JP2017214343A - Therapeutic agent for acne-vulgaris - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide agents in which symptoms which are side effects appearing during application of an adapalene aqueous gel agent to the affected area of the face, such as skin discomfort, skin irritation feeling, skin exfoliation, erythema, or pruritus, are reduced.SOLUTION: The present invention provides a cream obtained by compounding 1 to 3 mass% of squalane to 0.1 mass% of adapalene, and further compounding 0.1 to 0.5 mass% of glyceryl monostearate, 0.5 to 6.5 mass% of vaseline, 0.2 to 0.4 mass% of carboxyvinyl polymer, and 38 to 42 mass% of concentrated glycerin, and by adjusting pH to 6.0 to 7.5; or a lotion obtained by compounding 4 to 8 mass% of squalane to 0.1 mass% of adapalene, and further compounding 0.5 to 1.0 mass% of glyceryl monostearate, 0.2 to 0.4 mass% of carboxyvinyl polymer, and 45 to 55 mass% of concentrated glycerin, and by adjusting pH to 6.0 to 7.5.SELECTED DRAWING: None

Description

Detailed Description of the Invention

  The present invention relates to a therapeutic agent for acne vulgaris.

  The present invention reduces the unpleasant side effects such as skin dryness, skin discomfort, skin exfoliation, erythema, and pruritus that appear during use of the application of adapalene aqueous gel to the affected area of the face by devising the prescription, The present invention relates to a therapeutic agent for acne vulgaris that enables more continuous administration of adapalene.

  Dapalene belongs to the third generation of synthetic retinoids, penetrates the sebaceous glands and hair follicles, selectively binds to retinoin receptors, and suppresses keratinization of epidermal keratinocytes, thereby making it the first acne rash. Has the effect of reducing the size of the. Used in Europe in 1994, in the United States in 1996, and in Japan in 2008, propylene glycol, methyl paraoxybenzoate, carboxyvinyl polymer, polyoxyethylene polyoxypropylene glycol, sodium edetate hydrate, hydroxylated A gel-like ointment formulation (differin gel 0.1%) based on sodium and purified water has been released and is currently in clinical use (Non-patent Document 1)

  Differin Gel 0.1% is a preparation that applies an appropriate amount to the affected area after face washing only once for acne vulgaris on the face, once a day, and is used before going to bed. Discontinue use if symptoms do not improve within 3 months of treatment. If it is no longer necessary to apply this drug due to symptom improvement, stop application and do not use it for a long time. In addition, when hypersensitivity or severe skin irritation is observed, precautions such as discontinuation of use are required. In addition, side effects such as skin dryness, skin discomfort, skin exfoliation, erythema, pruritus, etc. during use may cause the application site to become irritated, dry, the face peels off, and itching occurs. Symptoms such as coming may appear, and these side effects often occur within 2 weeks of the start of treatment. If disappearance or reduction is not observed during continuous use, appropriate measures such as withdrawal should be taken as necessary. In clinical settings, for example, skin pretreatment is performed before administration, such as applying moisturizing lotion to the skin in advance to maintain the moisturized state and then applying 0.1% Differin Gel.

  Numerous studies have been made on the contrivances related to the administration method of adapalene. For example, Patent Documents 1 to 29 shown below are listed as examples. In any of these inventions, almost all cases relate to a method for treating a disease and aim to promote percutaneous absorption of adapalene. No example has been found in which the formulation of the preparation has been devised for the purpose of reducing side effects such as skin dryness, skin discomfort, skin exfoliation, erythema, pruritus, etc. that are observed during the period of application and use of adapalene.

  Examples of research so far include, for example, an adapalene-containing external preparation composition (Patent Document 1), oligo, which has increased permeability to keratin and skin by coexisting 0.5 to 25 parts by mass of ascorbic acid or a salt thereof. An external preparation composition (Patent Document 2) in which the permeability of adapalene to the skin is improved by allowing sugar aldonic acids to coexist with adapalene, a drug comprising 0.3% by weight of adapalene relative to the total weight Composition (patent document 3), adapalene-containing liquid agent coexisting diphenhydramine and / or chlorpheniramine maleate, lotion agent, gel agent, aerosol agent, cream agent or aqueous ointment (patent document 4), coexisting taurine Adapalene-containing external preparation composition excellent in permeability to keratin and skin (Patent Document 5), ubidecarenone, dipotassium glycyrrhizinate Adapalene-containing external preparation composition excellent in permeability to keratin and skin coexisting with at least one of tocopherol acetate, camphor and menthol (Patent Document 6), excellent in permeability to keratin and skin coexisting with arbutin Adapalene-containing external preparation composition (Patent Document 7), adapalene-containing external preparation (Patent Document 8) excellent in permeability to keratin and skin in the presence of ibuprofen piconol or glycyrrhetinic acid, riboflavin, nicotinamide, pan Tenor, ascorbic acid or a salt thereof, and adapalene-containing topical composition excellent in permeability to skin containing at least one of biotin (Patent Document 9), penetration into keratin and skin in the presence of isopropylmethylphenol Adapalene-containing external preparation composition (Patent Document 10) with excellent properties and corners in which menthyl lactate coexists And adapalene-containing external preparation composition excellent in permeability to skin (Patent Document 11), adapalene-containing external preparation composition excellent in permeability to keratin and skin coexisting with lidocaine (Patent Document 12), diphenhydramine and Adapalene-containing external preparation composition excellent in permeability to keratin and skin in the presence of at least one chlorpheniramine maleate (Patent Document 13), 0.5% by mass of dapsone, 0.1% by mass of adapalene 1.5% by weight benzyl alcohol, 5-25% by weight PEG 400, or 0.03% by weight citric acid or 1-4% by weight hydroxyethyl cellulose, or 0.5-2% by weight Carbopol 980, or 5% It contains -15% by mass of dimethyl isosorbide, or 2-3% by mass of hydroxyethyl cellulose, and glycerin, and has a pH of 5. 5, a composition for the treatment of acne vulgaris that is one form selected from the group consisting of gels, emulsions, creams, liquids, pastes, lotions, nanoemulsions, microemulsions, inverse emulsions, and liposomal creams (patents) Reference 14), an attempt has been made to use adapalene and benzoyl peroxide in combination with the expectation of increasing efficacy and reducing toxicity (co-composition of adapalene and benzoyl peroxide for the treatment of acne) (Patent Documents 15 to 22), a novel depigmenting composition (Patent Document 23) in the form of a petrolatum-free and elastomer-free anhydrous composition containing a solubilized phenol derivative and a retinoid, Patent Document 23, propylene glycol, Contains a surfactant (poloxamer) and has a pH of about 4.7 to 5.3 An adapalene aqueous gel (Patent Document 24), a method of using adapalene in the maintenance therapy of acne (Patent Document 25), a composition of adapalene for treating skin diseases: adapalene 3 mg, carbomer 940 (BF Goodrich Carbopol-980) 11 mg, disodium edetate 1 mg, methylparaben 2 mg, poloxamer 124 2 mg, propylene glycol 40 mg, sodium hydroxide: gel required to obtain pH 5.0 +/− 0.3, sufficient amount to make 1 g of purified water Composition (Patent Document 26), Topical aqueous gel composition based on polyacrylic acid polymer for treating skin diseases of human subjects having a pH of 3-9 and less than 15,000 cP (Patent Document) 27), Acne treatment composition and method of use (Patent Document 28) A pharmaceutical composition for the treatment of a triethyl citrate adapalene was basic components (Patent Document 29) it has been reported.

Prescription drug package insert: Differing gel 0.1% JP 2013-199485 A JP 2011-140499 A JP 2011-032287 A JP 2010-095534 A JP 2008-273941 A JP 2008-255017 A JP 2008-25501 A JP 2008-184446 A JP 2008-184445 A JP 2008-184444 A JP 2008-184443 A JP 2008-184442 A JP 2008-137936 A Special table 2013-500984 gazette JP 2011-0379904 A Special table 2013-518920 gazette Special table 2011-510907 gazette Special table 2010-513427 gazette Special table 2010-513428 gazette Special table 2009-54279 gazette Japanese Patent No. 4889922 Special table 2011-504923 gazette Special table 2011-521933 gazette Special table 2011-504912 gazette Special table 2008-517031 gazette JP 2005-526063 A Japanese Patent No. 4988129 US Extract 2011/0021447 US Sho 2010/0069490

  It is presumed that the side effect that appears during application and use of adapalene aqueous gel to the affected area of the face is due to the loss of the moisturizing function of the epidermis by suppressing the keratinization of epidermal keratinocytes. From experience in clinical use, firstly skin dryness occurs during the application period, and as a result, symptoms such as skin discomfort, skin exfoliation, erythema or pruritus develop. From such a background, a device for avoiding skin dryness during application and use to the affected area of the face is necessary to reduce the occurrence of side effects, and a preparation having such performance is desired.

  Therefore, the present inventors made a lot of creams or lotions containing 0.1% by mass of adapalene while combining a water-soluble polymer having moisture retention and an emulsifying system, thereby feeling dryness during use ( A treatment for acne vulgaris that suppresses the appearance of side effects such as increasing the moisturizing feeling of the skin to prevent skin dryness (feeling dry and stretched) and skin discomfort (swelling and itching) We examined to obtain.

  As a result, squalane, glyceryl monostearate, petrolatum, carboxyvinyl polymer, and concentrated glycerin are used in combination with adapalene, and the pH is adjusted to 6.0 to 7.5 with hydrochloric acid or sodium hydroxide, thereby stabilizing the storage. It has been found that a preparation for treating acne vulgaris that has good properties and suppresses the occurrence of side effect symptoms upon application can be obtained.

  At this time, as a result of examining the addition amount of the squalane of the present invention, it was 1 to 3% by mass in the cream and 4 to 8% by mass in the lotion, and the addition amount of glyceryl monostearate was 0.1 to 0.5% by mass and 0.1 to 0.5% by mass in a lotion.

  The amount of petroleum jelly added in the cream or lotion of the present invention is 0.5 to 6.5% by mass.

  The addition amount of the carboxyvinyl polymer of the present invention is 0.2 to 0.4% by mass in the cream and 0.03 to 0.05% by mass in the lotion.

  The addition amount of the concentrated glycerin of this invention is 38-42 mass% in a cream, and is 45-55 mass% in a lotion.

  Moreover, as a preparation for treating acne vulgaris, it is necessary to avoid skin irritation caused by the base as much as possible. Therefore, the pH of the preparation is adjusted to the range of weakly acidic to near neutrality as much as possible, from 6.0 to 7.5, regardless of whether it is acidic or alkaline.

  Although the compounding quantity of the water in the cream of this invention is not specifically limited, It is 10 to 90 weight%.

  Moreover, glycerin or propylene glycol is mentioned as polyhydric alcohol used for preparation of the cream of this invention, The addition amount is decided depending on design of a prescription.

    As the water-soluble polymer used for preparing the therapeutic agent for acne vulgaris of the present invention, carboxyvinyl polymer is most suitable. The addition amount is 0.2 to 0.4% by mass for creams and 0.03 to 0.05% by mass for lotions.

  The amount of petroleum jelly added in the cream or lotion of the present invention is 0.5 to 6.5% by mass.

  The addition amount of the concentrated glycerin of the present invention is 38 to 42% by mass in the cream and 45 to 55% by mass in the lotion.

  As the surfactant used for the preparation of the therapeutic agent for acne vulgaris according to the present invention, glyceryl monostearate is optimal, but depending on the design of the formulation, a cationic surfactant, an anionic surfactant, a zwitterion An ionic surfactant and a nonionic surfactant may be used in combination with glyceryl monostearate.

  In this case, examples of the nonionic surfactant used in combination include polyoxyethylene alkyl ether, polyoxyethylene alkylphenol ether, sorbitan fatty acid ester, glycerin fatty acid ester, sucrose fatty acid ester, and the like. N-alkyl-N, N-dimethylammonium betaine, imidazoline type amphoteric surfactants, and the like. Examples of anionic surfactants include sodium alkylbenzene sulfonate, sodium dodecyl sulfate, coconut alcohol ethoxy sulfate, Examples of the cationic surfactant include lauryldimethylbenzylammonium chloride, cetyltrimethylammonium chloride, and tetrabutylammonium chloride. And the like. Further, the selection and blending amount of these surfactants are determined depending on the formulation design.

  The oil used in the preparation of the therapeutic agent for acne vulgaris according to the present invention is not limited to those shown in the examples, and hydrocarbons, fats and oils, waxes, fatty acids, higher alcohols, and ester oils depending on the formulation design. Etc., and can be appropriately combined and blended without any particular limitation. In this case, hydrocarbons include liquid paraffin, squalane, synthetic squalane, white petrolatum, ceresin wax, solid paraffin, microcrystalline wax, etc., and fats and oils include olive oil, soybean oil, molasses, etc. Are beeswax, lanolin, etc., fatty acids are stearic acid, oleic acid, etc., higher alcohols are cetanol, octyldodecanol, etc., and esters are cetyl lactate, isopropyl myristate, etc. These addition amounts are determined depending on the formulation design.

  Although the compounding quantity of the water in the cream of this invention is not specifically limited, It is 10 to 90 weight%.

Moreover, glycerin or propylene glycol is mentioned as a polyhydric alcohol used for preparation of the acne vulgaris treatment agent of this invention, The addition amount is determined depending on design of prescription.

As the water-soluble polymer used in the preparation of the acne vulgaris treatment agent of the present invention, carboxyvinyl polymer is optimal, but other water-soluble polymers may be used in combination, and the type and addition thereof. The amount is determined depending on the formulation design.

  In addition, the therapeutic agent for acne vulgaris according to the present invention may contain components such as preservatives, sequestering agents, ultraviolet absorbers, pH adjusters and the like as necessary.

BEST MODE FOR CARRYING OUT THE INVENTION

  EXAMPLES Hereinafter, although this invention is demonstrated in detail using an Example and a comparative example, this invention is not limited to these Examples.

Production procedure of cream First, an aqueous layer having the components, amount and pH shown in Table 1 is prepared, and an oil layer is prepared under heating at 75 to 80 ° C. Next, the water phase and the oil phase are put into a vacuum emulsifier and stirred and emulsified for about 1 hour under conditions of 3000 ± 500 rpm and about 0.05 MPa under heating at 75-80 ° C., and sieved with a 50 mesh sieve when heated. And cool to room temperature. Separately, add the heparin analog aqueous solution and concentrated glycerin prepared in the components and amounts shown in Table 1 at room temperature, stir at a low speed so that bubbles do not get mixed, and knead uniformly, and fill the cream tube .

Production Procedure of Lotion First, prepare an aqueous layer having the components, amount and pH shown in Table 1, and separately prepare an oil layer under heating at 75 to 80 ° C. Next, the water phase and the oil phase are put into a vacuum emulsifier and stirred and emulsified for about 1 hour under conditions of 3000 ± 500 rpm and about 0.05 MPa under heating at 75 to 80 ° C., and sieved with a 50 mesh sieve when heated. And cool to room temperature. Separately, the heparin analog aqueous solution prepared in the amount and amount shown in Table 1 and concentrated glycerin are added at room temperature, and the mixture is stirred and mixed uniformly at a low speed so that bubbles do not mix, and filled into a lotion container.
A lotion is prepared according to the same production procedure as in Example 1 with the following ingredients and amounts.

A lotion is prepared according to the same production procedure as in Example 4 with the following ingredients and amounts.

Test example

1. Application test The effect of the concentration of the heparin-like substance on side effects (such as dry skin, skin discomfort, skin exfoliation, erythema or pruritus) at the time of application was observed.
Test method:
1-1. sample:
Inventive Examples 1 to 5: Comparative Example 1: (Squaran in Example 1 is changed to 0.5% by mass), Comparative Example 2: (Squaran in Example 1 is changed to 0.3% by mass), Comparative Example 3: (Squalane in Example 1 was changed to 0.1% by mass), Comparative Example 4: (commercial aqueous gel preparation).
1-2. Test Procedure Healthy adults (17-33 years old), no cuts, scratches, eczema, skin on the inner side of the upper arm of 5 men and women, 1 before bedtime to avoid excessive UV exposure from sunlight or sunburn lamps, etc. Apply once a day for 3 months, and if you feel hypersensitivity or severe skin irritation, assuming that the application is discontinued. In addition, the presence or absence and degree of symptoms such as skin discomfort (applying tingling and itching) and increased moisturizing feeling of the skin were observed.
The score at this time is almost unchanged (0), slightly changed (+1), slightly changed (+2), changed (+3), and strongly changed compared with the case of no application (0). +4).
1-2. Test results

4). Effect of Vaseline Addition Amount on Feel during Application In Example 1, the amount of petrolatum added is 0.3, 0.5, 1.5, 3.3, 5.5, 6.5, 7, 5, 8 A cream containing 5% by mass was prepared, and the feeling during application was compared. As a result, the coating feeling is slightly weak at 0.3% by mass, the coating feeling is good at 0.5, 1.5, 3.3, 5.5, 6.5% by mass, and the sticky feeling at 8.5% by mass. Met.

5. Effect of addition amount of concentrated glycerin on feel during application In Example 1, creams with the addition amount of concentrated glycerin being 28, 34, 38, 40, 42, 44% by mass were prepared and the feeling during application was compared. . As a result, it was difficult to spread on the skin at 28 to 34% by mass, the spreadability was moderate at 38 and 42% by mass, and the viscosity was felt low at 44% by mass. Therefore, the amount of concentrated glycerin added in the present invention is 38 to 42% by mass.

6). Effect of addition amount of carboxyvinyl polymer on feel during coating Cream agent in which the addition amount of carboxyvinyl polymer was 0.1, 0.2, 0.3, 0.4, 0.5% by mass in Example 1 In Example 5, lotions having 0.02, 0.03, 0.05, 0.1, and 0.2% by mass of carboxyvinyl polymer added were prepared, and the feeling during application was compared. As a result, with 0.1% by mass of the cream, the skin coverage is low, and when 0.5% by mass it is difficult to spread, and when 0.2 to 0.4% by mass, the spreadability is moderate and the coverage is also good. It was. In the lotion agent, the skin coverage was low at 0.02% by mass of the carboxyvinyl polymer, and the spreadability was moderate and good coverage at 0.03 and 0.05% by mass. Therefore, the addition amount of the carboxyvinyl polymer in the present invention was 0.2 to 0.4 mass% for the cream agent and 0.03 to 0.05 mass% for the lotion agent.

7). Effect of pH on the stability of adapalene aqueous solution
Test method:
In contrast to the formulation and production method of Example 1 of the present invention, 5.0, 5.5, 6.0, 6.5, 7. Prepared by adjusting to 0, 7.5 and 8.0, each sample was applied to the skin on the inner side of the upper arm for 5 adults (17 to 33 years old), without cuts, scratches, eczema, To avoid excessive UV exposure from sunburn lamps, etc., apply once a day for 3 months before going to bed. If hypersensitivity or severe skin irritation is observed, application should be discontinued. In addition, the presence or absence and extent of skin discomfort during use (the application site was tingling or itching) was observed.
The score at this time is almost unchanged (0), slightly changed (+1), slightly changed (+2), changed (+3), and strongly changed compared with the case of no application (0). +4).

A preparation with reduced symptoms such as skin discomfort, skin irritation, skin exfoliation, erythema or pruritus, which are side effects appearing during application of adapalene aqueous gel to the affected area of the face is desired. The cream or lotion containing 0.1% by mass of the adapalene of the present invention found by the present inventors is a preparation that can reduce the expression of side effects of the aqueous gel and increase the versatility.

Claims (6)

  Cream comprising 0.1% by weight of adapalene and 1% by weight or more of squalane   0.1 to 5% by mass of glyceryl monostearate, 0.5 to 6.5% by mass of petrolatum, 0.2 to 0.4% by mass of carboxyvinyl polymer, and 38 to 42% by mass of concentrated glycerin are blended. Claim 1 cream comprising   A cream according to claims 1 and 2 having a pH of 6.0 to 7.5   A lotion comprising 0.1% by weight of adapalene and 4% by weight or more of squalane.   The lotion according to claim 4, comprising 0.1 to 5% by mass of glyceryl monostearate, 0.2 to 0.4% by mass of carboxyvinyl polymer, and 45 to 55% by mass of concentrated glycerin.   Lotion according to claims 4 and 5 having a pH of 6.0 to 7.5