JPS63230634A - Transdermal preparation - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a percutaneously administered formulation, and more particularly to a percutaneously administered hydrocortisone butyrate propionate formulation with enhanced percutaneous absorption.

(Prior Art) In order for a drug contained in a transdermal preparation to exert its therapeutic effect, it is necessary for the drug to migrate from the base into the skin and further reach the affected area.

However, the stratum corneum, which is the upper layer of the skin, has a barrier function that prevents substances from entering from outside, so even if many drugs are released from the base and migrate to the upper part of the skin, they can still be absorbed into the skin by the barrier function of the stratum corneum. It is difficult to penetrate into

For this reason, in transdermal preparations, various efforts have been made to increase the transdermal absorption of drugs dispersed or dissolved in the base, and after applying the transdermal preparation to the affected area, moisture etc. do not penetrate. Sealing therapy has been carried out in which the area is covered with a film, and higher fatty acid esters have also been blended into the base.

(Problems to be Solved by the Invention) However, occlusive therapy often causes discomfort to the patient and may not be possible depending on the site, and regarding steroids, it is not always possible to incorporate higher fatty acid esters into the base. The transdermal absorbability was not improved.

An object of the present invention is to provide a transdermal preparation of hydrocortisone butyrate propionate that has improved transdermal absorption.

(Means for Solving the Problems) As a result of intensive research to improve the percutaneous absorption of hydrocortisone propionate butyrate, the present inventors found that butyric acid was added to a base containing isopropyl myristate, hydrogenated phospholipid, and water. The present invention was completed by discovering that by dispersing or dissolving hydrocortisone propionate, the transdermal absorbability of hydrocortisone propionate butyrate can be specifically increased in a simple application method (open system).

The formulation of the present invention comprises 2.5 to 15% by weight of hydrogenated phospholipids.
, 1-15% by weight of isopropyl mystiphosphate and 25% of water.
This is a transdermal preparation in which hydrocortisone butyrate propionate is blended in an amount of 01 to 1.00% by weight in a base containing 65% by weight of hydrocortisone butyrate.

The amount of hydrocortisone butyrate propionate is within the above range, but preferably (LO2~α3% by weight. If the amount is less than α01% by weight, it is difficult to expect the desired therapeutic effect (1,00% by weight). If the amount exceeds 100%, no significant increase in therapeutic effect can be expected, but only the cost will increase.

The amount of isopropyl myristate is within the range described above, preferably 2 to 10% by weight.

Hydrocortisone butyrate propionate does not have sufficient transdermal absorption when the amount is 1.0% by weight.

The hydrogenated phospholipid is a hydrogenated phospholipid such as soybean phospholipid or egg yolk phospholipid, preferably one with an iodine value of 15 or less, and 25 to 15% by weight of the total amount, preferably 5 to 10% by weight. %.

Water is 25 to 65% by weight of the total amount, preferably 40 to 60% by weight.
Blend the weight %.

In addition, the following components can be blended as oily components, if necessary.

That is, liquid to solid hydrocarbons (e.g., liquid paraffin, white petrolatum, solid paraffin.

microcrystalline wax, squalane, squalene 7, etc.), aliphatic higher alcohols (for example, cetyl alcohol, hexadecyl alcohol, stearyl alcohol, oleyl alcohol).

Esters of higher fatty acids and higher alcohols (e.g., beeswax, spermaceti, etc.), vegetable oils (e.g., olive oil, almond oil, peanut oil, etc.), modified vegetable oils (e.g., hydrogenated castor oil, medium-chain fatty acid glycerides, etc.), fatty acids and Esters of glycerin (e.g., glycerin monostearate).

glycerin monooleate, etc.), esters of fatty acids and propylene glycol (e.g., propylene glycol monostearate, propylene glycol monooleate, etc.), and higher fatty acids (e.g., palmitic acid, stearic acid, etc.) from 1 to 60% by weight of the total amount. can be blended.

Furthermore, a thickening agent (for example, carboxymethylcellulose, carboxyvinyl polymer [Hibis Wako: trade name, Wako Pure Chemical Industries, Ltd.], polyvinyl alcohol, etc.) is added in an amount of 0.01 to 2% by weight, preferably α02 to α5% by weight of the total amount. ), wetting agents (Tatoeba, propylene glycol, glycerin).

1.3-Butanediol, Nlupit, etc., the total amount of α1
-20% by weight, preferably α5-10% by weight),
Chelating agents (for example, disodium ethylenediaminetetraacetate, etc.), preservatives (for example, methyl parabenzoate, ethyl parabenzoate, etc.).

globil, butyl, dehydroacetic acid and its salts, etc.)
, pH adjusters (e.g. citric acid, lactic acid.

Tartaric acid and its salts and diisopropanolamine, etc.: The amount to be adjusted is determined based on the stability of the formulation;
Preparations are usually kept weakly acidic or preferably neutral. ) etc. can be blended.

Also, antibiotics (eg, gentamicin sulfate, fradiomycin sulfate, etc.) if needed.

Antihistamines (e.g. diphenhydramine.

bactericidal agents (such as dequalinium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, and sulfinmidine).

Vitamins (e.g. vitamin A, vitamin D.

Medicinal ingredients such as vitamin E (vitamin E, etc.) can be appropriately combined.

Furthermore, if necessary, a nonionic surfactant that is less irritating to the skin (for example, fatty acid monoglycerides, nrubitan fatty acid esters, polyoxyethylene higher fatty acid esters, etc.) can be blended.

The transdermal preparation of the present invention can be produced, for example, by the method described below.

That is, hydrogenated phospholipids were dissolved in heated inpropyl myristate and other oily components, hydrocortisone butyrate propionate was added thereto, and the mixture was further heated.・Add broiled water and other aqueous ingredients, stir well, and then cool. Alternatively, all ingredients are mixed together, heated and stirred, and then cooled.

There are no particular precautions to be taken during manufacturing, but when stirring during heating,
By micronizing emulsion particles using a homomixer or the like, a transdermal preparation with good storage stability can be obtained.

(Effects of the Invention) According to the present invention, the percutaneous absorption of hydrocortisone globionate butyrate is significantly enhanced, and a therapeutic effect equivalent to or higher than that of occlusive therapy can be achieved by simple application to the affected area.

(Examples) Hereinafter, the present invention will be specifically explained with reference to Examples and Test Examples.

Example 1 Inpropyl myristate 5% and liquid paraffin 25%
1 to 75℃ and add hydrogenated soybean phospholipid 7F to this.
was added and dissolved, and 0.12 of hydrocortisone butyrate propionate and 11 each of methyl and butyl oxybenzoate were added, stirred, and dissolved.To this, 70 g of globylene glycol 102 and 52.7 tons of purified water were added. ℃
After heating, the mixture was added and mixed with stirring, and cooled to room temperature while stirring to prepare a transdermal preparation.

Example 2 Glopionate hydrocortizo butyrate 70. Oj? .

A transdermal preparation was prepared according to the method of Example 1 using 2.5 t of hydrogenated phospholipid, 12 t of isopropyl myristate, and 61.29 t of purified water, and the other substances and their amounts were the same as in Example 1. expressed.

Example 3 Hydrocortisone butyrate propionate 1y, hydrogenated phospholipid 15f, impropyl myristate 15g and purified water 33.8F were used, and the other substances and their amounts were the same as in Example 1. A transdermal formulation was prepared according to the method.

Example 4 Hydrocortizo butyrate propionate 70.5t, hydrogenated phospholipid 101. A transdermal preparation was prepared according to the method of Example 1, using 52 F of isopropyl myristate and 49.3 F of distilled water, and using the same other substances and their amounts as in Example 1.

Test Example (1) Preparation of Sample Sample 1.
2.3.4 and control 1.2.3 were prepared.

Table 1 (Parts by weight) (2) Test animals A group of 5 male Wistar rats weighing 200 to 25 o2 was placed under ether anesthesia using electric clippers carefully to avoid damaging the skin. The hair on the abdomen was removed and the animal was wiped with 70% alcohol for testing.

(3) Skin absorption test After applying 5% carboxyvinyl polymer gel around a 2 d circle on the rat abdomen of each group and drying it, sample 1
．． 2.5J4 and control 1.2.3 1011v
(equivalent to Hydrocortisone Butyrate Propionate 10R) was applied uniformly to the circular exposed skin area of the abdomen of two groups of rats, one group was left open, and the other group was covered with saran. It was sealed with two tubes (trade name, manufactured by Asahi Kasei ■).

The rats were sacrificed 24 hours after application, and the skin down to the subcutaneous tissue was removed along with the sample. The drug was extracted from the excised skin by a conventional method and subjected to high performance liquid chromatography 2E [filling material: TSK-Gem, LS 410 (trade name, manufactured by Toyo Soda), column 150 sem x 4 - 2 flow rate tOd.
/min, eluent: methanol-water-acetic acid (65,5=3
5:0.5) mixture] was used to measure the ultraviolet absorption of 254 yam, and the skin absorption rate was calculated from the remaining amount of the drug.

The test results are shown in Table 2.

Table 2 Skin absorption rate

Claims (1)

[Claims] 1) Hydrogenated phospholipids 2.5-15% by weight, isopropyl myristate 1-15% and water 25-65% by weight
A transdermal preparation containing 0.01-1.00% by weight of hydrocortisone butyrate propionate in a base containing