JPS6393715A - Plaster for transcutaneous absorption - Google Patents

Abstract

PURPOSE:To obtain the titled plaster having high initial releasability of drug and capable of keeping the drug concentration in blood at a high level, by using a pressure-sensitive adhesive layer containing drug of an amount above its saturation solubility in a supersaturated dissolved state and forming the adhesive layer on a surface of a drug-impermeable substrate. CONSTITUTION:A surface of a drug-impermeable substrate is coated with a pressure-sensitive adhesive layer containing a drug at an amount of >=1.2 times, preferably 1.5-3.90 times the saturation solubility. The drug is solid at <=30 deg.C and present in the adhesive layer in a supersaturated dissolved state. If necessary, the pressure-sensitive adhesive layer may be added with <=30wt% absorbefacient. The plaster has high drug content per unit area and, accordingly, high transcutaneous transmission rate in proportion to the drug content.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a transdermal patch with excellent transdermal drug absorption.

(Prior Art) In order to obtain systemic or local medicinal effects, drugs (physiologically active substances) are absorbed through the skin using transdermal patches. Transdermal patches have a flexible support and an adhesive layer containing a drug. The adhesive layer is made of a polymer such as natural rubber, synthetic rubber, or acrylic resin.

The amount of drug contained in the adhesive layer is set to be less than the saturation solubility of the 2-usually 9-polymer. However, the drug t below the saturation solubility
In ui, there is less drug tlLt absorbed by the human body,
Insufficient medicinal effect. Increasing the thickness of the adhesive layer or increasing the size of the patch in order to increase the amount of drug absorption increases the cost and gives the user a sense of discomfort.

In order to solve these drawbacks, for example,
Japanese Patent Publication No. 185713 proposes a transdermal patch in which the adhesive layer contains a drug having a saturated solubility or higher than that of a single polymer (adhesive base). In this patch, the drug exceeding the saturation solubility is dispersed in the form of almost uniform recrystallized fine particles. When such a patch is applied to the skin surface, the drug in the adhesive is absorbed transdermally, and the drug in an undissolved state B (dispersed state) is sequentially replenished into the adhesive.

In this way, the drug concentration in the adhesive after application of the patch is
It is maintained at saturation solubility or at a predetermined concentration (below saturation solubility) determined by the balance between drug release rate and drug redissolution rate. Therefore, this patch has the effect of increasing the drug content per unit area, but this is the same effect as simply increasing the thickness of the adhesive layer9.
for example.

Almost no improvement was observed in the blood concentration of the drug or the initial absorption of the drug, and there was also no significant improvement in the amount of drug permeated through the skin. Furthermore, excess drug becomes large recrystallized fine particles that are unevenly distributed on the surface, which may reduce adhesiveness.

Japanese Patent Publication No. 60-59207 discloses a method for producing a composite preparation (patch) using a polymeric physical film as a support to which a drug on contact can migrate. This patch is
A layer of an adhesive is formed on the surface of the film (or sheet), in which a transdermally absorbable drug (which is solid at at least 0° C.) is added to an adhesive base in a proportion equal to or higher than the saturation solubility of the drug. In such patches, an amount of drug that exceeds the saturated solubility of the adhesive layer migrates into the support. When the patch is applied to the skin surface, as the drug in the adhesive is absorbed transdermally, the drug in the support is sequentially transferred into the adhesive and replenished, increasing the amount of drug absorbed. In such a patch, the drug does not crystallize and the tackiness of the adhesive decreases, and the drug release rate does not decrease due to the slow redissolution rate of the crystallized drug. However, it is not possible to contain an excess of drug in the adhesive base that exceeds the saturation solubility of the drug in the support.

The drug content is limited by the drug dissolving ability and thickness of the support. An amount of drug that compensates for the released drug is supplied from the support of this patch according to the distribution, but the drug concentration in the adhesive layer is kept below the saturation solubility. Therefore, similar to the above-mentioned patch containing drug fine particles in the adhesive layer, this patch shows almost no improvement in the blood concentration of the drug or the initial absorption of the drug, and there is no improvement in the amount of drug permeated through the skin. Not noticeable.

(Problems to be Solved by the Invention) The present invention is intended to solve the above-mentioned conventional problems, and its purpose is to achieve a high drug content per unit area, and to increase the drug content in proportion to the drug amount. The object of the present invention is to provide a transdermal patch with high skin permeability. Another object of the present invention is that, in addition to the above-mentioned characteristics, the initial release of the drug is high and a high level of blood concentration can be maintained. The purpose of the present invention is to provide a transdermal patch.

(Means for Solving the Problems) The transdermal patch of the present invention is a transdermal patch in which an adhesive layer containing a drug that is solid at at least 30° C. is formed on the surface of a drug-impermeable support. It's a drug.

The adhesive contains the drug at a ratio of 1.2 times or more of the saturated solubility, and the drug exists in the adhesive layer in a supersaturated dissolved state, thereby achieving the above object.

As the adhesive base used in the adhesive layer of the transdermal patch of the present invention, a polymer used in the adhesive layer of a conventional patch is used. For example.

Polyvinyl alkyl ether, poly(meth)acrylate, 2-ethylhexyl acrylate-2-ethylhexyl methacrylate copolymer, 2-ethylhexyl acrylate
Examples include vinylpyrrolidone copolymer, polyurethane, styrene-isoprene-styrene block copolymer, polyisobutylene rubber, polyisoprene rubber, butyl rubber, natural rubber, silicone resin, and terpene resin. For these polymers.

In order to impart pressure-sensitive adhesive properties, known tackifiers, softeners, fillers, anti-aging agents, etc. may be added.

The support for the patch is provided to provide self-supporting properties to the transdermal patch and to prevent volatilization or migration of the drug in the adhesive layer, and is made of a drug-impermeable material. For example, polyethylene, polypropylene, polyacrylic acid ester.

polyurethane, polyester, polyvinyl alcohol,
Films or sheets made of polyvinyl chloride, polyvinylidene chloride, polyamide, or ethylenic copolymer rubber; laminates thereof; porous films or sheets using the above materials; nonwoven fabrics.

Woven fabric9 Fibrous film or sheet such as paper; Metal foil;
There is a film or sheet of metal foil that has a metal vapor deposited surface. Among these, a support that has conformability to the skin surface is preferably used.

The thickness of the support is 500 μl or less, preferably 5 to 15 μl.
It is assumed to be 0 μm.

The drug contained in the transdermal absorbable preparation of the present invention.

It is a drug that is absorbed transdermally and exerts its medicinal effects.

For example, hydrocortiscin, prednisolone.

Beclomethasone propionate, flumethacin.

Corticosteroids such as betamethacin, triamcinolone, triamcinolone acetonide, fluocinolone, fluocinolone acetonide, fluocinolone acetonide acetate, clobetasol propionate; acetaminophen, mefenamic acid, flufenamic acid, indomethacin 2; diclofenac, diclofenac sodium; Alclofenac, oxyphenbutazone,
Phenylbutacin, ibuprofen, flurbuprofen, salicylic acid, methyl salicylate, l-menthol,
L'T IJiW such as camphor, sulindac, tolmetin sodium, naproxen, fenbufen, etc.
Anti-inflammatory agents; phenobarbicur, amobarbital, cyclobarbital. Hypnotic sedatives such as toluazolam, nitrazepam, lorazepam, haloperidol; fluphenazine, thioligine. Diazepam, fludiazepam, fludiazepam.

Tranquilizers such as chlorpromazine; clonidine.

Clonidine hydrochloride, pindolol, propranolol, propranolol hydrochloride, bufranol, indenolol,
Antihypertensive agents such as nivadipine, lofedixin, nipradilol, bucumolol, nifedipine; antihypertensive diuretics such as hydrothiazide, bendroflumethiazide, cyclopenthiazide; penicillin, tetracycline, oxytetracycline, fadiomycin sulfate.

Antibiotics such as erythromycin, chloramphenicol; anesthetics such as lidocaine, pensicaine, ethyl aminobenzoate; antibacterial substances such as benzalkonium chloride, nitrofurazone, nyscutin, acetosulfamine, clotrimazole; pentamycin, amphotericin B Antifungal substances such as , pyrrolenidrine, and clotrimazole; vitamins such as vitamin A, ergocalciferol, cholecalciferol, octothiamine, and riboflavin butyrate; antiepileptic agents such as nitrazepam, mepropamate, and clonazepam; isosorbidinite Coronary vasodilators such as erythritose tetranitrate, pentaerydose tetranitrate, propyl nitrate; antihistamines such as diphenhydramine hydrochloride, chlorpheniramine, diphenylimidazole; dextromethorphan, terbutaline.

Antitussives such as ephedrine, ephedrine hydrochloride, salbutamol, isoprotenol; sex hormones such as borogesterone, estradiol; anti-alpha agents such as doxebin; 5-fluorouracil, dihydroergotamine, fentanil, desmopressin, digoxin, metoclopramide, domperid, scopolamine, hydrobromic acid Scopolamine.

There are other drugs such as prostaglandins.

If necessary, an absorption enhancer is added to the adhesive layer of the transdermal patch of the present invention in order to promote transdermal absorption of the drug. Absorption enhancers include 9 e.g.

Diethylene glycol, propylene glycol.

Glycols such as polyethylene glycol; Oils and fats such as olive oil, squalene, and lanolin; Urea derivatives such as urea and allantoin; Isopropyl myristate,
Isopropyl valmitate.

Higher fatty acid esters such as diethyl sebacate.

These include higher fatty acid triglycerides; fatty acid esters; salicylic acid; and salicylic acid esters. The absorption enhancer may be used alone or in combination of two or more, and is contained in the adhesive layer in an amount of 30% or less.

The transdermal patch of the present invention is prepared in the same manner as a conventional patch using the above-mentioned adhesive base, support, drug and, if necessary, an absorption enhancer. for example.

A drug and, if necessary, an absorption enhancer are added to an organic solvent solution of a polymer serving as an adhesive base, and this is applied to the surface of a support and dried. An adhesive layer may be formed on a release paper and brought into close contact with the support. When preparing such a patch, the drug has a saturated solubility of at least 1.2 times, preferably 1.5 times, the saturation solubility of the drug in the adhesive base used (including tackifiers and absorption enhancers as necessary). It is blended into the adhesive at a ratio of ~3.0 times. The drug mixed in the adhesive exists in a supersaturated dissolved state. Therefore, compared to conventional patches in which drug recrystallized microparticles are present in the adhesive layer or patches with a support to which the drug can migrate, the drug concentration gradient when the patch is applied to the skin surface is large. Therefore, the amount of drug permeated through the skin increases according to Fick's diffusion equation. The transdermal patch of the present invention can therefore maintain high blood concentration levels for long periods of time and has high bioavailability.

The initial drug release properties are also good. When such a patch is used, the same level of medicinal efficacy as before can be obtained even in a smaller area.

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

In the Examples and Comparative Examples, the drug blood concentration of isosorbide dinitrate was measured by gas chromatography, and the drug blood concentration of indomethacin was measured by liquid chromatography.

The following praise = 100 parts by weight of a 20% by weight solution of 2-ethylhexyl acrylate-vinylpyrrolidone copolymer (containing 13 parts by weight of vinylpyrrolidone to 87 parts by weight of 2-ethylhexyl acrylate) in ethyl acetate. To.

5 parts by weight of isosorbide dinitrate (ISDN) was added and mixed uniformly using a discer. The obtained solution was poured into a polyethylene terephthalate (45 μm thick) (
PET) was applied onto a hoof-shaped film and dried to form an adhesive layer. I'ET film (thickness 1
0 μm) supports were laminated to obtain a transdermal patch. The thickness of the adhesive layer was 40 μm, and the drug concentration in the adhesive layer was 20% by weight. The 15DN saturation solubility of the adhesive base material is 11.1% by weight.

10 cd of the transdermal patch thus obtained.

It was applied to the backs of Japanese domestic rabbits that had undergone hair removal treatment, and changes in blood drug concentration over time were measured. These results are shown in Table 1. The results of Example 2 and Comparative Examples 1 to 3 are also shown in Table 1.

Comparison ■ Ethylene with a vinyl acetate content of 40% by weight as a soil support
A 100 μm thick laminated film (E
The procedure was the same as in Example 1 except that a VA film layer (thickness: 90 μm) was used. The adhesive patch of this comparative example is obtained by bringing a release film and an adhesive layer thereon into close contact with the EVA surface of a support film.

The amount of isosorbide dinitrate (ISDN) added is 2.
A transdermal patch was prepared in the same manner as in Example 1 except that the amount was 5 parts by weight. However, the thickness of the adhesive layer is 8
It is 0 μm. l5DN in the adhesive layer? ffi degree is 11
．． 1% by weight, and 15DN is distributed uniformly in the adhesive layer?
I understood.

1 Thoughts ± 1 A 20% by weight tetrahydrofuran solution of a mixture of 25 parts by weight of styrene-isoprene-styrene block copolymer, 25 parts by weight of polyisoprene rubber and 50 parts by weight of terpene resin was used as the adhesive base solution.

A transdermal patch was obtained in the same manner as in Example 1, except that 1.04 parts by weight of isosorbide dinitrate (ISDN) was added. However, the thickness of the adhesive layer is 100 μm.
It is. The ISDN concentration in the adhesive layer was 4.94% by weight, and 15DN was uniformly dissolved. The saturated solubility of 15ON in the adhesive base is 2.8% by weight.

The transdermal absorbable preparation I Q cnl thus obtained
of.

It was applied to the backs of Japanese domestic rabbits that had undergone hair removal treatment, and changes in blood drug concentration over time were measured.

Ethylene with a vinyl acetate content of 40% by weight was used as the adhesive support.
The procedure was the same as in Example 2 except that a 100 pm thick laminated film (EVA film layer thickness 90 pm) obtained by coextruding vinyl acetate copolymer (EVA) and PET was used. The adhesive patch of this comparative example is obtained by bringing the adhesive layer on the release film into close contact with the EVA surface of the support film.

Indomethacin was added as a drug to a 20% by weight ethyl acetate solution of 2-ethylhexyl-vinylpyrrolidone copolymer (containing 3 parts by weight of vinylpyrrolidone to 97 parts by weight of 2-ethylhexyl acrylate). 2 parts by weight was added to obtain a transdermal patch according to Example 1. The thickness of the adhesive layer was 50 μm, and the drug concentration in the adhesive layer was 9.09% by weight. The saturation solubility of indomethacin in the adhesive base is 4.8% by weight.

The transdermal patch 30d thus obtained.

It was applied to the backs of Japanese domestic rabbits that had undergone hair removal treatment, and changes in blood drug concentration over time were measured. These results are shown in Table 2. The results of Example 4 and Comparative Examples 4 to 6 are also shown in Table 2.

In this case, the starting support was vinyl acetate-butyl acrylate-methoxyethyl acrylate (weight ratio 40:30:30).
) Copolymer film (thickness: 50 μm) and polyvinylidene chloride film (thickness: 50 μm) were heated and pressurized to prepare a laminated film, which was the same as Example 3. The agent is obtained by bringing the adhesive layer on the release film into close contact with the copolymer film surface of the support film.

Comparative Example 1 A transdermal patch was prepared in the same manner as in Example 3, except that the amount of indomethacin added was 1 part by weight, and the blood concentration was measured. However, the drug concentration in the adhesive layer is
It was 4.76% by weight, and the drug was uniformly dissolved in the adhesive layer.

Example 1 except that a 15% by weight tetrahydrofuran solution of a mixture of 55 parts by weight of natural rubber and 45 parts by weight of terpene resin was used as the adhesive base solution, and 0.7 parts by weight of indomethacin was added as the drug. A transdermal patch was obtained in the same manner, and the blood concentration was measured. However, the thickness of the adhesive layer is 95 μm. Indomethacin was uniformly dissolved in the adhesive layer, and its concentration was 4.46% by weight. The saturated solubility of indomethacin in the adhesive base of this example is 2.3% by weight.

Vinyl acetate-butyl acrylate-methoxyethyl acrylate (weight ratio 40:30:30)
) The same as Example 4 except that a laminated film prepared by heating and pressurizing a copolymer film (thickness: 50 μm) and a polyvinylidene chloride film (thickness: 50 μl) was used. The adhesive patch of this comparative example is obtained by bringing the adhesive layer on the release film into close contact with the copolymer film surface of the support film.

(See blanks below) Tables 1 and 2 to 9 When the patch of the present invention is applied to the skin surface, the patch using a support to which the drug can transfer (Comparative Examples 1, 3.4, and 6) and the adhesive It is clear that the blood concentration of the drug is maintained at a high level for a long time compared to the patches containing the drug at or below the saturation concentration (Comparative Examples 2 and 5). It can be seen that the initial blood concentration of the drug is also at a high level.

(Effects of the Invention) According to the present invention, a transdermal patch in which the drug exists in the adhesive layer in a supersaturated dissolved state can be obtained. This transdermal patch has excellent drug release properties. Sustained drug release is also obtained. As a result, when this transdermal patch is applied to the skin, a high level of drug concentration in the blood can be obtained.

The initial blood concentration of the drug is high, and the blood concentration is also excellent in sustainability.

that's all

Claims (1)

[Scope of Claims] 1. A transdermal patch comprising an adhesive layer containing a solid drug at at least 30° C. formed on the surface of a drug-impermeable support, the adhesive layer containing a drug that is solid at at least 30°C; A transdermal patch containing the drug at a ratio of 1.2 times or more of the saturated solubility, wherein the drug is present in the adhesive layer in a supersaturated dissolved state.