JPH0717851A - Drug-containing salve using (meth)acrylic ester-based sticking agent - Google Patents

Abstract

PURPOSE:To provide the salve excellent in sustained release nature and percutaneous absorbability and causing no skin irritation. CONSTITUTION:The salve can be obtained by providing a flexible substrate with a pressure-sensitive sticking layer comprising (A) a sticking agent consisting of (1) copolymer(s) of at least one kind of (meth)acrylic ester essentially containing a (meth)acrylic aryl ester such as benzyl acrylate or (2) a mixture of such copolymer and (B) a drug such as isosorbide nitrate.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a medicated patch for percutaneous administration of a sustained-release drug. More specifically, the adhesive layer made of a specific acrylic acid ester-based adhesive containing the drug is flexible. The present invention relates to a patch formed on a carrier, which has excellent sustained release properties and good transdermal absorbability.

[0002]

2. Description of the Related Art It is known that drugs such as isosorbide dinitrate are percutaneously absorbed, and a number of products have already been developed as transdermal patches. As a pressure-sensitive adhesive used for these patches, when the drug is isosorbide dinitrate, the fact that a pressure-sensitive adhesive of silicone type, rubber type, acrylic type or the like is preferable is shown in, for example, JP-A-57-116011. ing. In addition, the 5th Annual Meeting of the Pharmaceutical Society of Japan (1989
(26th to 28th of a month), Oguni et al., For the patch using isosorbide dinitrate, acrylic type, silicone type,
Comparing rubber systems, the three reported that the transdermal absorbability was about the same.

In the above-mentioned Japanese Patent Application Laid-Open No. 57-116011, the specification was amended and the application was announced after that, since acrylic adhesives were particularly preferred among various adhesives. Japanese Examined Patent Publication 4-74329
issue).

Alkyl acrylate is used as an acrylic adhesive for patches. However, patches using these pressure sensitive adhesives as main components have a problem in skin irritation.

Another problem of the patch is the occurrence of skin irritation, and various proposals have been made as methods for reducing it. As one of them, there is a method of reducing the preparation size, and for that purpose, it is necessary to enhance the transdermal absorbability per unit area. However, in the acrylic pressure-sensitive adhesive as described above, there is a limit to the amount of compatible drug. Attempts have been made to add a percutaneous absorption enhancer such as isopropyl myristate to enhance percutaneous absorption.However, such a low molecular percutaneous absorption enhancer itself penetrates the skin and is absorbed into the body. In many cases, there are concerns over safety in the long run, and in many cases skin irritation is observed.

[0006]

SUMMARY OF THE INVENTION An object of the present invention is to provide a sustained-release drug-containing patch which has less skin irritation and good transdermal absorbability.

[0007]

The present invention is a patch comprising a pressure-sensitive adhesive layer containing a pressure-sensitive adhesive and a drug formed on a flexible carrier, wherein the pressure-sensitive adhesive is a (meth) acrylic. A (meth) acrylic ester-based pressure-sensitive adhesive comprising a copolymer of one or more (meth) acrylic acid esters containing an acid aryl ester as an essential component or a mixture of homopolymers of these (meth) acrylic acid esters. The present invention provides a drug-containing patch.

In the present invention, as the (meth) acrylic acid aryl ester, for example, (meth) acrylic acid benzyl ester; p-isopropyl group, 3,5-
A benzyl or phenethyl ester having a dimethyl group or a p-methyl group; phenoxyethyl, p-methylphenoxyethyl, phenoxymethyl, p-phenoxymethyl ester and the like can be mentioned.

As the pressure-sensitive adhesive for patches of the present invention, a copolymer of one or more (meth) acrylic acid esters containing these (meth) acrylic acid aryl esters as an essential component, or a polymer mixture thereof. A (meth) acrylic acid ester-based pressure sensitive adhesive consisting of The (meth) acrylic acid aryl ester polymer may be used alone.

When the (meth) acrylic acid ester-based adhesive of the present invention is used, the skin irritation of the obtained patch can be alleviated, and the transdermal absorbability of the drug contained in the adhesive layer can be enhanced. . In particular, when isosorbide dinitrate is contained as a drug, it is possible to obtain a patch having high transdermal absorbability because of excellent drug compatibility.

Examples of the (meth) acrylic acid esters other than the (meth) acrylic acid aryl ester include alkyl esters of (meth) acrylic acid having 1 to 14 carbon atoms. Examples of these (meth) acrylic acid alkyl esters include methyl (meth) acrylate, ethyl (meth) acrylate, propyl (meth) acrylate, butyl (meth) acrylate, amyl (meth) acrylate, hexyl (meth) acrylate, Heptyl (meth) acrylate, octyl (meth) acrylate, nonyl (meth) acrylate, decyl (meth)
An acrylate, 2-ethylhexyl (meth) acrylate, etc. can be mentioned.

In the case of a copolymer with an alkyl (meth) acrylate, it is desirable that the aryl (meth) acrylate is contained in an amount of at least about 20% by weight. When used as a polymer mixture, it is desirable to contain at least about 20% by weight of a homopolymer of (meth) acrylic acid aryl ester.

The (meth) acrylic ester-based pressure-sensitive adhesive of the present invention may be copolymerized with another copolymerizable monomer having a vinyl group, or a general pressure-sensitive adhesive may be added with a plasticizer and a filler. These may be added for the same purpose as described above, and may be added within a range that does not impair compatibility with drugs, transdermal absorbability, or adhesive strength.

As a drug that can be used in the patch of the present invention, isosorbide dinitrate (isosorbide dinitrate, which may be abbreviated as ISDN hereinafter) can be preferably mentioned. Some of them can be mentioned.

(1) Nitroglycerin, 1,2,3-propanetriol mononitrate, 1,2,3-propanetriol dinitrate and ester derivatives thereof, isosorbide-5-mononitrate, pentaerythritol tetranitrate, papaverine hydrochloride, Hepronicard,
Molsidomine, nicomol, synfibrado, verabamil, dilazemcinnarizine hydrochloride, dipyridamole,
Coronary vasodilators such as nifedipine, nicardipine, trapidil, trimetazidine hydrochloride, carbochromene, prenilamine lactate, dilazep hydrochloride, trapidil;

(2) Pindolol, disopyramide, bupranolol hydrochloride, trichlormethiazide, furosemide,
Antiarrhythmic agents or angina agents such as prazomine hydrochloride, metoprolol tartrate, carthiolol hydrochloride, oxprenol hydrochloride, propranolol hydrochloride;

(3) Prazosin hydrochloride, ecarazine hydrochloride,
Antihypertensive agents such as hydrazine hydrochloride; (4) Cardiotonic agents such as methyldigoxin, sodium benzoate caffeine, caffeine, topamine hydrochloride, octopamine hydrochloride, diprophylline, bucladesine sodium, oxprenol hydrochloride, digitalis, zicoxin, ubidecarenone, etc .;

(5) Procaterol Hydrochloride, Pyributerol Hydrochloride, Clofuedanol Hydrochloride, Salbutamol Sulfate,
Bronchial asthma agents such as trimethoquinol hydrochloride, human luterol mesylate, pindolol, isoprotenol, isoaminyl citrate, carbocysteine, cefradine, tranilast, theophylline;

(6) Anti-high-pressure agents or calcium antagonists such as clonidine, nifedipine, nicardipine, verapamil;

(7) Aspirin, salicylic acid, methyl salicylate, ethyl salicylate, choline salicylate, sodium salicylate, salicylosalicylic acid, salicylamide, glycol salicylate, 1-menthol, aminopyrine, antipyrine, clofazone, ketophenylbutazone. , Feprazone, nicotinic acid benzyl ester, capsicum extract, capsaicin, acetaminophen,
Oxyphenbutazone, pentazocine, eptazocine, diflunisal, phenazole, mepyrizole, piroxicam, benzydamine, phenacetin, tiaramid,
Zofexamac, flufenamic acid, aluminum flufenamic acid, indomethacin, tramadol hydrochloride, ibuprofen, alclofenac, acemethacin, sulpirine, guaiazulene, ketoprofen, naproxen, kridanak, sulindac, benoxabrofein, indobuene, mefenamic acid, tolmethine, methiazinic acid, methenoic acid. Acid, perisoxal citrate, pranoprofen, sontal, phenylbutazone, fenbufen, fenthiazak, diflunizar, thiaprofenic acid, tinoridine hydrochloride, zomepirac, pimeprofen, bendazac, fenoprofen calcium,
Anti-inflammatory analgesics or agents for skin diseases such as milobrofen and derivatives thereof;

(8) Local anesthetics such as lidocaine, benzocaine, ethyl aminobenzoate, procaine hydrochloride, dipcaine and procaine;

(9) Antihypertensive diuretics such as mefluside, penfluticid, bumetanide, hydrothiazide, pendroflunathiazide and reserpine;

(10) Hypnotic sedatives such as methacarone, glutethimide, flurazebam, bromvalerylurea flurazebam hydrochloride, nitrazebam, haloxazolam, triazolam, phenobarbital, chloral hydrate, nimetazepam, estazolam;

(11) Central nervous system acting agents such as levodova, fluphenazine, flutazolam, phenobarbital sodium, methylphenobarbital, thioridazine, diazepam, benzbromarone, reserbine, sulvialbrazom, chlorpromazine, haloperidol, nitrazepam, lithium carbonate ;

(12) Psychoactive agents such as 3- (2-aminobutyl) indole acetate;

(13) Epinephrine, cortisone acetate,
Hydrocortisone acetate, prednisolone, hydrourtisone sodium succinate, triamcinolone acetonide, triamcinolone diacetate, dexamethasone phosphate, methylprezonisolone acetate dichloridine, methylprednisolone acetate, fluocinolone acetonide, dexamethasone acetate, dexamethasone, fluoro Hormonal agents such as mesolone, esterone, estradiol, ethinyl estradiol, progesterone, betamethasone sodium phosphate, betamethasone, betamethasone valerate, formoyurtal, flumethasone pivalate, beclomethasone propionate, and fludroxyurtide;

(14) sulfa drugs such as sulfadimethoxine, sulfisoxazole and sulfisomidine,
Antituberculosis agents such as ethambutol hydrochloride, isoniazid, calcium para-aminosalicylate;

(15) Antihistamines or antiallergic agents such as chlorpheniramine, diphenylimidazole, ketotifen; (16) Analgesics such as morphine, buprenorphine and their derivatives; (17) Others, vinbocetin, nicotine and their derivatives. etc

When isosorbide dinitrate is used as the drug, the content of these drugs is 0.1 to 20% by weight based on the pressure-sensitive adhesive because it has excellent compatibility with the (meth) acrylic acid ester-based adhesive of the present invention. %, And thus a patch having high transdermal absorbability can be obtained. Also,
When estradiol is used as a drug, it is suitable to add 0.5 to 5% by weight of the adhesive, and in the case of buprenorphine, 1 to 10% by weight of the adhesive is suitable.

In the production of the drug-containing patch of the present invention, first, the (meth) acrylic acid ester-based adhesive is dissolved or dispersed in a single solvent or a mixed solvent such as ethyl acetate, hexane, acetone, methanol, or a fluorocarbon solvent. The mixture is mixed with a drug, or is coated on a release paper or release film without mixing the drug so that the thickness after drying is a predetermined thickness, that is, 5 to 100 μm,
The solvent is thoroughly removed by drying and evaporation.

When a pressure-sensitive adhesive layer containing a drug is obtained by mixing a drug in an adhesive solution, applying the drug, and drying it, the pressure-sensitive adhesive layer containing the drug is attached to a flexible carrier, A drug-containing patch can be obtained by cutting into a desired size.

On the other hand, when the coating is carried out without mixing the chemicals or without mixing the chemicals in a sufficient amount and then dried, a pressure-sensitive adhesive layer containing no chemicals or no chemicals is obtained. .

The particularly preferred patch of the present invention is obtained when it is applied and dried without mixing the drug in the pressure-sensitive adhesive solution or in a sufficient amount. The sufficient amount means an amount that does not substantially exert a medicinal effect.

That is, as is known, the less residual solvent in the final patch, specifically, 100 ppm or less,
Preferably, the residual solvent amount of 50 ppm or less reduces the skin irritation of the patch. Therefore, in order to obtain such a patch with less residual solvent, a solution or dispersion of an adhesive is applied onto a release film or the like, and when dried,
It is necessary to reduce the residual solvent by applying sufficient heat, and / or taking a sufficient drying time, or by heating the obtained adhesive layer or placing it under reduced pressure.

In the present invention, the above-mentioned (meth) acrylic acid ester-based adhesive solution or a mixed solution of the same and a drug is added to another adhesive, for example, a silicone-based adhesive, to the extent that the characteristics of the mixture are not practically affected. Agents, rubber-based pressure-sensitive adhesives, vinyl ether-based pressure-sensitive adhesives may be used alone or in combination, and if necessary, known absorption accelerators, dissolution aids, diffusion aids, fillers, etc. may be contained alone or in a mixture. You may use it.

When an absorption promoter is used, isopropyl myristate is particularly preferable as the absorption promoter, and when isopropyl myristate is used, it is preferable to use 0.05 to 2 parts by weight per 1 part by weight of the drug.

Examples of other absorption promoters or diffusion aids include sodium lauryl sulfate, sodium dodecylbenzene sulfonate, sodium alkyldiphenyl ether disulphonate, dioctyl sulfosuccinate, polyoxyalkylphenyl ether sulfate ammonium salt and the like. Surfactants; alcohols such as glycerin, diethylene glycol, propylene glycol, polyethylene glycol and higher aliphatic alcohols; dimethyl sulfoxide and alkylmethyl derivatives; salicylic acid, urea, dimethylacetamide, dimethylformamide, lanolin, allantoin, squalene, carbopol, Diisopropyl adipate, pyroglutamic acid lauryl ester, ethyl laurate, methyl nicotinate, sol Pyrrolidone derivatives such as tall and dodecyl pyrrolidone, olive oil, castor oil, liquid paraffin, vaseline, gelatin, amino acids, lactic acid,
Ethyl lactate, benzyl nicotinate, L-menthol, camphor, dodecylazacycloheptan-2-one and the like can be used. Such additives are preferably used in an amount of 0.05 to 2 parts by weight per 1 part by weight of the drug.

In the patch of the present invention, the (meth)
A pressure-sensitive adhesive layer composed of an adhesive composition containing an acrylate ester-based adhesive and a drug as essential components is formed on a flexible carrier, and such a flexible carrier may be a film, a woven fabric, or a knitted fabric. , A non-woven fabric or a composite of a film and a fabric is used.

As the material of such a film or cloth, polyester such as polyethylene terephthalate; polyolefin such as polyethylene or polypropylene; polyamide such as nylon 6; ethylene-vinyl acetate copolymer can be used. Among these materials, polyester is preferable in terms of stability and safety.

In particular, when a film is used on the outer surface of the patch as a flexible carrier having high stability, an adhesive or an adhesive is applied to the inner or outer surface of the film for the purpose of improving the handleability of the patch. When the cloth is attached via the agent, the obtained patch has high stability and good handleability. As described above, in order to have high stability and good handleability, the film thickness is 0.5 to 10 μm,
The fabric preferably has a basis weight of 8 to 100 g / m ² ,
It is particularly preferable that the film is a polyester film having a thickness of 0.5 to 4.9 μm and the cloth is a polyester having a basis weight of 8 to 60 g / m ² .

A particularly preferred embodiment of the patch is shown below.
That is, the patch comprises (a) film layer, (b) adhesive layer, (c) cloth, (d) adhesive layer, (e) release film layer, and the outermost layer is (a), ), (B),
(C), (d), (e) are laminated in this order, and (e) is discarded when used.

(A) is a polyester film layer having a thickness of 0.5 to 4.9 μm. As the film, for example, an ultra-thin polyester film (trade name, Teijin, developed and sold by Teijin Ltd. for capacitor use) Tetron film F type) is particularly preferred. (B) is an adhesive layer having a thickness of 5 to 40 μm, and (c) has a basis weight of 8 to
It is a polyester fabric of 60 g / m ² . (D) is a pressure-sensitive adhesive layer comprising the (meth) acrylic acid ester adhesive of the present invention having a thickness of 10 to 60 μm, and (e) is a fluororesin or silicone resin coated thickness 3
It is a polyester film-based release film layer having a thickness of 0 to 100 μm. The drug is mainly present in the (d) adhesive layer,
It may be present in (b) the adhesive layer and (c) the cloth.

In the production of the patch of such a preferred embodiment, (b) an adhesive layer and (d) an adhesive layer which do not sufficiently contain a drug are produced, and (a) a film layer and (c) a cloth (b).
To form a composite layer by adhering via, a drug dissolved in a solvent such as acetone is dropped, sprayed on the fabric portion of the composite layer,
It is contained by dipping or the like, after which the solvent of the drug is removed by evaporation, and then (d) the adhesive layer is pressure-bonded. The patch thus obtained has (e) a release film layer.

The patch thus obtained is left for a long time or heated to sufficiently diffuse the drug into the (d) adhesive layer. Naturally, in this process, the drug also diffuses into the (b) adhesive layer. Drug-containing patches usually have a size of 1
It is cut into 0 to 100 cm ² and used, but such cutting may be performed before heating or after heating.

[0045]

The present invention will be described in more detail with reference to the following examples. Parts in the examples are parts by weight. The ISDN concentration in blood was measured by the following method. That is, 1m
After separating plasma from 1 blood sampled, ISDN was extracted with 6 ml of n-hexane and concentrated, and 100 μl of ethyl acetate was added to the concentrate to obtain a sample. ISDN in the sample was analyzed by GC. -Quantified by the ECD method.

An example of the method of synthesizing the (meth) acrylic acid ester-based pressure-sensitive adhesive used in the examples is shown below. That is, 50 parts of benzyl acrylate, 47 parts of 2-ethylhexyl acrylate, 3 parts of acrylic acid, 1 part of benzoyl peroxide and 100 parts of ethyl acetate were charged into a reaction vessel having a reflux condenser and an agitator, and slowly charged at 60 ° C. under a nitrogen atmosphere. Polymerization was continued for 12 hours with stirring. The polymerization conversion rate was 99.9%. 500 parts of ethyl acetate was added to the obtained polymer solution to adjust the solid content concentration to about 20.
Adjusted to%. Even when the copolymerization ratio of the reaction monomer was changed, the polymer could be basically synthesized by almost the same operation.

The fabric sample was prepared by the following method.
297 parts dimethyl terephthalate, ethylene glycol 2
65 parts, 53 parts of sodium 3,5-di (carbomethoxy) benzenesulfonate (11.7 mol% relative to dimethyl terephthalate), manganese acetate tetrahydrate 0.084 parts and sodium acetate trihydrate 1.22 Part into a glass flask with a rectification column, conduct transesterification reaction according to a conventional method, and after the theoretical amount of methanol is distilled, put the reaction product into a polycondensation flask with a rectification column and add positive phosphorus as a stabilizer. Add 0.090 parts of a 56% aqueous solution of acid and 0.135 parts of antimony trioxide as a polycondensation catalyst at a temperature of 275 ° C.
After reacting under normal pressure for 20 minutes and under reduced pressure of 30 mmHg for 15 minutes, they were reacted under high vacuum for 100 minutes. The final internal pressure was 0.39 mmHg, the intrinsic viscosity of the obtained copolymer was 0.402, and the softening point was about 200 ° C. After completion of the reaction, the copolymerized polymer was made into chips according to a conventional method.

15 parts of this copolymerized polymer chip and 85 parts of polyethylene terephthalate chip having an intrinsic viscosity of 0.640 were mixed in a Nauta mixer (manufactured by Hosokawa Iron Works) for 5 minutes and then at 110 ° C. in a nitrogen stream. After drying for 2 hours and further at 150 ° C. for 7 hours, the mixture was melt-kneaded at 285 ° C. using a twin-screw extruder to form chips. This chip had an intrinsic viscosity of 0.535 and a softening point of 261 ° C.

This chip was dried by a conventional method, and a spinning spinneret having a circular slit having a width of 0.05 mm and a diameter of 0.6 mm having two circular arc-shaped openings was used. Then, a hollow fiber (hollow ratio 25%) having an outer diameter to inner diameter ratio of 2: 1 was produced. The obtained hollow fibers were scattered over the entire cross section of the hollow fibers and had fine pores arranged in the fiber direction, and at least a part of the fine pores communicated with the hollow portion. This hollow fiber was 300 denier / 24 filament, and using this raw yarn, it was drawn at a draw ratio of 4.2 times in accordance with a conventional method to obtain a 71 denier / 24 filament multifilament. This multifilament was formed into a knitted fabric, scoured and dried by a conventional method, and then treated with a 1% caustic soda aqueous solution and at a boiling temperature for 2 hours to obtain a knitted fabric having an alkali weight loss rate of 20%. The obtained knitted fabric was stretched 1.5 times in the machine direction and heated at 100 ° C. for 1 minute to heat set to obtain a knitted fabric having a basis weight of 17 g / m ² , that is, a fabric sample.

Examples 1 to 3 and Comparative Example 1 Benzyl acrylate (BA) as the (meth) acrylic acid aryl ester and 2-ethylhexyl acrylate (2EH) as the (meth) acrylic acid alkyl ester.
A), acrylic acid (AA) as other copolymerization component,
And methyl methacrylate (MMA) were used in the proportions shown in Table 1 and copolymerized by the method as described above to obtain a pressure-sensitive adhesive dope having a solid content concentration of 20%.

On the release film silicone-coated with this dope (base is a polyester film of 75 μm), the thickness after drying is 15 μm for each level.
Two types of adhesive layers of (adhesive layer b) and 40 μm (adhesive layer d) were obtained.

As the film a, a polyethylene terephthalate (Teijin Tetron film) having a thickness of 2.5 μm is used.
F type, manufactured by Teijin Limited, film for capacitors)
First, the adhesive layer b was pressure-bonded onto the film, and the fabric sample was pressure-bonded onto the free surface of the adhesive layer b.
Next, an acetone solution of ISDN was continuously added dropwise to the free surface of this fabric sample so that ISDN was 13.8 g per 1 m ² . Acetone was evaporated by air drying, and the adhesive layer d was pressure-bonded to the free surface of the cloth to obtain a laminate. At this time, a release film coated with an opalescent silicone-based release agent having a thickness of 75 μm was attached to the surface of the adhesive layer d which was not pressure-bonded to the cloth. The obtained laminate was cut into a size of 5.3 cm × 5.3 cm, and then 1
After each one was wrapped in aluminum, it was heated at 65 ° C. for 24 hours.

From the preparation thus obtained, a size of 10c
A test preparation for animal experiment of m ² was prepared, and applied on the back of a hairless rat having an average body weight of 200 g after hair removal, and blood was collected before application, 2 hours after application, 5 hours after application, and 24 hours after application,
The ISDN concentration in blood was measured for each. AUC and Cmax were calculated from the obtained blood concentrations. The results are shown in Table 1.

[0054]

[Table 1]

In the skin condition after the test, there were no particular problems with the adhesiveness to the skin and the skin irritation.

Examples 4 to 6 and Comparative Example 2 In the same manner as in Examples 1 to 3 and Comparative Example 1, except that the acetone solution of ISDN was not added dropwise, the test formulation having a size of 10 cm ² was prepared. Was prepared, and each preparation was attached to 5 humans and the adhesive state was observed. Also, 2
After 4 hours, the preparation was peeled off and the skin condition was observed. The results are shown in Table 2.

[0057]

[Table 2]

[0058]

EFFECTS OF THE INVENTION The drug-containing patch of the present invention has good transdermal absorbability and sustained release properties, does not cause skin irritation, and contains isosorbide nitrate as a drug, which mainly prevents angina. It can be used as a therapeutic agent.

Front Page Continuation (72) Inventor Yoshiki Suzuki 4-3 Asahigaoka, Hino City, Tokyo Teijin Limited Tokyo Research Center

Claims (4)

[Claims] 1. A patch comprising a pressure-sensitive adhesive layer containing a pressure-sensitive adhesive and a drug formed on a flexible carrier, the pressure-sensitive adhesive containing (meth) acrylic acid aryl ester as an essential component. A drug-containing patch which is a (meth) acrylic ester-based pressure-sensitive adhesive comprising a copolymer of one or more kinds of (meth) acrylic acid esters or a mixture of homopolymers of these (meth) acrylic acid esters. 2. The drug-containing patch according to claim 1, wherein the acrylic acid aryl ester is benzyl acrylate. 3. The drug according to claim 1, which is isosorbide dinitrate.
Or the drug-containing patch according to 2. 4. The drug according to claim 1 or 2, wherein the drug is one or more drugs selected from the group consisting of nitroglycerin, buprenorphine, estradiol, progesterone, ketotifen, vinvocetin, nicotine and derivatives thereof. Containing patch.