JPH07116045B2 - Transdermal formulation - Google Patents

Description

TECHNICAL FIELD The present invention relates to a transdermal preparation, and more particularly to a transdermal preparation of hydrocortisone propionate butyrate having improved transdermal absorbability.

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

However, the stratum corneum, which is the upper layer of the skin, has a barrier function to prevent the invasion of substances from the outside. Is difficult to penetrate.

Therefore, in the transdermal preparation, various measures have been taken to enhance the transdermal absorbability of the drug dispersed or dissolved in the base, and after the transdermal preparation is applied to the affected area, moisture etc. does not penetrate. A sealing treatment for covering it with a film is performed, or a higher fatty acid ester is incorporated into a base.

(Problems to be Solved by the Invention) However, sealing therapy often gives discomfort to the patient and may not be able to be carried out depending on the site, and regarding steroids, the incorporation of higher fatty acid ester into the base is not always necessary. It did not increase its transdermal absorbability.

An object of the present invention is to provide a transdermal preparation of hydrocortisone butyrate propionate having an improved transdermal absorbability.

(Means for Solving Problems) As a result of earnest research to enhance the transdermal absorbability of hydrocortisone propionate butyrate, the present inventors have found that butyric acid is added to a base containing isopropyl myristate, hydrogenated phospholipid and water. The present invention has been completed by finding that the transdermal absorbability of hydrocortisone propionate butyrate is specifically enhanced in a simple application method (open system) by dispersing or dissolving hydrocortisone propionate.

The formulation of the present invention comprises a base containing 2.5 to 15% by weight of hydrogenated phospholipids, 1 to 15% by weight of isopropyl myristate and 25 to 65% by weight of water, and 0.01 to 1.00% by weight of hydrocortisone butyrate propionate. It is a percutaneous administration preparation.

The blending amount of hydrocortisone propionate butyrate is within the above range, but is preferably 0.02 to 0.3% by weight. 0.0
With a blending amount of less than 1% by weight, the desired therapeutic effect is difficult to achieve,
When the amount is more than 1.00% by weight, the therapeutic effect cannot be expected to increase so much, but only the cost increases.

The compounding amount of isopropyl myristate is within the above range, but is preferably 2 to 10% by weight. If the amount is less than 1.0% by weight, the transdermal absorbability of hydrocortisone butyrate propionate is not sufficient.

Hydrogenated phospholipids are hydrogenated phospholipids such as soybean phospholipids and egg yolk phospholipids, preferably those having an iodine value of 15 or less, 2.5 to 15% by weight of the total amount, preferably 5 to 10% by weight. %.

Water is added in an amount of 25 to 65% by weight, preferably 40 to 60% by weight.

In addition, the following components can be added as an oil component, if necessary.

That is, liquid to solid hydrocarbons (eg, liquid paraffin, white petrolatum, solid paraffin, microcrystal wax, squalane, squalene, etc.), aliphatic higher alcohols (eg, cetyl alcohol, hexadecyl alcohol, stearyl alcohol, oleyl alcohol). Etc.), esters of higher fatty acids and higher alcohols (eg, beeswax, whale wax, etc.), vegetable oils (eg, olive oil, almond oil, peanut oil, etc.),
Modified vegetable oil (eg hydrogenated castor oil, medium chain fatty acid glyceride, etc.), ester of fatty acid and glycerin (eg, glycerin monostearate, glycerin monooleate, etc.), ester of fatty acid and propylene glycol (eg, propylene glycol monostearate) , Propylene glycol monooleate, etc.) and higher fatty acids (eg, palmitic acid, stearic acid, etc.) in an amount of 1 to 60% by weight based on the total amount.

Furthermore, thickening agents (for example, carboxymethyl cellulose, carboxyvinyl polymer [Hibiswako: trade name, manufactured by Wako Pure Chemical Industries, Ltd.], polyvinyl alcohol, etc., 0.01 to 2% by weight, preferably 0.02 to 0.5% by weight, based on the total amount. ), A wetting agent (for example, propylene glycol, glycerin, 1.3-butanediol, sorbit, etc., in an amount of 0.1 to 20% by weight, preferably 0.5 to 10% by weight), a chelating agent (for example, ethylenediaminetetraacetic acid diacetate). Sodium, etc., preservatives (eg, methyl paraoxybenzoate, ethyl, propyl, butyl, dehydroacetic acid and its salts, etc.), pH adjusters (eg, citric acid, lactic acid, tartaric acid and its salts, and diisopropanolamine) Etc .: The pH to be adjusted is determined based on the stability of the formulation, which is usually weakly acidic. However, it is preferable that it is kept neutral).

If necessary, antibiotics (eg, gentamicin sulfate, fradiomycin sulfate, etc.), antihistamines (eg, diphenhydramine, isothipendyl hydrochloride, etc.), bactericides (eg, decalinium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, sulfisomidine, etc.) ， Vitamins (eg vitamins
A, vitamin D, vitamin E, etc.) and the like can be appropriately combined and mixed.

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

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

That is, hydrogenated phospholipids are dissolved in warmed isopropyl myristate and other oily components, to which hydrocortisone butyrate propionate is added, and after further stirring well heated water and other aqueous components, Cooling. Alternatively, all the ingredients are mixed, heated and stirred, and then cooled.

There are no particular points to note in production, but when stirring while heating,
By finely dividing the particles of the emulsion using a homomixer or the like, a transdermal preparation having good storage stability can be obtained.

(Effect of the Invention) According to the present invention, the transdermal absorbability of hydrocortisone propionate butyrate can be remarkably increased, and a simple application to the affected area can provide a therapeutic effect equivalent to or higher than the sealing therapy.

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

Example 1 7 g of isopropyl myristate 5 g and liquid paraffin 25 g
After heating to 5 ℃, add 7g of hydrogenated soybean phospholipid to dissolve it, and add 0.1g of hydrocortisone butyrate propionate.
And 0.1 g each of methyl paraoxybenzoate and butyl oxybenzoate were added and stirred to dissolve. To this, 10 g of propylene glycol and 52.7 g of purified water were heated to 70 ° C. and then added with stirring and mixing,
The mixture was cooled to room temperature with stirring to prepare a transdermal preparation.

Example 2 Hydrocortisone butyrate propionate 0.01 g, hydrogenated phospholipid 2.5 g, isopropyl myristate 1 g and purified water 61.29
A percutaneous preparation was prepared according to the method of Example 1 by using g in the same manner as in Example 1 except for other substances and the amounts thereof.

Example 3 Using 1 g of hydrocortisone propionate butyrate, 15 g of hydrogenated phospholipids, 15 g of isopropyl myristate and 33.8 g of purified water, other substances and amounts thereof were the same as in Example 1, and transdermal according to the method of Example 1. Dosage formulations were prepared.

Example 4 Hydrocortisone butyrate propionate 0.5 g, hydrogenated phospholipid 10 g, isopropyl myristate 5 g and distilled water 49.3 g
The other substances and the amounts thereof were the same as in Example 1, and a transdermal preparation was prepared according to the method of Example 1.

Test Example (1) Preparation of Samples Samples 1, 2 and 3 were prepared according to the method of Example 1 with the formulation shown in Table 1.
3,4 and controls 1,2,3 were prepared.

(2) Test animals Five male Wistar rats weighing 200 to 250 g were set as one group, and the rats in each group were carefully anesthetized with ether and the abdominal hairs were carefully removed with an electric clipper to prevent skin damage. %
It was wiped with alcohol and used for the test.

(3) Skin absorption test A 5% carboxyvinyl polymer gel was applied to the circumference of a circle with an area of 2 cm ² of the rat abdomen of each group and dried, and then the sample
10 mg of 1,2,3,4 and Controls 1,2,3 (corresponding to 10 μg of hydrocortisone butyrate propionate) were separately added to 2
Each group was evenly applied to the exposed circular skin area of the rat abdomen, one group was left open as it was, and the other group was applied with Saran Wrap (trade name, manufactured by Asahi Kasei Co., Ltd.) to seal the sample application site.

24 hours after the application, the rat was killed, and the skin up to the subcutaneous tissue was removed together with the sample. A drug is extracted from the extracted skin by a conventional method, and high performance liquid chromatography [filler: TSK-Gel, LS410 (trade name, manufactured by Toyo Soda Co., Ltd.), column 150 mm × 4 mmφ, flow rate 1.0 ml / min, elution Liquid: Methanol-
A mixture of water-acetic acid (65.5: 35: 0.5)] was used to measure the ultraviolet absorption at 254 nm, and the skin absorption rate was calculated from the residual amount of the drug.

The test results are shown in Table 2.

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Claims (1)

[Claims] 1. A base containing 2.5 to 15% by weight of hydrogenated phospholipid, 1 to 15% by weight of isopropyl myristate and 25 to 65% by weight of water, and 0.01 to 1.00% by weight of hydrocortisone butyrate propionate. Transdermal formulation