JPS61167614A - Steroic-containing ointment - Google Patents

Abstract

PURPOSE:To provide the title ointment having improved stability of an ointment containing esterified corticosteroid (an anti-inflammatory agent), and having excellent stability and transcutaneous absorbability, by compounding an organic acid and a glycol to the ointment. CONSTITUTION:An ointment containing 0.01-1% esterified corticosteroid such as difluprednate, betametasone valerate, hydrocortisone butyrate propionate, etc., is compounded with (A) an organic acid, preferably a polybasic acid such as succinic acid, phthalic acid, tartaric acid, citric acid, malonic acid, etc. and (B) a glycol, e.g. polyethylene glycol (molecular weight: 200-600), propylene glycol, 1,3-butylene glycol, etc. The amount of the component A is 0.005-20%, especially 0.05-5% based on the component B, and that of the component B is 2-15% based on the whole ointment. The long-term storage stability of the ointment can be improved by this process.

Description

DETAILED DESCRIPTION OF THE INVENTION [Technical Field of the Invention] The present invention relates to steroid-containing ointments, and more particularly to esterified fluticosteroid-containing ointments with improved stability.

[Prior art and its problems 1 Corticosteroids have excellent anti-inflammatory effects and are therefore used as ointments, creams, or lotions to treat various skin diseases. Ointments and creams are said to have different release properties of active ingredients from the base depending on the type of base, which affects the medicinal efficacy. Furthermore, it is said that transdermal absorption is greatly affected by the particle size of the active ingredient in the same base, and that fine particles are better than coarse particles, and dissolved ones are better than fine particles. From such a thing,
For steroid-containing ointments, the active ingredient is dissolved in glycols such as propylene glycol, polyethylene glycol, and 1,3-butylene glycol, which have excellent solubility of the active ingredient, and then dispersed in a hydrocarbon base. is often used as a manufacturing method.

However, among the ointments prepared as described above, those whose active ingredients are esterified corticosteroids have problems in terms of stability as the ester bonds of the active ingredients are hydrolyzed during long-term storage. There is.

Therefore, as a result of extensive research aimed at improving the stability of ointments containing esterified corticosteroids, the present inventors found that by incorporating organic acids and glycols into ointments, they were stabilized. The present inventors have discovered that an ointment with excellent properties and transdermal absorbability can be obtained, and have completed the present invention.

[Structure of the Invention] The present invention relates to an ointment containing an esterified corticosteroid, which is characterized by containing an organic acid and a glycol.

The esterified corticosteroid used in the present invention may be any corticosteroid as long as at least one of the 17th and 21st positions of the steroid skeleton is esterified.

Acids that form esters include acetic acid, propionic acid,
Examples include butyric acid, valeric acid, succinic acid, pivalic acid, capric acid, benzoic acid, and phosphoric acid.

Specific examples of such esterified corticosteroids include monoesters such as hydrocortisone acetate, betamethacin valerate, clobetasol propionate, hydrocortisone acetate propionate, prednisolone acetate valerate, betamethacin dipropionate, beclomethasone dipropionate, Examples include diesters such as difluprednate.

These esterified corticosteroids are usually used alone, but may be used as a mixture of two or more.

The blending ratio of these esterified corticosteroids is
Usually, it is 0.01-1% based on the total ointment.

Examples of organic acids used in the present invention include lactic acid, succinic acid, phthalic acid, malonic acid, tartaric acid, citric acid, lauric acid, myristic acid, palmitic acid, glutamic acid, stearic acid, etc.; It is preferable to use polybasic acids such as tartaric acid, citric acid, and malonic acid.

These organic acids are usually used alone, but may be used as a mixture of two or more.

The blending ratio of these organic acids is usually 0.005 to 20%, preferably 0.05 to 5%, based on the glycols. The above blending ratio is 0.0 to glycols.
If it is less than 0.5%, the stability of the esterified corticosteroid will be insufficient, and if it exceeds 20%, it will take a long time to dissolve the organic acid in glycols, and the stability will reach a plateau. Become.

Examples of glycols used in the present invention include polyethylene glycol (molecular weight 200 to 600), propylene glycol, 1,3-butylene gelylcol, and the like.

These glycols are usually used alone, but may be used as a mixture of two or more.

The blending ratio of these glycols is usually 2 to 15% based on the entire ointment. If the blending ratio is less than the lower limit, the transdermal absorbability will be insufficient, and if it exceeds the upper limit, the affinity with the base component will be impaired and the transdermal absorbability will also decrease.

In the ointment of the present invention, a hydrocarbon base such as vaseline, liquid paraffin, paraffin, etc. is usually used as the base.

Other additives such as surfactants, thickeners, antioxidants, preservatives, etc. may be appropriately added to the ointment of the present invention.

As the surfactant, it is preferable to use nonionic surfactants such as sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, and glycerin fatty acid ester.

The blending ratio of these surfactants is usually 0.1 to 5% based on the total ointment.

Examples of thickeners include beeswax, spermaceti, stearyl alcohol, cetanol, lanolin, and the like. Examples of antioxidants include tocophenols, dibutylhydroxytoluene, propyl gallate, and the like. Examples of preservatives include sorbic acid, dehydroacetic acid, parahydroxybenzoic acid esters, and the like.

The ointment of the present invention can be prepared, for example, as follows.

That is, an esterified corticosteroid is dissolved in a glycol solution containing an organic acid. By adding this to a mixed solution of a base material previously heated and dissolved, and a surfactant, a thickener, etc. as necessary, stirring and mixing thoroughly under heating, and cooling while stirring, Ointments of the invention can be prepared.

[Effects of the Invention] According to the present invention, an ointment containing an esterified fluticosteroid that is excellent in both stability and transdermal absorbability can be provided.

[Examples of the Invention] Hereinafter, the present invention will be explained in more detail with reference to Examples and Test Examples, but these are not intended to limit the scope of the present invention in any way.

Example 1 White petrolatum 85.94g, liquid paraffin 20g,
An oil phase component was prepared by heating and melting 5 g of beeswax and Nilacol 5O-15 (Sorbitan Sesquioleate manufactured by Nikko Chemicals) Next, citric acid O and OTG were heated and dissolved in 8 g of propylene glycol. 0.05 g of difluprednate was added and dissolved therein. This was added to the oil phase component, thoroughly dispersed by stirring, and then cooled while stirring to obtain 100 g of an ointment.

Example 2 Betamethacin valerate O, 12g Propylene glycol 8g Tartaric acid 0.05g 5g Nyracol 5O-11g Liquid paraffin 10g White petrolatum Remaining amount meter 100g An ointment with the above formulation was prepared according to Example 1.

Test Example 1 The vasoconstrictive effects of the ointment prepared in Example 1 and an ointment prepared by mixing 0.05 g of diflupredone (diflupredone) with 99.95 g of white petrolatum as a control were compared. The samples were prepared by sequentially diluting the two types of ointments fourfold with respective ointment bases containing no active ingredient to give six levels of concentration. I! Twelve samples were randomly assigned to the upper backs of 10 normal male subjects, applied using a patch test adhesive (manufactured by Torii Pharmaceutical Co., Ltd.), and sealed in place. v. The sealing time was 4 hours, and the first criteria for judgment after removing the sample was ``significant pallor'' (◆+) and ``obvious pallor'' due to pallor accompanying the vasoconstriction reaction of steroids. Phenomenon” (+)
, "slight pallor" (±), "no response" (-), and (÷+) (÷) and (±) were considered positive for vasoconstriction reaction, and the ED5Q value was calculated and the effects were compared. . The results are shown in Table 1.

Table 1 As is clear from the results, the ointment of the present invention was found to be a formulation exhibiting excellent efficacy.

Test Example 2 The ointments prepared in Examples 1 and 2 and the ointment prepared by removing citric acid from the ointment of Example 1 as a control (
The ointment (hereinafter referred to as "Control 1") and the ointment prepared by removing tartaric acid from the ointment of Example 2 (hereinafter referred to as "Control 2") were stored at 40°C, and the residual rate of the esterified steroid was measured.

Table 2 As mentioned above, the ointment of the present invention containing Atsukiji was very stable compared to Controls 1 and 2, indicating that the esterified steroid was stabilized by the organic acid.

Example 3 An ointment was prepared in the same manner as in Example 1 except that 0.1 g of hydrocortisone acetate propionate was used in place of difluprednate, and an ointment was prepared by removing the citric acid from this ointment. As a result of examining the stability of these ointments in the same manner as in Test Example 2, it was found that the ointments were more stable when an organic acid was added.

Claims (1)

[Claims] An ointment containing an esterified corticosteroid, characterized in that it contains an organic acid and a glycol.