JPH01265035A - Percutaneous absorption accelerator and external-use composition containing the same - Google Patents

Abstract

PURPOSE:To obtain a percutaneous absorption agent containing 5,9,13- trimethyl-2,4,8-12-tetradecantetraenecarboxylic acid as an active ingredient, and a pharmaceutical composition which contains the same and can give effectively and safely the drugs which have been systemically administered. CONSTITUTION:The subject external-use drug composition contains 0.1-10wt.% of 5,9,13-trimethyl-2,4,8,12-tetradecantetraencecarboxylic acid and 0.1-10wt.% of drugs. The drugs are for local purposes such as thiabendazole or penicillin, for systemic purposes such as cortisone, malignant tumor agent, or heart stimulant and there is no special limitation, as long as they can be given percutaneously. They are prepared in the form of solution, ointment, cream, naval spray, gel, suppository, or sticking tapes. The inert base (support) for these preparations is, for example, water, ethanol, methylcellulose, gel-forming substances and mineral oil.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a transdermal absorption enhancer that promotes transdermal absorption of drugs and an external pharmaceutical composition containing the same.

[Conventional technology]

Systemic administration, which is one of the drug administration methods, is generally performed orally or by injection.

However, the problem in this case is that the first-pass effect in the liver or gastrointestinal tract cannot be avoided, and it is necessary to administer certain drugs with due consideration to the occurrence of side effects due to overdosage. Transdermal administration, which is another drug administration method, was limited to drugs that have local pharmacological effects.

Recently, attention has been focused on the effectiveness of transdermal administration methods in which a transdermal absorption enhancer that promotes transdermal absorption of drugs is used as a component of a topical pharmaceutical composition to address such problems. The advantages of this transdermal administration method include the following points.

1) Drugs previously used for systemic administration can be administered transdermally.

2) The effect on normal tissues that do not require drugs can be minimized.

3) Blood drug concentration can be kept constant.

4) Side effects are reduced because plasma concentrations do not reach toxic levels.

5) Long-term administration is possible.

6) It is easy for patients to accept.

By the way, the skin tissue is composed of the stratum corneum as the outermost layer, followed by the Mulvighi layer and the dermis, and the administered drug is absorbed through the stratum corneum, reaches the dermis, and is absorbed into the lymph vessels and blood vessels. However, the stratum corneum of normal skin is composed of multiple overlapping layers of tough stratum corneum, which act as a strong barrier against drugs, retaining penetrating drugs, and preventing subsequent drug absorption. Therefore, research has been conducted on the combination of transdermal absorption enhancers as a means for transdermal absorption of an effective amount of the drug. For example, U.S. Pat.
It has been disclosed that trimethylformamide and the like act as transdermal absorption enhancers. Another example is 1-substituted-azabicyclohebutan-2-one (U.S. Citizenship Permit No. 3,9).
No. 89,816), compositions of lower alkylamide and ethyl alcohol, Impropatool, etc. (U.S. Pat. No. 3,4
No. 72,431), compositions of 2-pyrrolidone and appropriate oils (U.S. Pat. No. 4,017,641), and the like are known. However, these transdermal absorption agents are still insufficient in terms of absorption promotion effect, safety, etc.

[Problem to be solved by the invention]

An object of the present invention is to provide a transdermal absorption enhancer having the activity of enhancing transdermal absorption of a drug, and an external pharmaceutical composition containing the transdermal absorption enhancer.

[Means to solve the problem]

According to the present invention, the above object is achieved by providing 5,9.13-t')methyl-2,4,8,12-tetradecanetetraenecarboxylic acid and 5,9'13-trimethyl- This is achieved by providing a topical pharmaceutical composition containing 2,4,8,12-tetradecanetetraenecarboxylic acid.

5.9.13-) Dimethyl-2,4,8,12-tetradecanetraenecaldic acid is produced by thermal decomposition of farnesylidenemalonic acid (200°C, in the presence of a copper-bronze catalyst).
It is known that it can be obtained by

(J, Chem Soc, Chem, Commu
n, (14), 630 (1979)] The external pharmaceutical composition of the present invention is 5,9.13-) IJ methyl-2,4,
It is prepared by blending 8,12-tetradecanetetraenecarboxylic acid with a drug and base composition. The drug to be mixed is not particularly limited as long as it is intended for local and systemic action and can be administered transdermally. Drugs intended for local action include anti-XM agents such as thiabendazole, amphotericin, griseofulvin, and fuazimycin, erythromycin, chloramphenicol, tetracycline, lincomycin hydrochloride,
Examples include antibiotics such as kanamycin sulfate and 4-nidyline.

On the other hand, drugs aimed at systemic effects include cortisone,
Betamethasone, glednisolone, dexamethasone, hydrocortisone, triamcinolone Q'% Nosteroidal anti-inflammatory agents, anti-tumor agents such as uracil, 5-fluorouracil, coronary vasodilators such as diltiazem hydrochloride, nitroglycerin, nifedipine, cardiotonic agents such as novoxin, digitoxin, etc. , lidocaine hydrochloride, quinison sulfate, propranolol hydrochloride, anti-arrhythmia drugs such as Hif)'O-R%, and asthma drugs such as sodium cromoglycate.

5,9,13-t! used in the present invention! The amount of 7-methyl-2,4,8,12-tetradecanetetraenecarboxylic acid is an amount effective to enhance transdermal absorption.

Generally, this amount is in the range of 0.01 to 20 weight percent, preferably 0.1 to 10 weight percent, based on the total weight of the external pharmaceutical composition. The amount of the drug to be added is 0.01 to 20M, preferably 0.01 to 20M, based on the total weight of the external pharmaceutical composition.
The range is 1% to 10% by weight.

However, since the usage of the drug contained therein can be substantially adjusted by increasing or decreasing the application area of the topical pharmaceutical composition to the skin, the amount of the drug contained in the composition may not necessarily be the same as above. It is not limited to the blending amount.

Dosage forms of the external pharmaceutical composition include solutions, ointments, creams, nasal sprays, dals, herbal medicines, lonoyons, aerosols, impregnating agents, adhesive tapes, and the like. Inert bases (carriers) constituting such dosage forms include water, ethanol, inglobil alcohol, propylene glycol, stearyl alcohol, methylcellulose, N-methylpyrrolidone, sorbitan monooleate, nrubital, methylcellulose, Examples include surfactants, dul-forming substances, mineral oil, stearic acid, spermaceti, and the like.

〔Example〕

The present invention will be explained below using Example F1, but the present invention is not limited to these embodiments. In the following examples, percutaneous absorption was evaluated by determining the amount of drug that permeated through the epidermis of rats using the diffusion cell method described below.

(Percutaneous absorption evaluation method using diffusion cell method) After pricking the abdomen of a rat, the skin is removed, and the skin is placed on a resegrator tank at the bottom of the diffusion cell and stabilized for 1 hour. Next, put Lindal's solution into the resegator tank. And the diffusion cell is 37
After adjusting the temperature to ℃, 5,9.13-trimethyl-2,4,8,1, which was adjusted to a constant temperature, was placed in the donor tank at the top of the diffusion cell.
A solution consisting of 2-tetradecanetetraenecaldic acid, a drug, and a base composition was poured into the receptor tank after 10 and 20 hours, and the concentration (μW) of the permeated drug was measured using high-performance liquid chromatography. It has become well established. Similarly, 5.9.13-t')methyl-2,
A control test was performed using an equal volume of Lindall's solution in place of 4,8,12-tetradecanetetraenecargonic acid.

Example 1 The following steroid anti-inflammatory solution was prepared.

Weight% (1) Prednisolone 1 (2)
5,9.13-trimethyl-2,4,8,12
-20 Tetradecane Tetraene Carnic acid (3) Inopropyl alcohol 69 (
4) Zoropylene glycol A steroid anti-inflammatory solution containing 10 Comparative Example 1 was prepared.

Weight (1) Prednisolone 1 (2) Lindal 20 (3) Inopropyl alcohol 6 (4) Zoropylene glycol 10 Comparative example 1 5,9.13-trimethyl-2,4 in Example 1
゜8.12-tetradecanetetraenecaldic acid instead of tic 1- n -Fdecyl aza7 lyrohebutane-2
-on was used to prepare a steroid anti-inflammatory solution.

Weight% (1) fL/donisolone 1(3
) Inopropyl alcohol 69(4)
The amount of prednisolone permeated through the skin of Zoropylene Glycol IO Example 1, Control Example, and Comparative Example 1 was measured by the diffusion cell method, and the results were as follows. The amount of permeation is indicated by 4 degrees (μVl) of prednisolone in the receptor tank.

After 10 hours After 20 hours Example 1 180.2 252.2 Control example 1
49,7 77.7 Comparative example 1 8
0.3 99.4 Example 2 The following anti-malignant tumor drug bath solution was prepared.

Weight% (1) Uracil 1 (2 N)
5,9.13-trimethyl-2,4,8,12-20
Tetradecane tetraenecarboxylic acid (3) Inopropyl alcohol 39 (4
) Purified water 30 (5) fo pyrene glycol 10 Control example 2 As a control test for Example 2, the following anti-malignant) tA tumor agent solution was prepared.

Weight Section (1) Uracil 1 (2)
Lindal 20 (3) Inopropyl Alcohol 39 (4) Kari Kesui 30 (5) Zoropylene Glycol 10 Comparative Example 2 As a comparative test for Example 2, the following anti-cancer drug solution was prepared.

X amount (1) Uracil 1 (3)
Isopropyl alcohol 39 (4) Kozue Nosui 30 (5) Propylene glycol 10 The amount of uracil permeated through the skin is shown in the same manner as in Example 1.

After 10 hours After 20 hours Example 2 180 252 Control example 2
50 78 Comparative Example 2 84
100 Example 3 The following coronary vasodilator solution was prepared.

The following total white weight% (1) Soltiazem hydrochloride 1.0 (3)
Isopropyl alcohol 69(4)
Propylene Glycol 10 Control Example 3 As a control test for Example 3, a solution of Tsuza's coronary vasodilator was prepared.

Weight% (1) Soltiazem hydrochloride 1.0 (2)
Ringer's 20(3) Isopropyl Alcohol 69(4) Propylene Glycol 10 The amount of diltiazem hydrochloride permeated through the skin is shown in the same manner as in Example 1.

After 10 hours After 20 hours Example 3 120 172 Control example 3
12 18 Example 4 The following cardiotonic solution was prepared into one sample.

Weight% (1) Tsugitoxin 1 (3)
Iso7'lopyl alcohol 69(4) Propylene glycol 1° Control Example 4 The following cardiotonic solution was prepared.

Weight 1% (1) Tsugitoxin 1 (2)
ri / ri'ru

2.

(3) Isopropyl alcohol 69 (
4) Propylene glycol 10 Example 1
The amount of tsugitoxin permeated through the skin is shown in the same manner as above.

Comparative Example 4 Q Q [Effect of the invention] By using the transdermal absorption enhancer provided by the present invention as a component of a topical pharmaceutical composition, the transdermal absorption of drugs conventionally used by transdermal administration can be improved. Patent applicant Ri Co., Ltd., which is characterized by the fact that it is possible to administer transdermally a drug that is conventionally administered by systemic administration, and to administer the drug more effectively and safely than before. La Shi

Claims (1)

[Scope of Claims] 1) A transdermal absorption enhancer for drugs containing 5,9,13-trimethyl-2,4,8,12-tetradecanetetraenecarboxylic acid as an active ingredient for promoting transdermal absorption. 2) External pharmaceutical composition containing 5,9,13-trimethyl-2,4,8,12-tetradecanetetraenecarboxylic acid.