JP2023026516A - Oily external liquid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pharmaceutical composition that has good storage stability and skin absorbency, and low skin irritation, and is easy to apply.

SOLUTION: An oily external liquid has a skin disease therapeutic agent, an oily solvent for dissolving the skin disease therapeutic agent, a liquid paraffin, and a surfactant, but substantially contains no water.

SELECTED DRAWING: None

COPYRIGHT: (C)2023,JPO&INPIT

Description

The present invention relates to an oily external liquid.

Ointments are widely used as external preparations for treating skin diseases. For example, Patent Document 1 describes a stable and well-absorbable ointment containing tacrolimus.

Patent No. 2526752

However, since ointments are harder than creams, external solutions, etc., they are not suitable for application to a wide range of skin. In addition, since it is difficult to apply to hairy areas such as the scalp, adherence may decrease when ointments are used in such treatments. Accordingly, an object of the present invention is to provide a pharmaceutical composition that has good storage stability and skin absorbability, has low skin irritation, and is easy to apply.

The present invention includes the following aspects.
[1] An oily external solution containing a therapeutic drug for skin diseases, an oily solvent for dissolving the therapeutic drug for skin diseases, an oily base, and a surfactant, and substantially free of water.
[2] The drug for treating skin diseases is tacrolimus, vitamin _D3 compound, adapalene, diflorazone acetate, deprodone propionate, hydrocortisone butyrate propionate, chlorhexidine gluconate, alkyldiaminoethylglycine hydrochloride, clindamycin phosphate. Acid esters, crotamiton, clotrimazole, gentamicin sulfate, betamethasone butyrate propionate, diphenhydramine, difluprenade, prednisolone valerate acetate, dexamethasone, terbinafine, clobetasol propionate, betamethasone valerate, benzoyl peroxide , betamethasone dipropionate, benzalkonium chloride, ketoconazole, povidone iodine, clobetasone butyrate, bifonazole, vidarabine, alclomethasone propionate, nadifloxacin, mometasone furoate, bendazac and lanoconazole The oily liquid for external use according to [1], which is a selected one or a combination of two or more.
[3] The oily liquid for external use according to [1] or [2], further containing squalane.
[4] The oily external solution according to any one of [1] to [3], wherein the surfactant content is 0.01 to 1.0% by mass.
[5] The oily liquid for external use according to any one of [1] to [4], which has a viscosity of 1.2 Pa·s or less when measured at 20°C with a cone-plate viscometer.

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a pharmaceutical composition that has good storage stability and skin absorbability, has low skin irritation, and is easy to apply.

[Oil-based solution for external use]
In one embodiment, the present invention provides an oily skin disease therapeutic drug, an oily solvent for dissolving the skin disease therapeutic drug, an oily base, and a surfactant, and substantially free of water. Provide topical solutions. As will be described later in Examples, the oily external solution of the present embodiment has good storage stability and skin absorbability, has low skin irritation, and is easy to apply.

Skin disease _therapeutic agents are not particularly limited. clindamycin phosphate, crotamiton, clotrimazole, gentamicin sulfate, betamethasone butyrate propionate, diphenhydramine, difluprenade, prednisolone valerate acetate, dexamethasone, terbinafine, clobetasol propionate, betamethasone valerate , benzoyl peroxide, betamethasone dipropionate, benzalkonium chloride, ketoconazole, povidone iodine, clobetasone butyrate, bifonazole, vidarabine, alclomethasone propionate, nadifloxacin, mometasone furoate, bendazac, lanoconazole etc. The oil-based external liquid of the present embodiment may contain one of these skin disease therapeutic agents alone, or may contain two or more of them in combination.

Tacrolimus is a compound represented by the following chemical formula (1) and generally exists in the form of a monohydrate. Tacrolimus is known to exhibit excellent therapeutic effects on, for example, atopic dermatitis.

Examples of vitamin D ₃ compounds include 22-oxa-1α,25-dihydroxyvitamin D ₃ (hereinafter sometimes referred to as “maxacalcitol”), calcipotriol, tacalcitol and the like. Maxacalcitol is a vitamin _D3 derivative that has a cytostatic effect on dermal fibroblasts and is used as a therapeutic drug for skin diseases such as psoriasis and keratosis. The chemical formula of maxacalcitol is shown in formula (2) below.

When the therapeutic drug for skin diseases is tacrolimus, the oily external solution of the present embodiment should contain 0.01 to 0.3% by mass of tacrolimus in terms of tacrolimus from the viewpoint of excellent efficacy and safe usage. is preferred.

When the skin disease therapeutic agent is maxacalcitol, the oily external solution of the present embodiment may contain 5 to 50 μg/g of maxacalcitol from the viewpoint of excellent efficacy and safe usage. preferable.

In the oily external solution of the present embodiment, the oily solvent for dissolving the therapeutic drug for skin diseases is not particularly limited as long as it can dissolve the therapeutic drug for skin diseases. is preferably not chemically destabilized.

For example, tacrolimus is a sparingly soluble substance that is poorly soluble in both water and oil. Therefore, it is necessary to use a solubilizer capable of dissolving tacrolimus in formulations containing tacrolimus. Surfactants are typically used as tacrolimus solubilizers, but many surfactants are highly irritating to the skin. Limited use.

In the oil-based external liquid of the present embodiment, an oil-based solvent is used as a solubilizer for the therapeutic agent for skin diseases. For example, when the therapeutic drug for skin disease is tacrolimus or maxacalcitol, diethyl sebacate, propylene glycol dicaprylate, or the like can be used as the oily solvent for dissolving these drugs.

The oily external liquid of this embodiment contains an oily base. Oily bases include hydrocarbons (liquid paraffin, light liquid paraffin, vaseline, paraffin, etc.), animal and vegetable oils (white beeswax, carnauba wax, lanolin, etc.), higher fatty acids (palmitic acid, stearic acid, oleic acid, etc.), Higher aliphatic alcohols (cetanol, stearyl alcohol, etc.), fatty acid esters (diisopropyl adipate, medium-chain fatty acid triglycerides, propylene glycol monocaprylate, propylene glycol dicaprylate, diethyl sebacate, etc.) and the like. Examples of medium-chain fatty acid triglycerides include tri(caprylic/capric)glyceryl.

One type of oily base may be used alone, or a plurality of types may be used in combination. Among them, the oily base preferably contains liquid paraffin from the viewpoint of easily adjusting the viscosity of the oily topical liquid to a range that facilitates application.

The oil-based external liquid of this embodiment contains a surfactant. The content of surfactant is preferably 0.01 to 1.0% by mass. The content of the surfactant may be 0.01 to 0.5% by mass, may be 0.01 to 0.3% by mass, or may be 0.01 to 0.2% by mass. good too.

External preparations containing surfactants tend to be highly irritating to the skin. However, as will be described later in Examples, the content of the surfactant within the above range can suppress the skin irritation of the oily external solution and improve the skin absorbability of the therapeutic agent for skin diseases. can.

The surfactant is not particularly limited as long as it is commonly used in formulations, and examples thereof include polyoxyethylene castor oil, triethylhexanoin, polyethylene glycol monostearate, and polyoxyethylene hydrogenated castor oil.

The oil-based external liquid of this embodiment does not substantially contain water. In the present specification, "substantially free of water" means that the water content determined by Karl Fischer method is 5% by mass or less, more preferably 2% by mass or less, and still more preferably 1% by mass or less. It means that there is Specifically, it is preferable not to intentionally add water during the production of the oil-based external solution. In addition, unavoidable contamination of water in manufacturing is allowed. Since the oil-based external solution of the present embodiment does not contain water, it tends to improve the storage stability of the drug for treating skin diseases.

It is preferable that the oil-based external liquid of the present embodiment further contain squalane. Squalane has a skin-protecting effect and is effective in improving the usability of the formulation.

The oil-based external liquid of the present embodiment may contain additives such as wetting agents, thickeners, coloring agents, fragrances, antioxidants, stabilizers, bactericides, and preservatives. Wetting agents include, for example, urea, glycerin, propylene glycol, sorbitol, enzymes, and the like. Thickeners include polyvinyl alcohol, polyvinylpyrrolidone, hypromellose, hydroxypropylcellulose, carboxyvinyl polymer, xanthan gum and the like. Coloring agents include, for example, caramel, talc, tar pigments commonly used in formulations, and the like. Examples of aromatic agents include camphor and methyl salicylate. Antioxidants include, for example, ascorbic acid, dibutylhydroxytoluene, tocopherol acetate and the like. Examples of stabilizers include ethylene glycol salicylate and sodium edetate. Examples of bactericidal agents include iodine agents and ethanol. Examples of antiseptics include sorbic acid and parabens. One type of these additives may be used alone, or a plurality of types may be used in combination.

The oil-based external solution of the present embodiment can be produced by mixing the above components by means commonly used for formulation.

The oily external use liquid of the present embodiment preferably has a viscosity of 1.2 Pa·s or less when measured at 20° C. with a cone-plate viscometer. The viscosity of the oil-based external use liquid of the present embodiment may be 1.0 Pa s or less, or 0.8 Pa s or less, as measured at 20° C. with a cone-plate viscometer. Well, it may be 0.6 Pa·s or less. Moreover, the lower limit of the viscosity of the oil-based external use liquid of the present embodiment is preferably 0.01 Pa·s or more when measured at 20° C. with a cone-plate viscometer. When the viscosity is within the above range, the pharmaceutical composition can be easily applied with an oily external solution.

The amount and frequency of application of the oil-based external solution of the present embodiment to the skin can be appropriately adjusted depending on the type of skin disease remedy, patient's symptoms, age, and the like. For example, when the disease is atopic dermatitis and the skin disease therapeutic agent is tacrolimus, application of 1 or 2 times per day is usually appropriate, and the amount used per day is , the active ingredient (converted to tacrolimus) is preferably 5 mg or less, and for children, the active ingredient is considered to be 1.5 mg or less.

EXAMPLES Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to the following examples.

[Experimental example 1]
(Manufacturing of water-based lotions, oil-based lotions, oil-based external liquids and creams)
Tacrolimus was used as a therapeutic drug for skin diseases. Aqueous (o/w) lotions, oily (w/o) lotions, oily topical solutions and creams were prepared.

(Aqueous lotion)
Each material of the active ingredient dissolved phase was mixed according to the composition shown in Table 1 below and dissolved by heating at 60 to 70° C. to prepare an active ingredient dissolved phase. Subsequently, each material of the water phase was mixed with the composition shown in Table 1 below to prepare the water phase. Subsequently, the dissolved phase of the active ingredient and the aqueous phase are mixed, mixed at 60°C for 10 minutes with an emulsification tester ET-3A (manufactured by Nikko Chemicals Co., Ltd.), and then stirred and cooled at 200 rpm until the temperature reaches 35°C or lower. Aqueous lotions of Production Examples 1 and 2 were obtained.

(Oil-based lotion)
Each material of the active ingredient dissolved phase was mixed with the composition shown in Table 2 below, and dissolved by heating at 60 to 70° C. to prepare an active ingredient dissolved phase. Subsequently, each material of the water phase was mixed with the composition shown in Table 2 below to prepare the water phase. Subsequently, the dissolved phase of the active ingredient and the aqueous phase are mixed, mixed at 60°C for 10 minutes with an emulsification tester ET-3A (manufactured by Nikko Chemicals Co., Ltd.), and then stirred and cooled at 200 rpm until the temperature reaches 35°C or lower. Oily lotions of Production Examples 3 to 5 were obtained.

(Oil-based topical liquid)
Each material of the active ingredient dissolved phase was mixed with the composition shown in Table 3 below, and dissolved by heating at 60 to 70° C. to prepare an active ingredient dissolved phase. Subsequently, each material of the base phase was mixed with the composition shown in Table 3 below to prepare the base phase. Subsequently, the active ingredient dissolved phase and the base phase were mixed, mixed at 60°C for 10 minutes with an emulsification tester ET-3A (manufactured by Nikko Chemicals Co., Ltd.), and then stirred and cooled at 200 rpm until the temperature reached 35°C or lower. to obtain the oily topical solutions of Production Examples 6 and 7.

(cream agent)
An O/W type cream having the composition shown in Table 4 below was prepared by the following method. First, carboxyvinyl polymer was swollen in purified water to obtain an aqueous carboxyvinyl polymer solution. Also, diisopropanolamine was dissolved in purified water to prepare a diisopropanolamine aqueous solution.

Subsequently, tacrolimus hydrate, dibutylhydroxytoluene and propyl paraoxybenzoate were dissolved in an oil agent, and polyoxyethylene hydrogenated castor oil 60 was added to form an oil phase. On the other hand, an aqueous carboxyvinyl polymer solution, 1,3-butylene glycol, methyl paraoxybenzoate, sodium edetate hydrate and purified water were mixed to form an aqueous phase.

Subsequently, the oil phase and the water phase are heated to 70 to 90° C. and dissolved respectively, then the water phase is added to the oil phase, and an emulsification tester ET-3A type (manufactured by Nikko Chemicals Co., Ltd.) is added. was used for emulsification. Subsequently, after adding an aqueous solution of diisopropanolamine, the mixture was stirred with a stirring rod until the product temperature reached room temperature to obtain a cream preparation of Production Example 8.

[Experimental example 2]
(Storage stability test)
The storage stability of the aqueous lotions of Production Examples 1 and 2, the oily lotions of Production Examples 3 and 5, and the oily external liquids of Production Examples 6 and 7, which were produced in Experimental Example 1, was examined. First, each formulation was placed in a polyethylene container and stored under an environment of 25° C. and 60% relative humidity for 6 months. Subsequently, the residual amount of tacrolimus in each formulation was measured by high performance liquid chromatography.

Table 5 below shows the evaluation results of storage stability. In Table 5, the residual rate represents the rate at which tacrolimus remained.

As a result, it became clear that the formulations (oil-based external liquids) of Production Examples 6 and 7 had high storage stability.

[Experimental example 3]
(Skin irritation test)
Using the oily lotions of Production Examples 3 to 5 and the oily external liquids of Production Examples 6 and 7 produced in Experimental Example 1, a rabbit skin primary irritation test was conducted to evaluate skin irritation. First, 0.5 g/1 site of each formulation was applied to the normal skin and damaged skin of the rabbit back for 24 hours. Skin reactions were then observed at 1, 24, 48 and 72 hours after removal of the occlusive patch. Three sites each of normal skin and damaged skin were tested and evaluated according to the Draze method. The results are shown in Table 6 below. In Table 6, numerical values indicate average values.

As a result, it became clear that the preparation of Production Example 7 (oil-based solution for external use) had a low irritation index. From the results of Experimental Examples 2 and 3, it was clarified that the oil-based external solution tends to have high drug storage stability and low skin irritation.

[Experimental example 4]
(Manufacturing of Oily External Liquid)
Tacrolimus was used as a therapeutic drug for skin diseases. Oil-based external solutions of Examples 1 to 4 were prepared with the compositions shown in Table 6 below. First, each material of the active ingredient dissolved phase was mixed with the composition shown in Table 7 below, and dissolved by heating at 60 to 70° C. to prepare an active ingredient dissolved phase. Subsequently, each material of the base phase was mixed with the composition shown in Table 7 below to prepare the base phase. Subsequently, the active ingredient dissolved phase and the base phase were mixed, mixed at 60°C for 10 minutes with an emulsification tester ET-3A (manufactured by Nikko Chemicals Co., Ltd.), and then stirred and cooled at 200 rpm until the temperature reached 35°C or lower. to obtain the oily topical solutions of Examples 1 to 4.

(Measurement of viscosity)
The viscosities of the oil-based external liquids of Experimental Examples 1 to 4 were measured. Viscosity was measured at 20° C. with a cone-plate viscometer. For comparison, the viscosity of a commercially available ointment (“Protopic Ointment 0.1%”, Astellas Pharma Inc.), the aqueous lotion of Production Example 1, and the cream of Production Example 8 were similarly measured. Table 8 below shows the viscosity measurement results.

[Experimental example 5]
(Storage stability test)
The storage stability of the oily topical solutions of Examples 1 to 4 produced in Experimental Example 4 was examined. First, each formulation was placed in a polyethylene container and stored under an environment of 25° C. and 60% relative humidity for 6 months. Subsequently, the residual amount of tacrolimus in each formulation was measured by high performance liquid chromatography.

Table 9 below shows the evaluation results of storage stability. In Table 9, the residual rate represents the rate at which tacrolimus remained.

As a result, it was found that all of the oily topical solutions exhibited high storage stability.

[Experimental example 6]
(Skin irritation test)
Using the oily external preparations of Examples 1 to 4 produced in Experimental Example 4, a rabbit skin primary irritation test was conducted to evaluate skin irritation. For comparison, a commercially available ointment (“Protopic Ointment 0.1%”, Astellas Pharma Inc.) was similarly evaluated for skin irritation.

First, 0.5 g/1 site of each formulation was applied to the normal skin and damaged skin of the rabbit back for 24 hours. Skin reactions were then observed at 1, 24, 48 and 72 hours after removal of the occlusive patch. Three sites each of normal skin and damaged skin were tested and evaluated according to the Draze method. The results are shown in Table 10 below. In Table 10, the numerical values indicate the average value of the irritation index.

As a result, it was clarified that the oily topical solutions of Examples 1 to 4 are safe from the viewpoint of skin irritation, and that the ointments have room for improvement from the viewpoint of skin irritation.

[Experimental example 7]
(Evaluation of coatability)
The applicability of the oily topical liquids of Examples 1 and 3 produced in Experimental Example 4 was evaluated. For comparison, a commercially available ointment (“Protopic Ointment 0.1%”, Astellas Pharma Inc.) and the cream of Production Example 8 were similarly evaluated for applicability. Specifically, four panelists evaluated each item of feel (touch), stickiness, and spreadability when applied to a wide area of the skin of the arm. The evaluation criteria were as follows. The results are shown in Table 11 below.

《Evaluation criteria for touch (touch)》
A: All four persons answered that the feel was good.
B: 3 persons answered that the feel was good.
C: Two persons answered that the feel was good.
D: 0 to 1 persons answered that the feel was good.

<<Evaluation criteria for stickiness>>
A: All four persons answered that it was not sticky.
B: 3 panelists answered that it was not sticky.
C: 2 panelists answered that it was not sticky.
D: 0 to 1 persons answered that it was not sticky.

《Evaluation Criteria》
A: All four persons answered that it was easy to stretch.
B: 3 persons answered that it was easy to stretch.
C: Two persons answered that it was easy to stretch.
D: 0 to 1 persons answered that it was easy to stretch.

As a result, it was found that the oily external use liquids of Examples had good applicability.

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a pharmaceutical composition that has good storage stability and skin absorbability, has low skin irritation, and is easy to apply.

Claims (3)

containing a therapeutic agent for skin diseases, an oily solvent for dissolving the therapeutic agent for skin diseases, an oily base, and a surfactant, and substantially free of water;
The skin disease therapeutic drug is tacrolimus, vitamin _D3 compound, adapalene, diflorazone acetate, deprodone propionate, hydrocortisone butyrate propionate, chlorhexidine gluconate, alkyldiaminoethylglycine hydrochloride, clindamycin phosphate, crotamiton, clotrimazole, gentamicin sulfate, betamethasone butyrate propionate, diphenhydramine, difluprenade, prednisolone valerate acetate, dexamethasone, terbinafine, clobetasol propionate, betamethasone valerate, benzoyl peroxide, betamethasone di selected from the group consisting of propionate, benzalkonium chloride, ketoconazole, povidone iodine, clobetasone butyrate, bifonazole, vidarabine, alclomethasone propionate, nadifloxacin, mometasone furoate, bendazac and lanoconazole one or a combination of two or more,
The surfactant is selected from the group consisting of polyoxyethylene castor oil, triethylhexanoin, polyethylene glycol monostearate, polyoxyethylene hydrogenated castor oil, etc.
An oily liquid for external use, wherein the content of the surfactant is 0.01 to 1.0% by mass. The oily external solution according to claim 1, further comprising squalane. 3. The oily liquid for external use according to claim 1, which has a viscosity of 1.2 Pa·s or less when measured at 20° C. with a cone-plate viscometer.