 μm.

Example 3 40% by weight of 2-ethylhexyl acrylate (80 g)
35% by weight (70 g) of methyl acrylate and 25% by weight (50 g) of vinylpyrrolidone were polymerized in the same manner as in Example 1 to obtain a polymer. A tetrahydrofuran solution of indomethacin was used as a drug, and this was used in Example 1.
A tape preparation was prepared by blending with the polymer in the same manner as in. However, the concentration of indomethacin in the solid content was 14% by weight, and the thickness of the adhesive layer after drying was 70 μm.

Example 4 40% by weight (80 g) of octyl acrylate, 50% by weight (100 g) of ethyl acrylate, 10% by weight (20 g) of vinylpyrrolidone, 0.02% by weight (40 mg) of trimethylolpropane trimethacrylate. Was polymerized in the same manner as in Example 1 to obtain a polymer. A tetrahydrofuran solution of piroxicam as a drug was added to the polymer in the same manner as in Example 1 to prepare a tape preparation.
However, the concentration of piroxicam in the solid content was 7% by weight, and the thickness of the adhesive layer after drying was 140 μm.

Example 5 A polymerization reaction was carried out in the same manner as in Example 4 to obtain a polymer. Using a solution of ISDN in ethyl acetate as a drug, this was mixed with the polymer in the same manner as in Example 1 to prepare a tape preparation. However, the concentration of solid ISDN is 1
The thickness of the pressure-sensitive adhesive layer was 8% by weight, and the thickness of the pressure-sensitive adhesive layer after drying was 56 μm.

Example 6 A polymerization reaction was carried out in the same manner as in Example 4 to obtain a polymer. A tetrahydrofuran solution of indomethacin was used as a drug, and this was blended with the polymer by the same operation as in Example 1 to prepare a tape preparation. However, the concentration of indomethacin in the solid content was 13% by weight, and the thickness of the adhesive layer after drying was 77 μm.

Comparative Example 1 70% by weight of 2-ethylhexyl acrylate (140
g), 30% by weight of vinylpyrrolidone (60 g), and 0.02% by weight of hexamethylene glycol dimethacrylate (40 mg) were polymerized in the same manner as in Example 1 to obtain a polymer. A tetrahydrofuran solution of piroxicam as a drug was added to the polymer in the same manner as in Example 1 to prepare a tape preparation. However, the concentration of piroxicam in the solid content was 5% by weight, and the thickness of the adhesive layer after drying was 20%.
It was set to 0 μm.

Comparative Example 2 70% by weight of 2-ethylhexyl acrylate (140
g), 30% by weight of vinylpyrrolidone (60 g), and 0.02% by weight of hexamethylene glycol dimethacrylate (40 mg) were polymerized in the same manner as in Example 1 to obtain a polymer. Using a solution of ISDN in ethyl acetate as a drug, this was mixed with the polymer in the same manner as in Example 1 to prepare a tape preparation. However, the concentration of ISDN in the solid content was 20% by weight, and the thickness of the adhesive layer after drying was 50 μm.
It was set to m.

Comparative Example 3 70% by weight of 2-ethylhexyl acrylate (140
g), 30% by weight of vinylpyrrolidone (60 g), and 0.02% by weight of hexamethylene glycol dimethacrylate (40 mg) were polymerized in the same manner as in Example 1 to obtain a polymer. A tetrahydrofuran solution of indomethacin was used as a drug, and this was blended with the polymer by the same operation as in Example 1 to prepare a tape preparation. However, the concentration of indomethacin in the solid content was 9% by weight, and the thickness of the adhesive layer after drying was 110 μm.

Example 7 30% by weight of butyl acrylate (60 g), 65% by weight of ethyl acrylate (130 g), 5% by weight of vinylpyrrolidone (10 g), and 0.03% by weight of hexamethylene glycol dimethacrylate (60 mg). Was polymerized in the same manner as in Example 1 to obtain a polymer. I as a drug
Using a solution of SDN in ethyl acetate, this was blended with the polymer in the same manner as in Example 1 to prepare a tape preparation. However, the concentration of ISDN in the solid content was 18% by weight, and the thickness of the adhesive layer after drying was 56 μm.

Example 8 30% by weight (60 g) of hexyl acrylate, 65% by weight (130 g) of ethyl acrylate and 5% by weight (10 g) of vinylpyrrolidone were polymerized in the same manner as in Example 7 to obtain a polymer. It was A tape preparation was prepared by blending a solution of ISDN in ethyl acetate as a drug with the polymer in the same manner as in Example 7. However, the concentration of solid ISDN is 1
The thickness of the pressure-sensitive adhesive layer was 8% by weight, and the thickness of the pressure-sensitive adhesive layer after drying was 56 μm.

Example 9 35% by weight of 2-ethylhexyl acrylate (70 g)
Then, 55% by weight of ethyl acrylate (110 g) and 10% by weight of vinylpyrrolidone (20 g) were polymerized in the same manner as in Example 7 to obtain a polymer. ISDN as a drug
The ethyl acetate solution of was used in the same manner as in Example 7 to blend with the polymer to prepare a tape preparation. However, I
The concentration of SDN in the solid content was 20% by weight, and the thickness of the adhesive layer after drying was 50 μm.

Example 10 40% by weight (80 g) of octyl acrylate, 25% by weight (50 g) of ethyl acrylate and 35% by weight (70 g) of vinylpyrrolidone were polymerized in the same manner as in Example 7 to obtain a polymer. Obtained. A tape preparation was prepared by blending a solution of ISDN in ethyl acetate as a drug with the polymer in the same manner as in Example 7. However, the concentration of ISDN in the solid content was 25% by weight, and the thickness of the adhesive layer after drying was 40 μm.

Example 11 45% by weight (90 g) of octyl acrylate, 35% by weight (70 g) of ethyl acrylate and 20% by weight (40 g) of vinylpyrrolidone were polymerized in the same manner as in Example 7 to obtain a polymer. Obtained. A solution of ISDN in ethyl acetate was used as a drug, and this was blended with the polymer in the same manner as in Example 7 to prepare a tape preparation. However, the concentration of ISDN in the solid content was 21% by weight, and the thickness of the adhesive layer after drying was 48 μm.

Comparative Example 4 20% by weight (40 g) of octyl acrylate and 80% by weight (160 g) of ethyl acrylate were polymerized in the same manner as in Example 7 to obtain a polymer. ISDN as a drug
The ethyl acetate solution of was mixed with the polymer in the same manner as in Example 7 to prepare a tape preparation. However, the concentration of ISDN in the solid content was 18% by weight, and the thickness of the adhesive layer after drying was 56 μm.

Comparative Example 5 30% by weight of butyl acrylate (60 g), 15% by weight of methyl acrylate (30 g) and 55% by weight of vinylpyrrolidone (110 g) were polymerized in the same manner as in Example 7 to obtain a polymer. Obtained. A tape preparation was prepared by blending a solution of ISDN in ethyl acetate as a drug with the polymer in the same manner as in Example 7. However, the concentration of ISDN in the solid content was 33% by weight, and the thickness of the adhesive layer after drying was 30 μm.

Comparative Example 6 30% by weight of 2-ethylhexyl acrylate (60 g)
25 wt% (50 g) of ethyl acrylate and 45 wt% (90 g) of vinylpyrrolidone were polymerized in the same manner as in Example 7 to obtain a polymer. A tape preparation was prepared by blending a solution of ISDN in ethyl acetate as a drug with the polymer in the same manner as in Example 7. However, the concentration of ISDN in the solid content was 32% by weight, and the thickness of the adhesive layer after drying was 31 μm.

Comparative Example 7 45% by weight (90 g) of octyl acrylate, 15% by weight (30 g) of methyl acrylate and 40% by weight (80 g) of vinylpyrrolidone were polymerized in the same manner as in Example 7 to obtain a polymer. Obtained. A tape preparation was prepared by blending a solution of ISDN in ethyl acetate as a drug with the polymer in the same manner as in Example 7. However, the concentration of ISDN in the solid content was 28% by weight, and the thickness of the adhesive layer after drying was 36 μm.

Comparative Example 8 45% by weight (90 g) of hexyl acrylate and 55% by weight (110 g) of ethyl acrylate were polymerized in the same manner as in Example 7 to obtain a polymer. ISDN as a drug
The ethyl acetate solution of was mixed with the polymer in the same manner as in Example 7 to prepare a tape preparation. However, the concentration of ISDN in the solid content was 15% by weight, and the thickness of the adhesive layer after drying was 67 μm.

Comparative Example 9 55% by weight of 2-ethylhexyl acrylate (110
g) and 45% by weight of vinylpyrrolidone (90 g) were polymerized in the same manner as in Example 7 to obtain a polymer. A tape preparation was prepared by blending a solution of ISDN in ethyl acetate as a drug with the polymer in the same manner as in Example 7. However, IS
The concentration of DN in the solid content was 32% by weight, and the thickness of the adhesive layer after drying was 31 μm.

Comparative Example 10 2-Ethylhexyl Acrylate 85% by Weight (170
g) and 15% by weight of vinylpyrrolidone (30 g) were polymerized in the same manner as in Example 7 to obtain a polymer. A tape preparation was prepared by blending a solution of ISDN in ethyl acetate as a drug with the polymer in the same manner as in Example 7. However, IS
The concentration of DN in the solid content was 15% by weight, and the thickness of the adhesive layer after drying was 67 μm.

Comparative Example 11 55% by weight (110 g) of hexyl acrylate, 15% by weight (30 g) of methyl acrylate and 30% by weight (60 g) of vinylpyrrolidone were polymerized in the same manner as in Example 7 to obtain a polymer. Obtained. A tape preparation was prepared by blending a solution of ISDN in ethyl acetate as a drug with the polymer in the same manner as in Example 7. However, the concentration of ISDN in the solid content was 22% by weight, and the thickness of the adhesive layer after drying was 45 μm.
I chose

Comparative Example 12 55% by weight (110 g) of octyl acrylate, 25% by weight (50 g) of ethyl acrylate and 20% by weight (40 g) of vinylpyrrolidone were polymerized in the same manner as in Example 7 to obtain a polymer. It was A tape preparation was prepared by blending a solution of ISDN in ethyl acetate as a drug with the polymer in the same manner as in Example 7. However, the concentration of ISDN in the solid content was 20% by weight, and the thickness of the adhesive layer after drying was 50 μm.

Comparative Example 13 80% by weight of 2-ethylhexyl acrylate (160
g) and 20% by weight of ethyl acrylate (40 g) were polymerized in the same manner as in Example 7 to obtain a polymer. A tape preparation was prepared by blending a solution of ISDN in ethyl acetate as a drug with the polymer in the same manner as in Example 7. However, I
The concentration of SDN in the solid content was 8% by weight, and the thickness of the adhesive layer after drying was 125 μm.

Comparative Example 14 90% by weight of 2-ethylhexyl acrylate (180
g) and 10% by weight of acrylic acid (20 g) in Example 7
Polymerization was carried out in the same manner as above to obtain a polymer. IS as a drug
A solution of DN in ethyl acetate was added to the polymer in the same manner as in Example 7 to prepare a tape preparation. However, the concentration of ISDN in the solid content was 12% by weight, and the thickness of the adhesive layer after drying was 85 μm.

Example 12 30% by weight of butyl acrylate (60 g), 65% by weight of ethyl acrylate (130 g), 5% by weight of vinylpyrrolidone (10 g), and 0.03% by weight of hexamethylene glycol dimethacrylate (60 mg). Was polymerized in the same manner as in Example 1 to obtain a polymer. I as a drug
Using a solution of SDN in ethyl acetate and lactic acid as an absorption promoter, these were blended into the polymer by the same procedure as in Example 1 to prepare a tape preparation. However, the concentrations of ISDN and lactic acid in the solid content were 18% by weight and 1.0% by weight, respectively, and the thickness of the adhesive layer after drying was 56 μm.
I chose

Example 13 40% by weight of 2-ethylhexyl acrylate (80 g)
35% by weight (70 g) of methyl acrylate and 25% by weight (50 g) of vinylpyrrolidone were polymerized in the same manner as in Example 1 to obtain a polymer. Using a solution of ISDN in ethyl acetate as a drug and lactic acid as an absorption promoter, these were blended with the polymer in the same manner as in Example 1 to prepare a tape preparation. However, the concentrations of solids of ISDN and lactic acid were 23% by weight and 5.0%, respectively.
The thickness of the pressure-sensitive adhesive layer was set to 43% by weight after drying.

Example 14 A polymerization reaction was carried out in the same manner as in Example 4 to obtain a polymer. Using a solution of ISDN in ethyl acetate as a drug and lactic acid as an absorption enhancer, these were blended with the polymer in the same manner as in Example 1 to prepare a tape preparation.
However, the concentrations of ISDN and lactic acid in the solid content were 18% by weight and 3.0% by weight, respectively, and the thickness of the adhesive layer after drying was 56 μm.

Example 15 40% by weight (80 g) of octyl acrylate, 50% by weight (100 g) of ethyl acrylate and 10% by weight (20 g) of vinylpyrrolidone were polymerized in the same manner as in Example 1 to obtain a polymer. Obtained. Using a solution of ISDN in ethyl acetate as a drug, lactic acid as an absorption promoter, and hydrogenated rosin ester (“ester gum H” as a tackifier).
(Manufactured by Arakawa Chemical Co., Ltd.), and these were blended with the polymer in the same manner as in Example 1 to prepare a tape preparation. However, the concentrations of ISDN, lactic acid, and hydrogenated rosin ester in the solid content were 12% by weight, 3.0% by weight, and 25% by weight, respectively, and the thickness of the adhesive layer after drying was 83 μm.

Example 16 A polymerization reaction was carried out in the same manner as in Example 15 to obtain a polymer. Using a solution of ISDN in ethyl acetate as a drug,
Furthermore, lactic acid is used as an absorption promoter, and hydrogenated rosin ester is used as a tackifier (“ester gum H” manufactured by Arakawa Chemical Co., Ltd.)
And each of them were mixed with the polymer by the same operation as in Example 1 to prepare a tape preparation. However, ISD
The concentrations of N, lactic acid, and hydrogenated rosin ester in the solid content were 15% by weight, 3.0% by weight, and 10% by weight, respectively, and the thickness of the adhesive layer after drying was 67 μm.

Comparative Example 15 2-ethylhexyl acrylate 85% by weight (170
g) and 15% by weight of vinylpyrrolidone (30 g) were polymerized in the same manner as in Example 1 to obtain a polymer. Using a solution of ISDN in ethyl acetate as a drug and lactic acid as an absorption enhancer, these were blended with the polymer in the same manner as in Example 1 to prepare a tape preparation. However, ISD
The concentrations of N and lactic acid in the solid content were 15% by weight and 5.0% by weight, respectively, and the thickness of the adhesive layer after drying was 67%.
μm.

Example 17 A polymerization reaction was carried out in the same manner as in Example 4 to obtain a polymer. A solution of ISDN in ethyl acetate was used as a drug, and diethyl sebacate was used as an agent for improving stickiness during sweating. These were blended with the polymer in the same manner as in Example 1 to prepare a tape preparation. However, the concentrations of ISDN and diethyl sebacate in the solid content were 18% by weight and 1% by weight, respectively, and the thickness of the adhesive layer after drying was 56%.
μm.

Example 18 A tape preparation was prepared in the same manner as in Example 17, except that the concentration of diethyl sebacate was changed to 10% by weight.

Comparative Example 16 A tape preparation was prepared in the same manner as in Example 17, except that the concentration of diethyl sebacate was changed to 20% by weight.

Example 19 A polymerization reaction was carried out in the same manner as in Example 15 to obtain a polymer. Using a solution of ISDN in ethyl acetate as a drug,
Further, lactic acid was used as an absorption promoter, diethyl sebacate was used as a sticking property improving agent during sweating, and hydrogenated rosin ester (“Ester gum H” manufactured by Arakawa Chemical Co., Ltd.) was used as a tackifier. A tape preparation was prepared by blending with the polymer in the same manner as in. However, ISDN,
The concentrations of lactic acid, diethyl sebacate and hydrogenated rosin ester in the solid content were 15% by weight, 3.0% by weight, and
The thickness of the pressure-sensitive adhesive layer was set to 5% by weight and 10% by weight, and the thickness of the adhesive layer after drying was set to 67 μm.

Example 20 A polymerization reaction was carried out in the same manner as in Example 4 to obtain a polymer. Tetrahydrofuran solution of indomethacin was used as a drug, and diethyl sebacate was used as a sticking property improving agent at the time of sweating, and these were blended into the polymer by the same operation as in Example 1 to prepare a tape preparation. However, the concentrations of indomethacin and diethyl sebacate in the solid content were 13% by weight and 5% by weight, respectively, and the thickness of the adhesive layer after drying was 77 μm.

Example 21 A polymerization reaction was carried out in the same manner as in Example 4 to obtain a polymer. A solution of ISDN in ethyl acetate was used as a drug, lactic acid was used as an absorption enhancer, and diethyl sebacate was used as an adhesiveness improver during sweating. These were blended into a polymer by the same procedure as in Example 1 to prepare a tape. The formulation was prepared. However, the concentrations of ISDN, lactic acid, and diethyl sebacate in the solid content were 17% by weight, 3.0% by weight, and 10% by weight, respectively, and the thickness of the adhesive layer after drying was 5%.
9 μm.

Performance Test of Tape Agents i) Human Skin Adhesion Test The tape formulations of each of the Examples and Comparative Examples were subjected to an adhesive property test on human skin by the method shown in Test 1.

Further, Examples 5, 16, 17, 18, 1
With respect to each of the tape preparations of 9, 20 and 21, and Comparative Example 16, an adhesiveness test of the tape preparation on the skin during human sweating was performed by the method shown in Test 2.

Test 1 Each tape preparation was attached to a human forearm after removing the release paper, and the preparation was peeled off 2 hours after application, and the adhesive strength was evaluated by sensory evaluation according to the following criteria. In addition, in order to examine the water resistance, a bath was applied 2 hours after application, the preparation was peeled off, and the adhesive strength was evaluated by sensory evaluation according to the following criteria. The number of repetitions was 3 times.
The obtained results are shown in Table 1, Table 2, Table 3 and Table 4.

In these tables, each mark in the column of human skin adhesiveness has the following meaning.

◯: Sufficient tackiness Δ: Sufficient tackiness X: Weak tackiness and problems in use

Test 2 Each tape preparation was attached to a human forearm after the release paper was removed, and after exercising to keep sweating for 30 minutes, the peeling state of the preparation and the adhesive strength at the time of peeling were measured by the following sensory tests. It was evaluated according to the standard. The number of repetitions was 4 times. Table 4 shows the obtained results.
Shown in.

In Table 4, the numerical values in the column of sweat resistance have the following meanings.

5: No peeling was observed and the adhesive strength was sufficient. 4: Peeling was slightly recognized, but the adhesive strength was sufficient. 3: Peeling was slightly recognized and the adhesive strength was slightly insufficient. 2: Almost peeled off, weak adhesive force 1: Peeled off within 30 minutes

Ii) Rabbit Skin Drug Transfer Test The tape preparations of Examples and Comparative Examples were subjected to a drug transfer test to rabbit skin by the method shown in Test 3.

Test 3 A test piece (area: 10 cm ² ) of the tape preparation was attached to the dehaired back of a Japanese white rabbit, and after 24 hours, it was peeled and collected. The recovery test piece is extracted with methanol,
The residual amount of drug in the tape preparation was measured by high performance liquid chromatography. Initial drug amount of tape preparation 10mg
And the difference between the remaining amount after the test and the amount transferred to the skin for 24 hours.
The number of repetitions was 4 times for each formulation.

The average value obtained by dividing the sum of the measured values at each time by the number of repetitions 4 was taken as the skin transfer amount of each tape preparation. The obtained results are shown in Table 1, Table 2, Table 3 and Table 4.

Iii) Rabbit Skin Irritation Test Each tape preparation of Examples and Comparative Examples was subjected to a rabbit skin irritation test by the method shown in Test 4.

Test 4 The tape preparation was applied to the dorsal skin of a rabbit treated in the same manner as in Test 3 for 24 hours, peeled off, and the erythema state of the skin was visually observed immediately after peeling and 1 hour after peeling. In addition,
No edema or crust formation was observed in this study. The number of repetitions was 4 times for each formulation.

The degree of erythema was evaluated on the basis of the following 5 grades 0 to 4.

0 ... no erythema 1 ... slightly erythema barely discernible 2 ... clear erythema 3 ... medium erythema 4 ... strong erythema of deep crimson color The skin irritation index of the tape preparation was used. The obtained results are shown in Table 1, Table 2, Table 3 and Table 4.

Iv) Rabbit Skin Adhesive Residue Test For each tape preparation of Examples and Comparative Examples, the adhesive residue on the skin of rabbits was examined by the method shown in Test 5.

Test 5 The tape preparation was applied for 24 hours by the same operation as in Test 4, and the presence or absence of adhesive residue immediately after peeling was visually observed. The number of repetitions was 4 times for each formulation.

The evaluation criteria are as follows.

0: No adhesive residue 1: Adhesive residue is observed in a very small part.

The average value (value obtained by dividing the sum of evaluation points by the number of repetitions 4) was used as the adhesive residue index of each preparation. The obtained results are shown in Table 1, Table 2, Table 3 and Table 4.

[0181]

[Table 1]

[Table 2]

[Table 3]

[Table 4] As is clear from the above performance test results, the tape preparation according to the present invention maintains a high release property for a relatively highly polar drug for a long time, has a good adhesiveness and adheres to the skin for a long time, and is released. Compared with other preparations having the same level of sex, it is recognized that the skin has good water resistance even after sweating and when taking a bath after being applied to the skin, and has low skin irritation.

Continuation of front page (51) Int.Cl. ⁵ Identification number Office reference number FI technical display location // A61K 31/405 ABE 7252-4C 31/54 AAH 7252-4C

Claims (4)

[Claims] 1. A tape preparation having an adhesive layer comprising an adhesive containing a drug in a compatible state on a support, wherein the adhesive has an alkyl group having 4 to 18 carbon atoms (meth). Copolymerization obtained by polymerizing 25 to 50% by weight of alkyl acrylate, 20 to 70% by weight of alkyl (meth) acrylic acid alkyl group having 2 or less carbon atoms, and 2 to 40% by weight of vinylpyrrolidone. A tape preparation characterized by being a product. 2. The tape preparation according to claim 1, wherein the drug is isosorbide dinitrate, and the concentration in the adhesive layer is 8 to 40% by weight. 3. The tape preparation according to claim 2, wherein the adhesive layer contains lactic acid in an amount of 0.1 to 10% by weight. 4. The tape preparation according to claim 1, wherein the adhesive layer contains diethyl sebacate in an amount of 0.1 to 15% by weight.