JP4686144B2 - Oily ointment - Google Patents

Description

  The present invention relates to an oily ointment useful for the prevention and treatment of skin diseases containing ester steroids and diphenhydramines. More specifically, the present invention relates to an oily ointment having an excellent storage stability in which the degradation of ester steroids is prevented by dibutylhydroxytoluene and menthol.

Conventionally, a combination of an anti-inflammatory agent such as ester steroid and an antihistamine such as diphenhydramine hydrochloride has been used for the prevention and treatment of skin diseases such as rough skin, eczema and dermatitis. A drug is also known in which a mixture of an ester-based steroid and diphenhydramine is blended with a dermatitis anti-inflammatory analgesic, fragrance, and menthol as a refreshing agent (see, for example, Patent Document 1). In addition, it has also been proposed to add dibutylhydroxytoluene, which is an antioxidant, to a mixture of an ester-based steroid and diphenhydramine, but a specific stabilizing effect has not been confirmed (for example, see Patent Document 2).
JP-A-5-286860 JP 2001-247463 A

  When diphenhydramines are blended with ester-based steroids, there is a problem in that ester decomposition of steroids is accelerated, and it is required to develop an oily ointment that solves this problem.

  An object of the present invention is to provide an oily ointment excellent in storage stability containing an ester-based steroid and diphenhydramines.

When the present inventors add dibutylhydroxytoluene, which is known as an antioxidant, to an oily ointment containing an esteric steroid and diphenhydramines, the discoloration of the oily ointment can be slightly suppressed. Degradation of the steroid is accelerated, and when menthol is added to the combination of the ester steroid and diphenhydramine, the hydrolysis of the ester steroid is promoted, however, the ester steroid and diphenhydramine are contained. It has been found that when dibutylhydroxytoluene and menthol are added in combination to an oleaginous ointment, the degradation of the ester steroid is surprisingly prevented.
Therefore, an oily ointment containing an ester steroid and diphenhydramines excellent in storage stability can be achieved by adding dibutylhydroxytoluene and menthol as a stabilizer.

  The use of this stabilizer suppresses the degradation of ester steroids, prevents malodor due to organic acids that are degradation products of ester steroids, prevents discoloration of oily ointments, and has excellent storage stability. Is provided.

As anti-inflammatory steroids, for example, prednisolone, hydrocortisone, dexamethasone, betamethasone and the like are used, and these are usually used in the form of an ester (ester steroid). The ester-based steroid used in the present invention is preferably an ester with an organic acid and having anti-inflammatory activity. Examples of the steroid include hydrocortisone, prednisolone, dexamethasone, betamethasone and the like. Examples of the organic acid include acetic acid, butyric acid, valeric acid, and propionic acid. Specific examples of ester steroids used in the present invention include prednisolone valerate acetate, methylprednisolone acetate, hydrocortisone acetate, hydrocortisone butyrate, alcromethasone propionate, clobetasone butyrate, deprodon propionate, beclomethasone propionate, dexamethasone valerate, valeric acid Betamethasone, hydrocortisone butyrate propionate, diflucortron divalerate, dexamethasone dipropionate, betamethasone dipropionate, diflorazone acetate and clobetasol propionate are preferred, and prednisolone valerate is preferred.
The amount of the ester-based steroid varies depending on the steroid used, so that it cannot be generally specified. However, about 0.01 to 10 w / w% can be added in the external preparation for skin, preferably 0.1. ~ 0.2 w / w%.

  The diphenhydramine of the present invention is diphenhydramine or a salt thereof. A compounding quantity can contain 0.1-5 w / w%, Preferably, it is 1-2 w / w%.

  In the present invention, dibutylhydroxytoluene and menthol are added as stabilizers. Menthol is 1-menthol or dl-menthol, and preferably 1-menthol. The addition amount is 0.3 to 2 w / w%, preferably 0.5 to 1 w / w%. The amount of dibutylhydroxytoluene added is 0.01 to 0.1 w / w%, preferably 0.02 to 0.08 w / w%.

  As oil, white petrolatum, liquid paraffin, gelled hydrocarbon, medium chain fatty acid triglyceride, solid paraffin, white beeswax, cetostearyl alcohol, cetanol, stearyl alcohol, stearic acid, isopropyl myristate, octyldodecanol, isopropyl palmitate, There are cetyl lactate, lanolin butyrate, etc., preferably white petrolatum and liquid paraffin.

  In addition to the above components, the oily ointment of the present invention usually contains other components used for external preparations for pharmaceuticals and cosmetics within the qualitative and quantitative ranges that do not impair the purpose and effect of the present invention. can do.

  As surfactants, glyceryl monostearate, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene hydrogenated castor oil 5, polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 40, Polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 100, sorbitan monostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan sesquioleate, polyoxyethylene stearyl ether, etc. can be added. It is glyceryl stearate.

  Oil-soluble ingredients such as tocopherol acetate, tocopherol, soybean lecithin, antioxidants such as benzotriazole, isopropylmethylphenol, edetic acid, benzoic acid, salicylic acid, sorbic acid, dehydroacetic acid, paraoxybenzoic acid alkyl esters (methylparaben, ethylparaben, Propylparaben, butylparaben, etc.), antibacterial and antiseptic agents such as hexachlorophene, etc., solubilizing agents such as crotamiton, isopropyl adipate, olive oil, camphor, hardened oil, squalane, squalene, local anesthetics such as lidocaine and dibucaine, Calciferol, retinol, and the like, and their vitamins can be added, but crotamiton, tocopherol acetate, and isopropylmethylphenol are preferred.

  Water-soluble components such as sodium edetate, sodium benzoate, sodium salicylate, sodium sorbate, sodium dehydroacetate, sodium paraoxybenzoate, propylene glycol, 1,3-butylene glycol, polyethylene glycol, glycerin Solvents such as methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, local anesthetics such as lidocaine and dibucaine salts, pyridoxal, pyridoxine, riboflavin, ascorbic acid, etc. and vitamins such as salts or esters Preferably, it is propylene glycol.

  As a pH adjuster, sodium hydroxide, hydrochloric acid, phosphoric acid, phosphate, carbonate, citric acid, citrate, diethanolamine, triethanolamine, and isopropanolamine can be dissolved in a small amount of water and added in an appropriate amount. The pH of the oleaginous ointment of the present invention to which a pH adjusting agent is added is 3.5 to 5.0, preferably 3.6 to 4.8.

  The external preparation for skin of the present invention is applied to the outer skin of pharmaceuticals, quasi drugs, cosmetics, etc., and the dosage form takes the form of an oily ointment. The amount of oil based on the oleaginous ointment can be adjusted within the range of forming the oleaginous ointment, but is generally 60 to 90 w / w%, preferably 70 to 85 w / w%, particularly preferably 75. ~ 85%.

  The oily ointment of the present invention can be produced by methods well known to those skilled in the art. First, an oily composition is prepared by dissolving dibutylhydroxytoluene, menthol, and other oil-soluble components in a composition obtained by heating and melting part of an oil and a surfactant. The oily composition is gradually cooled while stirring and mixing to 45 to 55 ° C. The ester steroid is mixed and dispersed with a part of the oil and added to the oily composition. Further, the pH adjuster is dissolved in water, and stirred and mixed with the water-soluble component to adjust the pH to 3.5 to 5.0. The oily ointment of the present invention is prepared by gradually cooling to room temperature while stirring and mixing. Diphenhydramines of diphenhydramines are added as oil-soluble components, and diphenhydramine salts are added as water-soluble components.

EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated further in detail, the technical scope of this invention is not limited at all by this. In addition, a compounding quantity is weight%.
[Examples 1 to 3]
Preparation Method of Oily Ointment An oily composition was prepared by dissolving menthol, dibutylhydroxytoluene, and other oil-soluble components in a composition obtained by melting a part of the oil and a surfactant with heating (70 ° C.). The oily composition was gradually cooled to 50 ° C. while stirring and mixing. The ester steroid is mixed and dispersed with a part of the oil and added to the oily composition. Further, the pH adjuster was dissolved in a small amount of purified water, and an appropriate amount was added to adjust the pH to 4.2. The mixture was stirred and mixed with diphenhydramine hydrochloride and other water-soluble components. The oily ointment of the present invention was prepared by gradually cooling to room temperature while stirring and mixing.
Table 1 shows the components of the oily ointment of Examples 1 to 3 prepared using the above-described method for producing an oily ointment.

  In order to confirm the effect when dibutylhydroxytoluene and menthol were used as stabilizers, those using neither dibutylhydroxytoluene nor menthol (Comparative Example 1) and those using only one of them (Comparative Examples 2, 3) And the oily ointment of Examples 1-3. In the stabilization test, the oily ointments of Examples 1 to 3 and Comparative Examples 1 to 3 were placed in a polyethylene container and stored at 50 ° C. and 75% RH for 3 months. Thereafter, the appearance and the residual rate of prednisolone acetate (PVA) valerate were measured. Storage at 50 ° C. and 75% RH is a measure of the stability of a general pharmaceutical product for a storage period of 3 years. The results are shown in Table 1.

Appearance test: At the start of the test, all of Examples 1 to 3 and Comparative Examples 1 to 3 were white, but those of Comparative Examples 1 to 3 were pale yellow and slightly yellow after the test was completed. . On the other hand, the thing of Examples 1-3 maintained white.
PVA residual rate test: The amount of residual PVA was measured according to the Japanese Pharmacopoeia general test method and liquid chromatograph method. In Comparative Example 1, it decreased to almost the standard value lower limit, and in Comparative Examples 2 and 3, it was below the standard value.

[Examples 4 to 20]
According to the preparation method of said oily ointment, the oily ointment of Examples 4-20 was prepared. The compositions are shown in Tables 2-4.

Claims (3)

An oily ointment comprising prednisolone valerate acetate , diphenhydramines, dibutylhydroxytoluene, menthol, and oil. Oleaginous ointment according to claim 1 diphenhydramine Min acids are diphenhydramine hydrochloride.   The oily ointment according to claim 1 or 2, containing 0.01 to 0.1 w / w% dibutylhydroxytoluene and 0.3 to 2 w / w% menthol.