JPH0751515B2 - Transdermal formulation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a transdermal preparation.

Transdermal preparations intended for systemic action have made remarkable progress in recent years with the progress of drug delivery systems (DDS), and their usefulness as sustained release preparations has been particularly recognized. Silicone elastomer is a particularly safe base for transdermal drug delivery,
It is widely used as a base for implantable preparations and percutaneous absorption preparations, as well as a drug holding carrier for various other preparations, that is, a carrier for active ingredients. On the other hand, it is known that the drug release from the drug holding carrier is an important factor in the transdermal preparation for the purpose of systemic action. However, when the vapor pressure of a drug such as nitroglycerin is extremely high, the drug retained by the silicone elastomer, that is, the release of the medical compound as the active ingredient is extremely high and a highly useful product has been developed. The release rate of the drug from the elastomer is extremely low, and the elastomer preparation is used only for a drug having a small effective dose such as scopolamine.

The present inventors have earnestly studied to eliminate the drawbacks of the conventional transdermal preparations, and as a result, a silicone elastomer containing a drug, that is, a mixture of a medical compound as an active ingredient and an aliphatic ester or sugar alcohol, dispersed therein. Found that the drug release from this point is high, and completed the present invention.

The gist of the present invention is to provide a percutaneous absorption preparation comprising a pharmaceutical compound having percutaneous absorbability as an active ingredient and a carrier for holding the active ingredient consisting of a silicone elastomer,
A percutaneous absorption preparation is characterized in that an aliphatic ester, a sugar alcohol, or both are mixed and mixed with a medical compound to enhance the drug releasing ability.

In the percutaneously absorbable preparation of the present invention, a pharmaceutical compound as an active ingredient and a mixture of a fatty acid ester or a sugar alcohol or both of them are dispersed and blended in a silicone elastomer forming a carrier for retaining the active ingredient. Is preferred.

The drug used in the present invention, that is, the medical compound as an active ingredient is not particularly limited as long as it is transdermally absorbable, for example, penicillin, cephalosporin antibiotics,
Antibacterial antibiotics such as erythromycins, tetracyclines, macrolide antibiotics, aminoglycoside antibiotics, fosfomycin antibiotics; aspirin, sulpirine, paraaminoacetophenol, amphenac sodium, diclofenac sodium, ethyl paraaminobenzoate, saltyl Antipyretic analgesic and anti-inflammatory agents such as methyl acidate, mefenamic acid, ibuprofen, tiaramide hydrochloride, indomethacin; antihistamines such as α-clopheniramine maleate, diphenylpyraline, diphenhydramine, clemastine fumarate, promethazine hydrochloride; diazepam, chlorpromazine, chlordiazepoxide, chlorpromazine hydrochloride. , Sulpiride, haloperidol, ethyl loflazepate and other psychotropic agents; vitamins
Vitamins such as A, B, C, D, E; anti-diabetic agents such as tolbutamide; cardiotonics such as prenylamine lactate, digitoxin and dibuxin; sleeping agents such as barbituric acid system; diuretics such as furosemide, sodium salicylate and thiobromine Antiarrhythmic agents such as propranolol hydrochloride and pindolol; antihypertensive agents such as hydralazine hydrochloride; vasodilators such as diltiazem hydrochloride, dipyrdamol hydrochloride, nifedipine, nitroglycerne, isosorbide nitrate, propanetilnitrate; adrenal hormone agents such as dexamethasone and prednisolone; Chemotherapeutic agents such as nalidixic acid and sulfa drugs; anticancer agents such as busulfan, 5-FU, vincristine, adriamycin, teralubicin, bleomycins, mitomycin C and cisplatin.

In addition, aliphatic esters include propylene glycol caprate, glycerin tricaplate, glycerin 2-
Examples include ethylhexanate, neopentyl glycol 2-ethylhexanate, sorbitan threolate, and the like.
Sugar alcohols include sorbitol, mannitol and the like. Further, the silicone elastomer is, for example, polydimethylsiloxane, hydrogenpolysiloxane copolymer or hydroxypolydimethylsiloxisan, hydrogenpolysiloxane copolymer, and is, for example, Dow Corning Co., Ltd. trade name Q7-2218, Q7-
Those available at 4290 are preferred.

A preferred method for producing the transdermal preparation of the present invention is, for example, as follows. That is, after mixing a drug, that is, a pharmaceutical compound as an active ingredient and sugar alcohols, fatty acid esters are further uniformly mixed to form a paste-like mixture.
This paste is uniformly mixed in a two-component curable silicone polymer (liquid low polymerization state) and dispersed as fine particles. At this time, if necessary, a plasticizer (for example, Cylastic 360 Glue (trade name, liquid silicone manufactured by Dow Corning)), an absorption accelerator (for example, isopropyl myristate, Azone, urea, lactic acid, glycerin, monoglyceride, diisopropyl adipate). Etc.) and fillers (for example, silica, calcium carbonate, talc, kaolin, etc.) can be blended.

When the above silicone polymer is preliminarily blended with a curing catalyst, the silicone polymer is put into an appropriate mold and cured or molded at room temperature or by heating to obtain the percutaneously absorbable preparation of the present invention. On the other hand, when the silicone polymer is not preliminarily blended with the catalyst, a curing catalyst (for example, tin octoate or platinum octoate) is appropriately added to the above mixture, and the mixture is quickly and sufficiently mixed and put in an appropriate mold. The percutaneous absorption preparation of the present invention is obtained by curing and molding at room temperature or by heating.

The percutaneous absorption preparation of the present invention comprises a medical compound of 0.05 to 40 parts (by weight), sugar alcohols of 1 to 30 parts, and fatty acid esters of 1 to 1.
It is preferable to prepare it in a composition containing 30 parts, 20 to 80 parts of a silicone elastomer and an appropriate amount of a catalyst.

In the transdermal preparation of the present invention, the release of the drug from the silicone elastomer is enhanced by blending fatty acid esters, sugar alcohol, or both of them. Therefore, the percutaneous absorption preparation of the present invention has high drug release,
Since a necessary and sufficient amount of drug can be absorbed through the skin, application is easy and side effects can be suppressed.

Hereinafter, the present invention will be specifically described with reference to Examples and Test Examples.

Example 1 Isosorbide dinitrate (vasodilator) 20.0 g and sorbitol 2
0.0 g was mixed, and 10.0 g of a 7: 3 mixed solution of sorbitan trioleate and propylene glycol dicaprate was kneaded to obtain a paste-like mixture. This after the silicone elastomer Q ⁷ -4290 (A) and (B) were each combined uniformly kneaded by adding 25.0 g, was cured and molded to stand being had to the mold 7 hours at 60 ° C.. The transdermal preparation of the present invention was obtained.

Example 2 20.0 g of isosorbide dinitrate and 20.0 g of sorbitol were mixed,
A 7: 3 mixture of 10.0 g of sorbitan trioleate and propylene glycol dicaprate was kneaded to obtain a paste-like mixture. Silicone elastomer Q7-
After 49.75 g of 2218 was added and kneaded uniformly, 0.25 g of tin octoate was added thereto and quickly and uniformly mixed, put in a mold and left at room temperature for 10 minutes to cure and mold. The transdermal preparation of the present invention was obtained.

Test Example 1 The drug release from the preparation was tested using the samples shown in Table 1 below.

Sample 1 is isosorbide dinitrate silicone elastomer
This is a comparative preparation prepared by uniformly kneading with Q7-2218, then placing it in a mold and curing and molding at 60 ° C. for 7 hours. Sample 2 is a preparation prepared by mixing isosorbide nitrate with sorbitol, uniformly kneading with silicone elastomer Q7-2218, and then placing the mixture in a mold and allowing it to stand at 60 ° C. for 7 hours for curing. Sample 3 was the preparation prepared in Example 1 as a sample. The size of each sample is 6.5 mm in diameter,
It is a disk shape with a thickness of 1.5 mm, and each sample is subjected to a release amount test using a formulation release tester (manufactured by Toyama Sangyo Co., Ltd.) with a 20% aqueous solution of polyethylene glycol 400 as a release solvent. The amount released was measured by gas chromatography.

The results are shown in the graph of FIG. In Figure 1, A, B,
C shows the cumulative release rate of the samples 1, 2, and 3 with respect to the drug additive. FIG. 1 shows that the drug release of samples 2 and 3 (invention) is much higher than that of sample 1 (comparative).

Test Example 2 The drug release from the preparation was tested using the samples shown in Table 2 below.

Sample 4 was prepared by uniformly kneading isosorbide dinitrate with Q7-4290.
This is a comparative preparation prepared by adding tin octoate (curing catalyst), mixing it quickly and uniformly, placing it in a mold and allowing it to stand at room temperature for 10 minutes to cure.

Sample 5 was prepared by mixing isosorbide dinitrate with sorbitol and kneading with Q7-4290 uniformly, then adding tin octoate and quickly and uniformly mixing, placing in a mold and letting it stand at room temperature for 10 minutes to cure. It is a prepared formulation. As the sample 6, the formulation prepared in Example 2 was used as a sample.

The cumulative release amount of isosorbide nitrate over time was measured using each sample in the same manner as in Test Example 1.

The results are shown in the graph of FIG. In FIG. 2, D,
E and F show the cumulative release rate over time with respect to the drug addition amount of Samples 4, 5 and 6, respectively. FIG. 2 shows that the drug release of samples 5 and 6 (invention) is much higher than that of sample 4 (comparative).

[Brief description of drawings]

FIG. 1 shows a transdermal preparation (Test Example 1) which is an example of the present invention.
2 and 3) of Comparative Example 2 and a comparative control transdermal preparation (Sample 1 of Test Example 1), showing the cumulative release rate of isosorbide dinitrate with respect to the amount of drug added, and FIG. 2 shows another example of the present invention. The cumulative release rate over time with respect to the drug addition amount of isosorbide nitrate in the percutaneously absorbable preparations (Samples 5 and 6 of Test Example 2) and the comparative transdermally absorbable preparation (Sample 4 of Test Example 2) are shown. In FIG. 1, A, B, and C are samples 1, 2, and 3 of Test Example 1, respectively.
2 shows the drug release curves of the above, and D, E, and F in FIG.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Sadao Watanabe 580 Horikawa-cho, Sachi-ku, Kawasaki-shi, Kanagawa Meiji Seika Co., Ltd., Pharmaceutical Research Laboratory (56) Reference JP-A-60-204715 (JP, A)

Claims (1)

[Claims] 1. A percutaneous absorption preparation containing a percutaneously absorbable pharmaceutical compound as an active ingredient and a carrier for retaining the active ingredient consisting of a silicone elastomer, wherein fatty acid esters, sugar alcohol or both are mixed with the pharmaceutical compound. A percutaneous absorption preparation characterized in that the drug releasing ability is enhanced by blending it.