CN101340916A - External preparation with improved temporal stability of steroid - Google Patents

Abstract

It is intended to provide a preparation for external use which is prepared by adding a benzoic ester-based local anesthetic drug and an oxycarboxylic acid to a steroid-containing preparation for external use to thereby improve the temporal stability of the steroid and impart a favorable feel in using.

Description

External preparation with improved temporal stability of steroid

technical field

The present invention relates to an external preparation containing a steroid, which improves the temporal stability of a steroid and provides a good usability. More specifically, it relates to an external preparation containing a steroid with improved stability over time by further including a benzoate-based local anesthetic and a hydroxycarboxylic acid in the external preparation containing a steroid and having a good usability.

Background technique

Conventionally, compounds having a steroid skeleton have been widely used as active ingredients of pharmaceuticals. For example, topical preparations containing adrenal corticosteroids having anti-inflammatory effects are used in the treatment of inflammatory skin diseases such as inflammation and dermatitis associated with insect bites. Examples of adrenal corticosteroids used in the above external preparations include hydrocortisone, dexamethasone and the like. In addition, steroid-containing external preparations include, for example, skin external preparations containing a combination of prednisolone acetate valerate and an antihistamine (Patent Document 1). However, in the steroid-containing external preparations provided conventionally, the stability of the steroid over time is not necessarily sufficient.

As an advanced technology related to improving the stability of steroids in preparations, there are known, for example: skin external preparations containing steroids, glycerin and polar oils (patent document 2); steroid-containing poultices containing 0.005 ~ 0.05% by weight of steroid as an active ingredient, crotamiton and a surfactant containing 15% by weight or less of crotamiton as a stabilizer, the mixing amount of crotamiton is 200 to 3000 times by weight of the mixing amount of the above-mentioned steroid, And the mixing amount of the above-mentioned surfactant is 1/20～1/5 weight times of the mixing amount of the above-mentioned crotamiton (patent document 3); An anhydrous external preparation composition of an acrylic polymer (Patent Document 4). However, when a polar oil is mixed, the polar oil and water may separate. In addition, crotamiton may cause skin irritation and worsen the feeling of use, so it is not preferable to mix it in a large amount. In addition, in an anhydrous external preparation composition, for example, since it does not contain water, the spreadability of the preparation may be poor, and the feeling in use may be poor.

Patent Document 1: Japanese Patent Laid-Open No. 2002-356430

Patent Document 2: Japanese Patent Laid-Open No. 2001-247463

Patent Document 3: Japanese Patent Laid-Open No. 2000-26299

Patent Document 4: Japanese Patent Laid-Open No. 2001-233772

Contents of the invention

The problem to be solved by the invention

As described above, among external preparations containing steroids, no external preparations have been found that have sufficiently improved the stability of steroids over time and have good usability.

An object of the present invention is to provide an external preparation containing a steroid, which has improved stability over time of a steroid and has a good usability.

way of solving the problem

Therefore, the inventors of the present invention conducted intensive studies to solve the above problems, and found that by further mixing a benzoate local anesthetic and a hydroxycarboxylic acid in the external preparation, the stability of the steroid in the external preparation can be significantly improved over time, The present invention has been accomplished by providing an external preparation with a good feeling of use.

That is, the present invention is as follows.

(1) An external preparation further comprising a benzoate-based local anesthetic and a hydroxycarboxylic acid in a steroid-containing external preparation.

(2) The external preparation of (1), wherein the steroid is an ester steroid.

(3) The external preparation of (1) or (2), wherein the steroid is dexamethasone acetate.

(4) The external preparation of (1) to (3), wherein the benzoate local anesthetic is lidocaine.

(5) The external preparation of (1) to (4), wherein the hydroxycarboxylic acid is citric acid or malic acid.

(6) The external preparation of (1) to (5), which further contains an antihistamine.

(7) The external preparation of (6), wherein the antihistamine is diphenhydramine hydrochloride.

(8) The external preparation of (1) to (7), which further contains a lower alcohol.

(9) The external preparation of (1) to (8), which is a liquid preparation, a cream or a gel.

The best way to practice the invention

In the present invention, steroids are not limited to steroids with anti-inflammatory effects (adrenal corticosteroids), and include all steroids that can be mixed into external preparations as long as they can be stabilized by benzoate local anesthetics and hydroxycarboxylic acids. Adrenocorticosteroids are preferred in the invention. Specific examples of such steroids are: hydrocortisone, amcinonide, prednisolone, methylprednisolone, difluocorolone, dexamethasone, betamethasone, diflurasone, difluprednate, Triamcinolone, triamcinolone acetonide, halcinonide, flumethasone, budesonide, mometasone, fluocinolone, fluometuron, fludrocetone, aclomethasone, clobetasol, Predone, beclomethasone, clobetasone and their esters, ketals, acetals and hemiacetal derivatives, etc., but not limited to these.

In the present invention, ester steroids that form esters with organic acids are specifically preferred such as: dexamethasone acetate, prednisolone acetate, hydrocortisone acetate, betamethasone valerate, prednisolone acetate valerate, etc.; Dexamethasone acetate is particularly preferred. In the present invention, steroids may be used alone or in combination of two or more.

The external preparation of the present invention has the advantageous effect of sufficiently improving the stability over time even for ester steroids which are particularly prone to hydrolysis and have low stability among steroids.

In the present invention, the blending amount of the steroid in the total amount of the external preparation is not particularly limited, but from the viewpoint of the pharmacological effect and safety of the steroid, it is generally desirable to be 0.001 to 1% by mass, preferably 0.005 to 0.5% by mass, especially Preferably it is 0.01 to 0.5% by mass.

The benzoate-based local anesthetic in the present invention is a known component having an anesthetic effect, but it has not been known so far to improve the temporal stability of steroids in external preparations as in the present invention. In the present invention, specific examples of benzoate local anesthetics include: lidocaine, lidocaine hydrochloride, dibucaine hydrochloride, procaine hydrochloride, etc., but are not limited to these. In addition, even unknown components can be used as long as they can stabilize both hydroxycarboxylic acid and steroid. Lidocaine is particularly preferred in the present invention. In the present invention, the benzoate local anesthetics may be used alone or in combination of two or more.

In the present invention, the mixing amount of the benzoate local anesthetic in the total amount of the external preparation is not particularly limited, but it is generally desirable to be 0.01 to 4% by mass, preferably 0.05% by mass, from the viewpoint of stabilization of the steroid and anesthesia. ~2% by mass, particularly preferably 0.1-1% by mass.

In the present invention, a hydroxycarboxylic acid means a substance having a carboxyl group and a hydroxyl group in one molecule of an organic compound. In the present invention, the hydroxycarboxylic acid may be a pharmacologically acceptable salt thereof. Examples of salts include sodium salts, potassium salts, calcium salts and the like. Specific examples of hydroxycarboxylic acids include, but are not limited to, lactic acid, citric acid, and malic acid. Citric acid or malic acid is particularly preferred in the present invention. In the present invention, organic carboxylic acids may be used alone or in combination of two or more.

In the present invention, the blending amount of hydroxycarboxylic acid in the total amount of the external preparation is not particularly limited, but it is usually desirably 0.001 to 2% by mass, preferably 0.01 to 1% by mass, and particularly preferably 0.1 to 0.5% by mass.

The relative proportions of the steroid, benzoate local anesthetic, and hydroxycarboxylic acid in the total amount of the external preparation of the present invention are not particularly limited, especially from the viewpoint of the stability of the steroid over time, when the steroid is 1 , Benzoate local anesthetics are preferably 0.01-4000, more preferably 0.1-400, especially preferably 0.2-100; hydroxycarboxylic acids are preferably 0.001-2000, more preferably 0.02-200, especially preferably 0.2-50 .

In the present invention, the dosage form of the external preparation is not particularly limited. For example, it may be a dosage form that seeks the stability of steroids, such as an external preparation containing water. Specific examples include: liquid preparation, cream, gel, ointment, patch wait. In the present invention, liquid formulations, creams, or gels are particularly preferred from the viewpoint of the usability of the formulations.

It is presumed that the stability of steroids in the external preparation of the present invention is mainly derived from the inhibition of hydrolysis of steroids, especially ester-based steroids. Therefore, in a suitable embodiment of the external preparation of the present invention, the content of water is preferably 0.1 to 99% by mass, more preferably 5 to 95% by mass, particularly preferably 10 to 90% by mass relative to the total amount of the external preparation.

In this invention, pH of an external preparation is 3-8 normally, Preferably it exists in the range of 4-7. For example, dexamethasone acetate is known to be unstable when the pH of topical formulations is below 3 or above 8. From the viewpoint of stability, the more preferable pH for dexamethasone acetate is 5-6.5. In addition, when the pH of the preparation for external use is lower than 3 or higher than 8, skin irritation may sometimes occur.

In the external preparation of the present invention, an antihistamine may be further mixed. An antihistamine is a known component having an antipruritic effect, and by mixing the antihistamine in the external preparation of the present invention, an immediate antipruritic effect can be obtained. Specific examples of antihistamines include, but are not limited to, diphenhydramine hydrochloride, diphenhydramine, chlorpheniramine, isopendine hydrochloride, and the like. The above-mentioned antihistamines may be used alone or in combination of two or more. In the present invention, diphenhydramine and diphenhydramine hydrochloride are particularly preferred.

In the present invention, the compounding amount of the antihistamine in the total amount of the external preparation is not particularly limited, but it is generally desirable to be 0.1 to 4% by mass, preferably 0.5 to 3% by mass, and particularly preferably It is 0.75 to 2% by mass.

In the external preparation of the present invention, a lower alcohol may be further mixed. By mixing lower alcohols in the external preparation of the present invention, the skin permeability of the steroid is improved. In addition, the lower alcohol is volatilized by the heat of vaporization, and a cooling feeling is provided. Examples of lower alcohols include ethanol, n-propanol, and isopropanol, among which ethanol and isopropanol are preferred in the present invention.

The compounding quantity of a lower alcohol is not specifically limited, Usually, it is 0.1-70 mass %, Preferably it is 5-60 mass %, Especially preferably, it is 10-50 mass %. If the blending amount of the lower alcohol is less than 0.1% by mass, sufficient cooling sensation cannot be given to the skin, and if it is more than 70% by mass, the irritation to the skin may become stronger.

The external preparation of the present invention may further contain active ingredients other than steroids, antihistamines, and benzoate local anesthetics, moisturizers, preservatives, stabilizers, and wetting agents.

Examples of active ingredients other than steroids, antihistamines, and benzoate local anesthetics include anti-inflammatory agents such as potassium or ammonium glycyrrhizic acid; whitening agents such as ascorbic acid or ascorbic acid derivatives, and the like.

Examples of humectants include cellulose derivatives, xanthan gum, sodium carboxymethylcellulose, pectin, hyaluronic acid, sodium alginate, carrageenan, and the like.

Examples of preservatives include parabens, benzalkonium chloride, and the like.

Examples of stabilizers include sodium sulfite, sodium bisulfite, dibutylhydroxytoluene, butylhydroxyanisole, edetic acid and the like.

Examples of wetting agents include polyhydric alcohols such as propylene glycol, 1,3-butanediol, isopropylene glycol, and polyethylene glycol.

The external preparation of the present invention can be easily prepared according to methods known to those skilled in the art. For example, when preparing a liquid preparation as an external preparation, the external preparation of the present invention can be prepared by dissolving the respective components in an appropriate solvent and then mixing them.

The external preparation of the present invention is used for diseases or symptoms to which steroids or steroids and antihistamines are applicable, for example, it is used for the treatment and symptom relief of skin disease sites with symptoms such as itching and redness. When in use, an appropriate amount of the external preparation of the present invention is applied to the affected part.

Example

The present invention will be described in detail below using examples, but the present invention is not limited thereto.

[Example 1]

Add 0.025g of dexamethasone acetate and 0.5g of lidocaine into 45g of ethanol and dissolve to prepare an ethanol solution. Next, 2 g of diphenhydramine hydrochloride and 0.25 g of citric acid were added to 30 g of purified water and stirred to prepare an aqueous solution. Thereafter, the above-mentioned aqueous solution and ethanol solution were mixed, and purified water was added to make the total amount 100 mL, whereby the liquid preparation (pH 6.0) of Example 1 was obtained.

[Comparative Example 1]

An ethanol solution in which lidocaine was not mixed in the preparation of Example 1 was prepared, mixed with the aqueous solution prepared in the same manner as in Example 1, and stirred. Sodium citrate was then added to bring the pH to 6.0. Purified water was added to this solution so that the total amount would be 100 mL, whereby the liquid preparation of Comparative Example 1 was obtained.

[Comparative Example 2]

An aqueous solution in which phosphoric acid was added instead of citric acid to the formulation of Example 1 was prepared and mixed with the ethanol solution obtained in the same manner as in Example 1. Disodium hydrogen phosphate was added to the mixture to bring the pH to 6.0. Purified water was added to this solution so that the total amount would be 100 mL, whereby the liquid formulation of Comparative Example 2 was obtained.

[Test Example 1]

The pH of the samples of Example 1, Comparative Example 1, and Comparative Example 2 was measured immediately after preparation and after storage at 60° C. for 2 weeks. In addition, the residual ratio of dexamethasone acetate after storage at 60° C. for 2 weeks was calculated by separating and measuring the content of dexamethasone acetate immediately after sample preparation and after storage at 60° C. for 2 weeks by HPLC. The results are shown in Table 1.

Table 1

In Example 1, Comparative Example 1 that does not contain benzoate local anesthetic-lidocaine, and Comparative Example 2 that does not contain citric acid as hydroxycarboxylic acid-citric acid, the pH after storage at 60°C for 2 weeks is different from that of each The pH of the formulation was the same immediately after preparation. The residual rate of dexamethasone acetate after storage at 60°C for 2 weeks (content after storage at 60°C for 2 weeks/content immediately after preparation×100) was less than 90% in Comparative Example 1 and Comparative Example 2 , and about 95% in Example 1, the stability of dexamethasone acetate is significantly improved. In addition, the preparation of Example 1 has quick-drying properties and exhibits a good feeling of use.

[Example 2]

Add 0.025g of dexamethasone acetate and 0.5g of lidocaine into 45g of ethanol and dissolve to prepare an ethanol solution. Next, 2 g of diphenhydramine hydrochloride and 0.32 g of malic acid were added to 30 g of purified water and stirred to prepare an aqueous solution. Thereafter, the aqueous solution and the ethanol solution were mixed, and purified water was added to make the total amount 100 mL, thereby obtaining the liquid preparation (pH 6.06) of Example 2. The pH was 6.09 after storage at 60°C for 10 days. The residual rate of dexamethasone acetate (content after storage at 60° C. for 10 days/content just after preparation×100) was 96.6%, and the stability of dexamethasone acetate was significantly improved. In addition, in the content measurement of dexamethasone acetate, HPLC was used similarly to Test Example 1.

[Preparation Example 1] (liquid preparation)

Dexamethasone acetate 0.025%w/v

Diphenhydramine Hydrochloride 2.0% w/v

Lidocaine 0.5% w/v

l-Menthol 3.0% w/v

dl-camphor 2.0% w/v

Citric Acid 0.3%w/v

Ethanol 30% w/v

Appropriate amount of purified water

           

Total 100mL

Add dexamethasone acetate, l-menthol, dl-camphor and lidocaine into ethanol and dissolve to prepare ethanol solution. Alternatively, add diphenhydramine hydrochloride and citric acid to purified water and stir to prepare an aqueous solution. After that, the above-mentioned aqueous solution and ethanol solution were mixed to obtain a liquid preparation for external use.

[Preparation Example 2] (liquid preparation)

Prednisolone Acetate 0.5% w/v

Lidocaine 0.5% w/v

Citric acid 0.3%w/v

Ethanol 30% w/v

Purified water Appropriate amount

           

Total 100mL

Add prednisolone acetate and lidocaine into ethanol and dissolve to prepare ethanol solution. Add citric acid to purified water and stir to make an aqueous solution. After that, the above-mentioned aqueous solution and ethanol solution were mixed to obtain a liquid preparation for external use.

[Preparation Example 3] (Gel)

Hydrocortisone acetate 0.5% by mass

Diphenhydramine hydrochloride 1.0% by mass

Lidocaine 0.5% by mass

Citric acid 0.3% by mass

Ethanol 30% by mass

Carbopol 1.2% by mass

Diisopropanolamine Appropriate amount (adjust pH)

Purified water Appropriate amount

             

Total 100g

Diphenhydramine hydrochloride and citric acid are dissolved in water, and then polycarboxyethylene is added to form a gel phase. Using a separate container, dissolve hydrocortisone acetate and lidocaine in ethanol to prepare an ethanol phase. Mix the gel phase and the ethanol phase, add diisopropanolamine, adjust the pH to 6, and obtain the gel for external use.

[Preparation Example 4] (liquid preparation)

Dexamethasone acetate 0.025%w/v

Dibucaine Hydrochloride 0.5%w/v

Lidocaine 0.5% w/v

Citric Acid 0.3%w/v

Isopropyl Alcohol 30% w/v

Appropriate amount of purified water

           

Total 100mL

Add dexamethasone acetate and lidocaine to isopropanol and dissolve to make an isopropanol solution. In addition, dibucaine hydrochloride and citric acid were added to purified water and stirred to prepare an aqueous solution. After that, the above-mentioned aqueous solution and isopropanol solution were mixed to obtain a liquid preparation for external use.

[Preparation Example 5] (liquid preparation)

Dexamethasone acetate 0.025%w/v

Diphenhydramine Hydrochloride 2.0% w/v

Lidocaine 0.5% w/v

Citric Acid 0.3%w/v

Propylene Glycol 5.0%w/v

Macrogol 400 10% w/v

Appropriate amount of purified water

           

Total 100mL

Add dexamethasone acetate and lidocaine to the mixed solution of propylene glycol and polyethylene glycol 400, heat and dissolve to prepare a polyol solution. Alternatively, diphenhydramine hydrochloride and citric acid were added to purified water and stirred to prepare an aqueous solution. After that, the above-mentioned aqueous solution and polyol solution are mixed to obtain a liquid preparation for external use.

[Preparation Example 6] (Cream)

Betamethasone valerate 0.012% by mass

Diphenhydramine hydrochloride 2.0% by mass

Lidocaine hydrochloride 0.5% by mass

Citric acid 0.1% by mass

Sodium citrate Appropriate amount (to adjust pH)

Diisopropyl adipate 3.0% by mass

Medium-chain fatty acid triglycerides 10.0% by mass

Tween 20 5.0% by mass

Tween 60 2.0% by mass

Propylene glycol 10.0% by mass

1,3-Butanediol 5.0% by mass

Macrogol 400 10% by mass

Purified water Appropriate amount

           

Total 100g

Add betamethasone valerate, diisopropyl adipate, Tween 20, and Tween 60 to the medium-chain fatty acid triglyceride, heat to 75°C, and dissolve. Next, dissolve diphenhydramine hydrochloride, lidocaine hydrochloride, propylene glycol, 1,3-butanediol, polyethylene glycol 400, and citric acid in water, and stir the aqueous solution and the previous solution until uniformly emulsified, Then sodium citrate was added to adjust the pH to 5.5 to obtain a cream for external use.

Industrial applicability

The present invention provides an external preparation containing a steroid, which improves the temporal stability of a steroid and provides a good feeling of use. The present invention can be used in the field of medicine and the like.

Claims (9)

1. external preparation, this external preparation is further to contain benzoates local anesthetic and hydroxy carboxylic acid in containing the external preparation of steroid.

2. the external preparation of claim 1, wherein steroid is that ester is a steroid.

3. claim 1 or 2 external preparation, wherein steroid is a dexamethasone acetate.

4. each external preparation in the claim 1～3, wherein benzoates local anesthetic is a lignocaine.

5. each external preparation in the claim 1～4, wherein hydroxy carboxylic acid is citric acid or malic acid.

6. each external preparation in the claim 1～5 wherein further contains antihistaminic.

7. the external preparation of claim 6, wherein antihistaminic is a diphhydramine hydrochloride.

8. each external preparation in the claim 1～7 wherein further contains lower alcohol.

9. each external preparation in the claim 1～8, this external preparation is liquid preparation, cream or gel.