JPH066534B2 - Transdermal patch - Google Patents

Description

TECHNICAL FIELD The present invention relates to a transdermal patch having excellent transdermal absorbability of a drug.

(Prior Art) In order to obtain a drug effect systemically or locally, a transdermal patch is used to absorb a drug (physiologically active substance) through the skin. The transdermal patch has a flexible support and a pressure-sensitive adhesive layer containing a drug. The pressure-sensitive adhesive layer is made of a polymer such as natural rubber, synthetic rubber or acrylic resin.

The amount of the drug contained in the pressure-sensitive adhesive layer is usually set to be equal to or lower than the saturated solubility of the polymer. However, if the amount of the drug is less than the saturated solubility, the amount of the drug absorbed by the human body is small, and thus a sufficient drug effect cannot be obtained. If the thickness of the pressure-sensitive adhesive layer is increased or the size of the patch is increased in order to increase the drug absorption amount, the cost becomes high and the user feels uncomfortable.

In order to solve such a defect, for example, JP-A-60-1
Japanese Patent No. 85713 proposes a transdermal patch in which a drug having a saturated solubility of a polymer (adhesive base) or more is contained in an adhesive layer. In this patch, the drug having a saturated solubility is dispersed in a substantially uniform recrystallized fine particle state. When such a patch is applied to the skin surface, the drug in the adhesive is percutaneously absorbed, and accordingly, the drug in a non-dissolved state (dispersed state) is sequentially replenished in the adhesive. In this way, the drug concentration in the adhesive after application of the patch is maintained at a saturated solubility or is determined by a balance between the drug release rate and the drug re-dissolution rate (below the saturated solubility).
Maintained at a concentration. Therefore, this patch has the effect of increasing the content of the drug per unit area, but it is the same effect as simply increasing the thickness of the adhesive layer, for example, the blood concentration of the drug or the drug. Almost no improvement in initial absorbability was observed, and the improvement in drug permeation through the skin was not significant. In addition, excessive drug may be distributed in the surface as huge recrystallized fine particles, which may reduce the stickiness.

Japanese Examined Patent Publication No. 60-59207 discloses a method for producing a composite preparation (patch) using as a support a polymer film capable of migrating a contacted drug. This patch forms a layer of adhesive on the surface of the above film (or sheet) by adding a transdermal drug (solid at least at 0 ° C.) to an adhesive base at a ratio of saturated solubility of the drug or more. I will do it.
In such a patch, an amount of drug exceeding the saturated solubility of the pressure-sensitive adhesive layer migrates into the support. When the patch is applied to the surface of the skin, the drug in the support is sequentially transferred into the adhesive for transdermal absorption of the drug in the adhesive, and the drug absorption is increased. In such a patch, the drug does not crystallize and the adhesiveness of the adhesive decreases, and the drug release rate does not decrease due to the slow re-dissolution rate of the crystallized drug. However, an excessive amount of drug exceeding the drug saturation solubility of the support cannot be contained in the adhesive base, and thus the drug content is limited by the drug solubility and thickness of the support.
From the support of this patch, an amount of the drug that supplements the released drug is supplied in accordance with the distribution, but the drug concentration in the adhesive layer is kept below the saturated solubility. Therefore, this patch is also similar to the patch containing the drug fine particles in the adhesive layer,
Almost no improvement in blood concentration of the drug or initial absorbability of the drug was observed, and improvement in the skin permeation amount of the drug was not remarkable.

(Problems to be Solved by the Invention) The present invention is to solve the above-mentioned conventional problems, and an object of the present invention is to provide a drug having a high drug content per unit area and in proportion to the drug amount. To provide a percutaneous absorption patch having high skin permeability. Another object of the present invention is, in addition to the above characteristics, a high initial release property of a drug,
Another object of the present invention is to provide a transdermal patch that can maintain a high level of blood concentration.

(Means and Actions for Solving Problems) The transdermal patch of the present invention is a transdermal skin in which an adhesive layer containing a solid drug at least 30 ° C. is formed on the surface of a drug impermeable support. Absorption patch, wherein the adhesive contains the drug in a ratio of saturated solubility or more, the patch is preheated, the drug is present in the adhesive layer in a supersaturated dissolution state, thereby The above object is achieved.

As the pressure-sensitive adhesive base used in the pressure-sensitive adhesive layer of the transdermal absorption patch of the present invention, a polymer used in a normal pressure-sensitive adhesive layer of a patch is used. For example, polyvinyl alkyl ether, poly (meth) acrylate, 2-ethylhexyl acrylate-2-ethylhexyl methacrylate copolymer, 2-ethylhexyl acrylate-vinylpyrrolidone copolymer, polyurethane, styrene-isoprene-styrene block copolymer, Polyisobutylene rubber, polyisoprene rubber, butyl rubber, natural rubber, silicone resin,
There is a terpene resin. Known tackifiers, softening agents, fillers, antioxidants, etc. may be added to these polymers in order to impart pressure-sensitive adhesiveness.

The support of the patch is provided in order to impart self-supporting property to the transdermal patch and prevent volatilization and migration of the drug in the pressure-sensitive adhesive layer, and a drug-impermeable material is used. For example, a film or sheet made of polyethylene, polypropylene, polyacrylic ester, polyurethane, polyester, polyvinyl alcohol, polyvinyl chloride, polyvinylidene chloride, polyamide, ethylenic copolymer rubber; a laminate of these; There are porous films or sheets using raw materials; fibrous films or sheets such as non-woven fabrics, woven fabrics, and papers; metal foils; films or sheets of metal foils whose surfaces are metal-deposited. Of these, a support having conformability to the skin surface is preferably used. The thickness of the support is 500 μm or less, preferably 5 to 150 μm.

The drug contained in the percutaneously absorbable preparation of the present invention is a drug which is transdermally absorbed and exerts a medicinal effect, for example, hydrocortisone, prednisolone, beclomethasone propionate, flumethasone, betamethasone, triamcinolone, triamcinolone acetolone. Corticosteroids such as nido, fluocinolone, fluocinolone acetonide, fluocinolone acetonide acetate, clobetasol propionate; acetaminophen, mefenamic acid, flufenamic acid, indomethacin, diclofenac, diclofenac sodium, alclofenac, oxyphene Butazone, phenylbutazone, ibuprofen, flurbuprofen, salicylic acid, methyl salicylate, l-menthol, camphor, sulindac, tolmetin sodium , Naproxen, fenbufen and other analgesic / anti-inflammatory agents; phenobarbital, amobarbital, cyclobarbital, toluazolam, nitrazepam, lorazepam, haloperidol, and other sedatives; fluphenazine, thioridazine, diazepam, fludiazepam, flunitrazepam, chlorpromazine, etc. Antihypertensive agents such as clonidine, clonidine hydrochloride, pindolol, propranolol, propranolol hydrochloride, bufuranol, indenolol, nivadipine, lofedixin, nibradirol, bucumolol, nifedipine; antihypertensive diuretics such as hydrothiazide, bendroflumethiazide, cyclopentiazide; Penicillin, tetracycline, oxytetracycline, fradiomycin sulfate, erythromycin Emissions, chloramphenicol antibiotics such as chloramphenicol; lidocaine, benzocaine, an anesthetic, such as aminoethyl benzoate, benzalkonium chloride, nitrofurazone, nystatin, antibacterial substances such as acetoacetic sulphates amines, clotrimazole;
Antifungal substances such as pentamycin, amphotericin B, pyrrolenitrin, clotrimazole; vitamin A,
Vitamin preparations such as ergocalciferol, cholecalciferol, octothiamine and riboflavin butyrate; antiepileptic agents such as nitrazepam, mepropamate and clonazepam; isosorbide dinitrate, erythritol tetranitrate, pentaerythrose tetranitrate, pro Coronary vasodilators such as patylnitrate; diphenhydramine hydrochloride, chlorpheniramine,
Antihistamines such as diphenylimidazole, antitussives such as dextromethorphan, terbutaline, ephedrine, ephedrine hydrochloride, salbutamol, and isoprotenol; sex hormones such as borogesterone and estradiol; antidepressants such as doxepin; 5-fluorouracil, dihydroergotamine, fentanyl, desmopressin, desmopressin, , Metoclopramide, domperide, scopolamine, scopolamine hydrobromide, and other drugs such as prostaglandin.

To the adhesive layer of the transdermal absorption patch of the present invention, an absorption promoter is added, if necessary, in order to promote percutaneous absorption of the drug. Examples of the absorption enhancer include glycols such as diethylene glycol, propylene glycol and polyethylene glycol; oils and fats such as olive oil, squalene and lanolin; urine derivatives such as urea and allantoin; isopropyl myristate and isopropyl palmitate;
Higher fatty acid esters such as diethyl sebacate, higher fatty acid triglycerides; fatty acid (mono) diethanolamides; salicylic acid; salicylates. The absorption promoter is used alone or in combination of two or more, and is contained in the pressure-sensitive adhesive layer in an amount of 30% by weight or less.

The percutaneous absorption patch of the present invention is prepared according to an ordinary patch using the above-mentioned adhesive base, support, drug and, if necessary, absorption promoter. For example, a drug and, if necessary, an absorption promoter are added to an organic solvent solution of a polymer serving as an adhesive base, and the support surface is coated and dried. A pressure-sensitive adhesive layer may be formed on the release paper and brought into close contact with the support. When preparing such a patch, the drug
It is blended in the pressure-sensitive adhesive at a ratio of 1.2 times or more, preferably 1.5 to 3.0 times, the saturated solubility of the drug of the pressure-sensitive adhesive base (including a tackifier and an absorption promoter if necessary). The drug mixed in the adhesive exists in a supersaturated dissolution state.

When such a patch is stored for a long time, the drug in a supersaturated dissolution state becomes fine crystals and gradually precipitates in the pressure-sensitive adhesive layer. Therefore, in the present invention, this patch is heated before use. By heating, the precipitated drug again becomes in a supersaturated dissolution state and remains in the pressure-sensitive adhesive layer. The heating temperature may be any temperature at which the contained drug can be redissolved in the adhesive. Here, the term "heating" includes not only the direct application of heat but also the treatment by a microwave oven or the like that radiates an electromagnetic wave to activate molecular motion and generate heat.

Thus, the patch containing the drug in a supersaturated dissolution state,
The drug concentration gradient when the patch is applied to the skin surface is larger than that of the conventional patch in which the drug recrystallized fine particles are present in the pressure-sensitive adhesive layer and the patch including the support to which the drug can be transferred. Therefore, the percutaneous drug permeation amount according to the Fick's diffusion equation increases. Therefore, the transdermal patch of the present invention can maintain a high blood concentration level for a long time and has high bioavailability. The initial release of the drug is also good. When such a patch is used, the same level of medicinal effect as conventional can be obtained even with a smaller area.

(Examples) 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.

Example 1 100 parts by weight of a 20% by weight ethyl acetate solution of 2 ethylhexyl acrylate-vinylpyrrolidone copolymer (containing 87 parts by weight of 2 ethylhexyl acrylate and 13 parts by weight of vinylpyrrolidone) was added to isosorbidogenite. A rate (ISDN) of 5 parts by weight was added and uniformly mixed by a dissolver. The obtained solution was applied on a polyethylene terephthalate (PET) release film having a thickness of 45 μm and dried to form a pressure-sensitive adhesive layer. This adhesive layer was laminated on a PET film (thickness 10 μm) support to obtain a transdermal patch. The pressure-sensitive adhesive layer had a thickness of 40 μm, and the drug concentration in the pressure-sensitive adhesive layer was 20% by weight. The ISDN saturated solubility of the adhesive substrate is 11.1% by weight.

When the thus obtained patch was left at room temperature for 3 months, fine ISDN crystals were precipitated in the pressure-sensitive adhesive layer.
The patch was heated in a gear oven at 70 ° C for 10 minutes. The ISDN crystals were completely dissolved and existed in the adhesive in a supersaturated dissolved state. 10 cm ^{3 of the} transdermal absorption patch obtained in this manner was applied to the back of a dehaired Japanese White Rabbit and the time-dependent change in drug blood concentration was measured.
The results are shown in Table 1. Example 2 and Comparative Examples 1-
The results of 3 are also shown in Table 1.

Comparative Example 1 The same as Example 1 except that the patch on which ISDN crystals were deposited was directly applied to the back of the rabbit without heating and the blood concentration was measured.

Comparative Example 2 A transdermal patch was prepared in the same manner as in Example 1, except that the amount of ISDN added was 2.5 parts by weight. However,
The thickness of the adhesive layer is 80 μm. The ISDN concentration in the adhesive layer was 11.1% by weight, and ISDN was uniformly dissolved in the adhesive layer even after 3 months.

Example 2 A 20 wt% 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 an adhesive base solution, and 1.04 parts by weight of ISDN was added. A transdermal patch was obtained in the same manner as in Example 1 except for the above. However, the thickness of the adhesive layer is 100 μm. The ISDN concentration in the adhesive layer was 4.94% by weight, and ISDN was uniformly dissolved. The saturated solubility of ISDN of the above adhesive base is 2.8% by weight.
Is.

When the thus obtained patch was left at room temperature for 3 months, fine ISDN crystals were precipitated in the pressure-sensitive adhesive layer.
The patch was sealed with an aluminum packaging material and heated in boiling water for 10 minutes. The ISDN crystals were completely dissolved and existed in the adhesive in a supersaturated dissolved state. Using this patch, the blood concentration of ISDN was measured in the same manner as in Example 1.

Comparative Example 3 The same as Example 2 except that the patch on which ISDN crystals were deposited was directly applied to the back of the rabbit without heating and the blood concentration was measured.

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

When the patch thus obtained was allowed to stand at room temperature for 3 months, fine crystals of indomethacin were precipitated in the pressure-sensitive adhesive layer. The patch was heated in a microwave oven (940W) for 5 minutes. The crystals of indomethacin were completely dissolved and became present in the adhesive in a supersaturated dissolved state. Using this patch, the blood concentration of indomethacin was measured in the same manner as in Example 1. The results are shown in Table 2. The results of Example 4 and Comparative Examples 4 to 6 are also shown in Table 2.

Comparative Example 4 The same as Example 3 except that the patch on which the indomethacin crystals were deposited was directly applied to the back of the rabbit without heating and the blood concentration was measured.

Comparative Example 5 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 thickness of the adhesive layer was 95 μm, and the drug concentration in the adhesive layer was 4.76% by weight.
The drug was uniformly dissolved in the adhesive layer even after a lapse of months.

Example 4 As Example 1 except that a 15 wt% 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 part by weight of indomethacin was added as the drug. A transdermal patch was obtained and the blood concentration was measured. However, the thickness of the pressure-sensitive adhesive layer is 100 μm. Indomethacin was uniformly dissolved in the adhesive layer, and its concentration was 4.46% by weight. The saturated solubility of indomethacin of the adhesive base of this example is 2.3% by weight.

When the patch thus obtained was allowed to stand at room temperature for 3 months, fine crystals of indomethacin were precipitated in the pressure-sensitive adhesive layer. The patch was heated in a microwave oven (940W) for 5 minutes. The crystals of indomethacin were completely dissolved and became present in the adhesive in a supersaturated dissolved state. Using this patch, the blood concentration of indomethacin was measured in the same manner as in Example 1.

Comparative Example 6 The same as Example 4 except that the patch in which indomethacin crystals were deposited was directly applied to the back of the rabbit without heating and the blood concentration was measured.

From Table 1 and Table 2, it is clear that the blood concentration of the drug is maintained at a high level for a long time by using the patch of the present invention in which the drug is present in the adhesive layer in a supersaturated dissolution state. It can be seen that the initial blood concentration of the drug is also high.

(Effect of the Invention) According to the present invention, a transdermal patch in which the drug is present in the adhesive layer in a supersaturated dissolution state is thus obtained. This transdermal patch has excellent drug release properties. A sustained drug release is also obtained. As a result, when this transdermal patch is applied to the skin, a high level of blood drug concentration can be obtained.
The initial blood concentration of the drug is also high and the blood concentration is excellent in sustainability.

Claims (2)

[Claims] 1. A drug-impermeable support surface having at least 30
A percutaneously absorbable patch having a pressure-sensitive adhesive layer containing a drug which is solid at 0 ° C., wherein the adhesive contains the drug at a ratio of saturated solubility or more, and the patch is preheated to Is present in the pressure-sensitive adhesive layer in a supersaturated dissolution state. 2. The adhesive has a saturation solubility of 1.
The percutaneous absorption patch according to claim 1, which is contained at a ratio of 2 times or more.