JP5961062B2 - Skin preparation for external use - Google Patents

Description

  The present invention relates to an external preparation for skin and an eczema drug, and is particularly used for improving atopic dermatitis, eczema / dermatitis, psoriasis, rash, and the like.

  Corticosteroids (steroids) have excellent effects on many skin diseases such as atopic dermatitis, eczema / dermatitis group, urticaria group such as urticaria, and psoriasis, and are widely used clinically as external preparations.

  For steroidal anti-inflammatory agents, steroidal anti-inflammatory agents are dissolved with a specific oil component, emulsified with an acrylic acid / alkyl methacrylate copolymer, and further, alcohol having 16 or more carbon atoms and nonpolar oil or triglyceride. A blended O / W emulsion-type composition (Patent Document 1), 5-10% by weight of nitrocellulose, 3-8% by weight of 3-methylbutyl acetate or 3-7% by weight of isobutyl acetate, and acetone It is a kind of natural oil of perilla oil, sesame oil, sesame oil, olive oil, horse oil, hinoki oil, castor oil, dissolved in a mixture of 12-8% by weight and further added with 50-80% by weight of ethyl alcohol. It contains the above and dissolves so as to enhance the strength, flexibility and ODT effect of the film during film formation. Incorporated sexual hormone and formed a transparent or translucent film on the skin at the application site to seal the affected area and enhance the transdermal absorbability of the drug on the skin tissue Techniques for enhancing the transdermal absorbability of steroids, such as a film preparation (Patent Document 2) that forms a close membrane, have been proposed. However, bases such as oily components are limited, and there are problems such as usability because they are film preparations. Under such circumstances, it has been desired to develop an external preparation that is highly effective and excellent in usability without being bound by the base component.

  On the other hand, bioactive components (component (B)) of diphenhydramine hydrochloride and dipotassium glycyrrhizinate have an itching inhibitory action and an anti-inflammatory action, and are widely used as an active ingredient in antipruritic antiphlogistics of over-the-counter drugs (non-patent literature) 1, 2) are not known to have any effect on the transdermal absorbability and retention of steroids.

JP2009-114081 WO2008 / 050491

Encron cream EX package insert Mentholatum Freddie Medical Cream A

  The present invention has been made in view of the above circumstances, and is not restricted by a base component, and has a high transdermal absorbability of steroids and exhibits its effect sufficiently. It can be applied to a coating and has excellent usability. It aims at providing an external preparation composition.

Therefore, the present inventor, without being bound by the base component, as a result of earnestly examining a method excellent in usability that can be applied to a coating agent, which is highly effective in the transdermal absorption of steroids and exhibits its effect sufficiently.
As a skin external preparation, a kind of steroid ((A)) selected from clobetasone butyrate, alcrometasone propionate, betamethasone valerate, prednisolone valerate, betamethasone dipropionate, mometasone furanate, clobetasol propionate, diflorazone acetate Component) and the bioactive component (component (B)) of diphenhydramine hydrochloride and dipotassium glycyrrhizinate improve the transdermal absorbability of the steroid of component (A) and enhance the whitening effect. The present invention was completed based on the finding that it was sufficiently exerted, applied to coating agents and excellent in usability.

  The present invention is a steroid ((A) component selected from clobetasone butyrate, alcromethasone propionate, betamethasone valerate, prednisolone valerate, betamethasone dipropionate, mometasone furanate, clobetasol propionate, and diflorazone acetate. And a specific bioactive component (component (B)) of diphenhydramine hydrochloride and dipotassium glycyrrhizinate to provide a skin external preparation composition with improved transdermal absorbability of the steroid of component (A) It is.

That is, the present invention
(A) One kind of steroid (B) diphenhydramine hydrochloride selected from clobetasone butyrate, alcrometasone propionate, betamethasone valerate, prednisolone valerate, betamethasone dipropionate, mometasone furanate, clobetasol propionate, diflorazone acetate And a skin external preparation composition comprising a physiologically active ingredient of dipotassium glycyrrhizinate.

  By containing the component (A) and the component (B), the transdermal absorbability of the component (A) is improved by the component (B), and the whitening effect can be enhanced.

  As an example of the component (A), clobetasone butyrate is 40 to 80 times that of clobetasone butyrate, 1 to 2% of diphenhydramine hydrochloride by weight concentration in the preparation, and 20 to 40 times that of component (A), in the weight concentration of the preparation. By adding 0.5 to 1% dipotassium glycyrrhizinate, the transdermal absorbability of the component (A) is improved, and the whitening effect of the component (A) can be enhanced by about 2.5 times.

  Corticosteroids have a delayed vasoconstrictive action, and as a result, the skin becomes pale and vitiligo occurs at a strength corresponding to the amount of drug transferred from the drug application site. Therefore, a high degree of correlation is observed between the whitening reaction and the clinical effect, and if the whitening effect is large, the clinical effect is considered to be large.

  ADVANTAGE OF THE INVENTION According to this invention, the skin external preparation composition which improved the transdermal absorbability of the steroid which is (A) component can be provided by containing (A) component and (B) component. Since the steroid absorbability is high, the amount of steroid added per preparation can be reduced, and the side effects of the steroid can be reduced.

Hereinafter, the present invention will be described in more detail. In the external preparation composition for skin of the present invention, the component (A) is clobetasone butyrate, alcrometasone propionate, betamethasone valerate, prednisolone valerate acetate, betamethasone dipropionate, furan A steroid selected from mometasone carboxylate, clobetasol propionate, and diflorazone acetate, preferably clobetasone butyrate, in an amount of 0.01 to 1.0% by weight in the preparation.
Preferably, the content is 0.01 to 0.3% by weight.

  (B) component used by this invention is diphenhydramine hydrochloride and dipotassium glycyrrhizinate, and these compounding quantities are the effective doses of each component, diphenhydramine hydrochloride (0.5-2.0 wt%), It is preferable to use dipotassium glycyrrhizinate (0.3 to 1.0% by weight).

  The external preparation for skin of the present invention contains, in addition to the above essential components, oily components, aqueous components, preservatives, pH adjusters, thickeners, stabilizers, etc., which are usually used for external preparations for skin. You may do it.

Examples of the oil component include cetostearyl alcohol, medium chain fatty acid triglyceride, polyoxyethylene hydrogenated castor oil, glycerin stearate, liquid paraffin, petrolatum, squalane, beeswax, palmitic acid and the like.
Examples of the aqueous component include water, propylene glycol, glycerin, polyethylene glycol, 1,3-butylene glycol and the like.

  Examples of the preservative include parabens.

  Examples of the pH adjuster include phosphoric acid, citric acid, sodium hydroxide, potassium hydroxide, and organic amine.

  Examples of the thickener include crystalline cellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxyvinyl polymer, acrylic acid / alkyl methacrylate copolymer, carmellose sodium, polyvinyl alcohol and the like.

  Examples of the stabilizer include tocopherol, BHT (dibutylhydroxytoluene), sodium edetate hydrate, and the like.

  Moreover, the dosage form of the external preparation for skin of this invention is arbitrary, and a lotion, cream, gel, ointment etc. are mentioned. However, it is not limited to the above dosage form. The skin external preparation of this invention can be prepared according to the manufacturing method of a normal skin external preparation (16th revision Japanese pharmacopoeia manual 2011, A126-A149).

  The external preparation for skin of the present invention can be used for the treatment of atopic dermatitis, eczema / dermatitis, psoriasis, prurigo group, palmoplantar pustulosis, cutaneous pruritus, erythema and erythroderma.

  Next, the effectiveness of the external preparation for skin of the present invention will be described with reference to experimental examples. EXAMPLES Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example.

As a test sample,
A cream containing 0.025% clobetasone butyrate, 2.0% diphenhydramine hydrochloride and 1.0% dipotassium glycyrrhizinate (Example 1),
0.025% clobetasone butyrate-containing cream (Comparative Example 1),
A cream containing 0.025% clobetasone butyrate and 2.0% diphenhydramine hydrochloride (Comparative Example 2),
A cream containing 0.025% clobetasone butyrate and 1.0% dipotassium glycyrrhizinate (Comparative Example 3),
A cream containing 0.020% clobetasone butyrate, 2.0% diphenhydramine hydrochloride and 1.0% dipotassium glycyrrhizinate (Example 2),
0.020% clobetasone butyrate-containing cream (Comparative Example 4),
0.05% clobetasone butyrate-containing cream (Comparative Example 5),
A cream containing 0.050% alcromethasone propionate, 2.0% diphenhydramine hydrochloride and 1.0% dipotassium glycyrrhizinate (Example 3),
0.05% cream of alcrometasone propionate (Comparative Example 6),
A cream containing 0.060% betamethasone valerate, 2.0% diphenhydramine hydrochloride and 1.0% dipotassium glycyrrhizinate (Example 4),
0.060% betamethasone valerate-containing cream (Comparative Example 7),
0.15% cream containing prednisolone acetate valerate, 2.0% diphenhydramine hydrochloride and 1.0% dipotassium glycyrrhizinate (Example 5),
0.150% cream containing prednisolone valerate (Comparative Example 8),
A cream containing 0.032% betamethasone dipropionate, 2.0% diphenhydramine hydrochloride and 1.0% dipotassium glycyrrhizinate (Example 6),
0.032% betamethasone dipropionate-containing cream (Comparative Example 9),
A cream containing 0.050% mometasone furancarboxylate, 2.0% diphenhydramine hydrochloride and 1.0% dipotassium glycyrrhizinate (Example 7),
0.050% furancarboxylic acid mometasone ester-containing cream (Comparative Example 10),
A cream containing 0.025% clobetasol propionate, 2.0% diphenhydramine hydrochloride and 1.0% dipotassium glycyrrhizinate (Example 8),
0.025% clobetasol propionate-containing cream (Comparative Example 11),
A cream containing 0.025% diflorazone acetate, 2.0% diphenhydramine hydrochloride and 1.0% dipotassium glycyrrhizinate (Example 9),
Skin with a vasoconstrictor action by steroids was tested by skin whitening test using patch test usually used for clinical pharmacological efficacy of topical skin preparation using 21 samples of cream containing 0.025% diflorazone acetate (Comparative Example 12) Using the intensity of the whitening reaction of each sample as an index, the steroid transdermal absorbability of each sample was compared.

  That is, about 20 mg of each sample was applied to a patch test tape (manufactured by Smart Practice Japan, USA) and applied to the forearm (arm below the elbow) of a healthy adult male. 5 hours later (Example 1, Comparative Examples 1 to 3) or 4 hours later (Examples 2 and 3, Comparative Examples 4 to 6) or 3 hours later (Examples 4 to 9 and Comparative Examples 7 to 12) Then, the patch test tape and the drug were removed, and the degree of paleness of the skin at the application site was determined by visual observation every 30 minutes and every hour after 1 to 10 hours. As the judgment criteria, a five-step evaluation shown in Table 1 was used.

ＡＵＥＣ（薬剤除去後の蒼白化の強度―時間曲線下面積）

AUEC (intensity of whitening after drug removal-area under the time curve)

  When the component (A) is clobetasone butyrate, as is clear from AUEC (after 0 to 10 hours) in Table 2, Example 1 containing the component (B) is equivalent to Comparative Example 1 not containing the component (B). Compared with it, the whitening effect was clearly stronger. Moreover, compared with the comparative examples 2 and 3 which each contain one component among (B) components, Example 1 shows a clearly strong whitening effect, and the comparative example 1 from AUEC (after 0 to 10 hours) of Example 1 is shown. The value obtained by subtracting AUEC (after 0 to 10 hours) is larger than the sum of the values obtained by subtracting AUEC (from 0 to 10 hours) of Comparative Example 1 from AUEC (from 0 to 10 hours) of Comparative Examples 2 and 3, respectively. From this, the synergistic effect by 2 types of (B) component is suggested.

  In addition, Example 2 (0.020% clobetasone butyrate) containing the component (B) showed a significantly stronger whitening effect than Comparative Example 4 (0.020% clobetasone butyrate) containing no component (B), Similarly, the whitening was similar to that of Comparative Example 5 (0.050% clobetasone butyrate) containing no component (B). This suggests that the whitening effect of the component (A) is enhanced by about 2.5 times by the component (B).

  In addition, (A) component is a steroid selected from alcrometasone propionate, betamethasone valerate, prednisolone valerate, betamethasone dipropionate, mometasone furanate, clobetasol propionate, diflorazone acetate and component (B) In Examples 3 to 9 containing no, the whitening effect was clearly stronger than Comparative Examples 6 to 12 containing no component (B).

  Thus, by blending diphenhydramine hydrochloride and dipotassium glycyrrhizinate physiologically active ingredient (component (B)) into the external preparation containing steroid that is component (A), the steroid of steroid that is component (A) is transcutaneously. Absorbability was improved and whitening effect was enhanced. It is a recognized fact that formulations with strong whitening have a high clinical effect.

Next, the present invention will be described more specifically with reference to prescription examples, but is not limited thereto.
[Formulation example] Cream agent clobetasone butyrate (component (A)) 0.025
Diphenhydramine hydrochloride (component (B)) 2.0
Dipotassium glycyrrhizinate (component (B)) 1.0
Oil phase cetostearyl alcohol 7.0
Medium chain fatty acid triglycerides 5.0
Polyoxyethylene hydrogenated castor oil 60 5.0
Glycerol monostearate 2.0
Methyl paraoxybenzoate 0.06
Propyl paraoxybenzoate 0.02
Aqueous phase Propylene glycol 5.0
Crystalline cellulose carmellose sodium 1.50
Sodium edetate hydrate 0.01
Phosphoric acid appropriate amount Purified water balance Total 100.0 (wt%)
The oil phase and the aqueous phase are heated to 80 ° C., mixed and emulsified, then cooled to 60 ° C., the water-soluble (B) component is added to adjust the pH, and then the (A) component is added to the cream. Was prepared.

Claims (5)

(A) One kind of steroid selected from clobetasone butyrate, alcromethasone propionate, betamethasone valerate, prednisolone valerate, betamethasone dipropionate, mometasone furanate, clobetasol propionate, diflorazone acetate (B) diphenhydramine hydrochloride And an external preparation composition for skin, comprising a physiologically active ingredient of dipotassium glycyrrhizinate. (A) One kind of steroid selected from clobetasone butyrate, alcromethasone propionate, betamethasone valerate, prednisolone valerate, betamethasone dipropionate, mometasone furanate, clobetasol propionate, diflorazone acetate (B) 1-2 The skin external preparation composition according to claim 1, comprising a physiologically active ingredient of% (weight) diphenhydramine hydrochloride and 0.5 to 1% (weight) dipotassium glycyrrhizinate. (A) Clobetasone butyrate (B) The physiologically active component of diphenhydramine hydrochloride and dipotassium glycyrrhizinate is contained, The skin external preparation composition of Claim 1 characterized by the above-mentioned. (A) Clobetasone butyrate (B) 1 to 2% (by weight) diphenhydramine hydrochloride and 0.5 to 1% (by weight) dipotassium glycyrrhizinate physiologically active components, The skin external preparation composition of any one of Claims 1. (A) Clobetasone butyrate (B) 1 to 2% (by weight) diphenhydramine hydrochloride and 0.5 to 1% (by weight) physiologically active components of dipotassium glycyrrhizinate Oily component, water-soluble component, surfactant, preservative, pH It is a cream agent characterized by containing a regulator, The skin external preparation composition of any one of Claims 1-4 characterized by the above-mentioned.