JPS62215528A - Pharmaceutical for percutaneous administration - Google Patents

Abstract

PURPOSE:The titled pharmaceutical, obtained by blending a base containing blended isopropyl myristate with hydrocortisone butyrate propionate and having remarkably improved percutaneous absorbability. CONSTITUTION:A pharmaceutical for percutaneous administration obtained by blending a base containing 0.5-100wt% (preferably 2-10wt% for ointment, cream or gel agent) isopropyl myristate blended therein with 0.01-1.00wt%, preferably 0.02-0.3wt% hydrocortisone butyrate propionate. The isopropyl myristate is added to mineral oils, e.g. white petrolatum, liquid paraffin, etc., higher fatty acids, e.g. lauric acid, etc., water soluble high polymers, surfactants, etc., as the base for use. An ointment, cream, gel or solution agent may be cited as the dosage form.

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 formulation of proacetic acid and hydroflutisone onate, which has 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 in the base, and higher fatty acid esters have also been incorporated into the base.

(Problems to be Solved by the Invention) However, in the case of steroids, the combination of higher fatty acid esters with the base did not improve their percutaneous absorption.

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

(Means for Solving the Problems) As a result of intensive research to improve the transdermal absorption of steroids, the present inventors found that in the combination of hydrocortisone butyrate propionate and isopropyl myristate, hydrocortisone acetate propionate The present invention was completed by discovering that transdermal absorbability is specifically increased.

The object of the present invention is isopropyl myristate at 0.5
0.01 to 1.00 of the base containing ~100% by weight
This is a transdermal preparation containing % by weight of hydrocortisone butyrate propionate.

The amount of isopropyl myristate is within the above-mentioned range, but in the case of ointments, creams, gels, etc., it is preferably 2 to 10% by weight. In the case of a liquid preparation, the base may be entirely composed of isopropyl myristate; if the amount is less than 0.5% by weight, percutaneous absorption of hydroflutisone acetate propionate will not be sufficient.

The amount of hydroflutisone butyrate propionate is within the above range, preferably 01O2 to 0.3% by weight.
It is. If the amount is less than 0.01% by weight, it is difficult to expect the desired therapeutic effect, and if the amount is more than 1.00% by weight, no significant increase in the therapeutic effect can be expected, but only the cost will increase.

Base is mineral oil (e.g. white petrolatum, liquid paraffin, solid paraffin, ceresin, plastibase, etc.)
, higher fatty acids (e.g. lauric acid, myristic acid,
Valmitic acid, stearic acid, etc.) Higher alcohols (e.g., stearyl alcohol, cetyl alcohol, lauryl alcohol, etc.) Water-soluble polymer compounds (e.g., carboxyvinyl polymer, sodium carboxymethylcellulose, polyoxyethylene sorbitan fatty acid ester, sorbitan) Fatty acid ester, propylene glycol fatty acid ester, polyoxyethylene fatty acid ester, sodium lauryl sulfate, etc. 111 or two or more of them with an appropriate amount of isopropyl myristate added, or isopropyl myristate alone is used.

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

(ointment) Mineral oil that has been heated and dissolved in advance at 70-80°C.

Higher fatty acids, higher alcohols, etc., and hydroflutisone acetate propionate are added to isopropyl myristate, stirred and dissolved, and cooled to room temperature while stirring to form a product.

(Cream) Preheat to 70-80°C. Dissolved mineral oil.

Higher fatty acids. Add hydrocortisone butyrate propionate to the higher alcohol, surfactant, and isopropyl myristate, stir and dissolve, add an appropriate amount of purified water, and cool to room temperature while stirring and mixing to obtain a product.

(Gel agent) Add isopropyl myristate to a solution of equal amounts of ethanol and purified water, disperse uniformly, add hydrocortisone acetate propionate, stir and dissolve, then add an appropriate amount of water-soluble polymer compound little by little. Finally, add an appropriate amount of 5% ammonia water and stir to obtain a product.

(Liquid) PIE hydroflutisone propionate is added to a mixture of a suitable solvent and isopropyl myristate or to isopropyl myristate alone and stirred to form a product.

The preparation of the present invention prepared in this way significantly promotes the transdermal absorption of hydroflutisone acetate propionate, as is clear from the test examples described below.

(Effects of the Invention) The formulation of the present invention is useful as a medicine because it significantly increases the percutaneous absorption of hydrocortisone butyrate propionate by incorporating isopropyl myristate.

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

Example 1 0.02 g of hydroflutisone acetate propionate was added and dissolved in a mixed solution of 47 g of ethanol, 47 g of purified water, and 3 g of isopropyl myristate, and 1 g of carboxyvinyl polymer was added little by little while stirring and dissolved.

Further, 2 g of 5% ammonia water was added to this to obtain a gel.

Example 2 0.02 g of hydrocortisone butyrate propionate and 3 g of isopropyl myristate were dissolved and stirred in 97 g of Plastibase, which had been heated and dissolved in advance at 70 to 80°C. The mixture was cooled to room temperature while stirring, and an ointment was prepared. obtained the drug.

Example 3 35 g of liquid halafine, 10 g of stearyl alcohol,
3 g of polyoxyethylene (20) sorbitan monostearate and 3 g of isopropyl myristate at 70-80°C
Dissolved and stirred.

Add 0.02 g of hydroflutisone acetate propionate to this, stir and dissolve, then add 46 g of purified water and stir and mix.
The mixture was cooled to room temperature while stirring to obtain a cream.

Example 4 0.1 g of hydrocortisone butyrate was dissolved in 60 g of isopropyl myristate with stirring to obtain a liquid preparation.

Example 5 A gel was obtained in the same manner as in Example 1, except that 45 g of ethanol, 45 g of purified water, and 7 g of isopropyl myristate were used.

Example 6 A gel was obtained in the same manner as in Example 1, except that 48 g of ethanol, 48 g of purified water, and 1 g of isopropyl myristate were used.

Example 7 Example 1 except that 48.25 g of ethanol, 48.25 g of purified water, and 0.5 g of isopropyl myristate were used.
A gel was obtained in the same manner as above.

Example 8 Liquid paraffin 35g, stearyl alcohol 10g,
3 g of polyoxyethylene (20) sorbitan monostearate and 2 g of isopropyl myristate at 70-80°C
Stir and dissolve.

To this, 0.2 g of hydrocortisone butyrate propionate was added and mixed with stirring, and the mixture was cooled to room temperature while stirring to obtain a cream.

Example 9 0.02 g of hydrocortisone acetate propionate and 10 g of isopropyl myristate were added to 90 g of white vaseline, which had been previously heated and dissolved at 70 to 80°C, and dissolved with stirring, and the mixture was cooled to room temperature while stirring. An ointment was obtained.

Test Example 1 (1) Sample 1 was the gel prepared in Example 1 (containing 3% by weight of isopropyl myristate). Sample 2 was prepared according to Example 1 using diisopropyl adipate instead of isopropyl myristate, and sample 3 was also prepared using isopropyl palmitate.

Further, according to Example 1, a gel containing no higher fatty acid ester was prepared as a control.

(2) One group consisted of five male Wistar rats weighing 200 to 250 g, and each group of rats was anesthetized with ether.
The hair on the abdomen was carefully removed using electric clippers to avoid damaging the skin, and the animals were wiped with 70% alcohol and used for testing.

(3) After applying 5% carboxyvinyl polymer gel around a circle with an area of 2C on the abdomen of each group of rats and drying it, apply the gel equivalent to 10 fish of samples 1, 2.3 and Funtrol's hydroflutisone butyrate propionate. The amount was evenly applied to a circular skin exposure on the abdomen of each separate group of rats.

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 then subjected to high performance liquid chromatography [filling material: TSK-Gem].
LS410 (product name, manufactured by Toyo Soda (RO)), column 1
50mm×4mmφ, flow rate 1.0ynQ/min.

Eluent: methanol-water-acetic acid (65,5:35:0.
5) mixed solution], the ultraviolet absorption at 245 nm was measured, and the skin absorption rate was calculated from the remaining amount of the drug.

The results are shown in Table 1.

Table 1 Test Example 2 1) The gel prepared in Example 1 (containing 0.02% by weight of hydrocortisone acetate propionate) was used as sample 1, and the same amount of hydrocortisone acetate propionate was added in accordance with Example 1. Sample 2 was prepared using hydrocortisone, and sample 3 was also prepared using the same amount of hydrocortisone butyrate.

(2) According to Test Example 1, 7￥F syneresis was applied to hydrocortisone butyrate propionate and hydrocortisone acetate.
Methanol-water-acetic acid (6s, s: 3s:o, s) mixture, methanol-water-acetic acid (for hydrocortisone)
Using the 49:50.5:0.5) mixture, the skin absorption rate of the drug was investigated for Samples 1, 2 and 3.

The results are shown in Table 2.

Table 2 Test Example 3 (1) The samples prepared in Examples 1, 2, 3, 4.5, and 6.7 were designated as Samples 1, 2, 3, 4, and 5°6.7, respectively.

Sample 8 was a gel prepared in the same manner as in Example 1 except that 48.4 g of ethanol, 48.4 g of purified water, and 0.2 g of isopropyl myristate were used.

By removing isopropyl myristate from the formulation of sample 1,
A sample prepared according to Example 1 by increasing the same amount of ethanol and purified water was used as Control 1, and a sample was prepared according to Example 2 by removing isopropyl myristate from the formulation of Sample 2 and increasing Plastibase accordingly. This sample was designated as Control 2.

By removing isopropyl myristate from the formulation of sample 3,
A sample prepared according to Example 3 by increasing the amount of purified water was designated as Funtrol 3.

In addition, a sample prepared in accordance with Example 4 by removing isopropyl myristate from the formulation of Sample 4 and using propylene glyfur to replace it was called Funtrol 4, and a sample prepared using polyethylene glyfur in the same manner was called Funtrol 4. It was set as roll 4'.

(2) Sample 1, 2.3, 4°5.6, according to Test Example 1
The skin absorption rate of the drug (hydrocortisone acetate propionate) was investigated for Funtrol 7.8 and Funtrol 1, 2, 3° 4.4'.

The results are shown in Table 3.

From Test Examples 1 and 2 in Table 3, the combination of hydrocortisone butyrate propionate and isopropyl myristate has excellent transdermal absorption of the drug, which is not seen in combinations of other steroids and higher fatty acid esters. Admitted.

From Test Example 3, it was found that the combination of hydrocorticin butyrate propionate and isopropyl myristate promoted transdermal absorption of the drug in any base.

Claims (1)

[Claims] 1) 0.5-100% by weight of isopropyl myristate
A transdermal preparation in which 0.01 to 1.00% by weight of hydrocortisone butyrate propionate is blended into the blended base.