KR101986177B1 - Pharmaceutical composition with improved bioavailability for acne treatment - Google Patents

Abstract

The present invention relates to a pharmaceutical composition comprising a retinoid and benzoyl peroxide, and more particularly to a pharmaceutical composition for the treatment of acne with improved bioavailability in the form of a cream gel comprising adapalene and dispersed benzoyl peroxide , The pharmaceutical composition according to the present invention is excellent in skin affinity due to the presence of pseudamide ceramides which are very similar to natural ceramides and contains a multilamellar emulsion which is very similar to the lamellar structure, A feeling of use and feel to the skin, and a skin protection film.
In addition, the pharmaceutical composition according to the present invention is non-toxic and has excellent therapeutic effect on acne lesions without inducing skin irritation.

Description

[0001] The present invention relates to a pharmaceutical composition for enhancing the bioavailability of a drug for treating acne,

The present invention relates to a pharmaceutical composition comprising a retinoid and benzoyl peroxide, and more particularly to a pharmaceutical composition for treating acne with improved bioavailability in the form of a cream gel comprising adapalene and dispersed benzoyl peroxide .

Acne is caused by a combination of various factors. The most important cause is the increase of sebaceous glands and the activation of sebaceous glands in puberty, resulting in abnormal keratinization due to excess sebum, resulting in keratosis or hyperkeratosis of keratinocyte. If sebaceous glands are not secreted naturally and they accumulate in the hair follicle along with keratin and cell debris, a characteristic lesion of acne will develop. Depending on its shape, it is divided into blackhead comedo and whitehead comedo. When bacteria such as Propionibacterium acnes are proliferated, inflammatory lesions are formed, and red or white acne Lesions such as papules, pustules, and nodules.

Therefore medications for the control of acne sebum finally, abandonment or more calibration process, propionic sludge tumefaciens (Propionibacterium acnes ), which can be useful drugs.

Among the acne remedies, topical topical agents have not been proven to be effective in suppressing sebum secretion, and comedolytic agents and antibacterial agents are generally used.

In addition, the components of the antiseborrhoeic and antiinfective active agents of acne remedies include benzoyl peroxide (especially Eclaran® by Pierre Fabre), tretinoin (in particular, Retacnyl® by Galderma) or Retinoids such as isotretinoin (Roaccutane (R) from Laboratoires Roche), or naphthoic acid derivatives. Naphthoic acid derivatives such as 6- [3- (1-adamantyl) -4-methoxyphenyl] -2-naphthoic acid, known as adapalene (product Differine® from Galderma), are considered to be as effective as tretinoin.

The topical or systemic treatments for acne vary, and in many cases they are combined and treated, so the number of ways to treat with a drug varies. In the case of a composite product, a complex product containing benzoyl peroxide and an antibiotic is used, and it is known that it exhibits an increased anti-acne efficacy as compared with a preparation containing benzoyl peroxide or an antibiotic alone. U.S. Pat. No. 4,497,794 discloses a combination preparation containing benzoyl peroxide and erythromycin for the treatment of acne, and the commonly prepared composition is the brand name benzamycin (Dermik Laboratories, Berwyn, Pa.). Benzoyl peroxide and lincomycin family antibiotics such as clindamycin are disclosed in U.S. Patent No. 5,767,098, U.S. Patent No. 5,733,886 and U.S. Patent No. 5,466,446, the composition of which is sold under the trademark Dermik Laboratories, The composition made by Stiefel is Stiefel Laboratories, Inc., Coral Gables, FL.

The combination of several topical agents (antibiotics, retinoids, peroxides, zinc) is used in skin diseases to enhance the efficacy of the active ingredient and reduce its toxicity (Cunliffe WJ, J. Dermatol. 2), S13-S14), and the combined application of various skin diseases products has a problem that the compliance of the patient with the medication can be lowered and the treatment period can be delayed.

Therefore, it is an indispensable part of product development to strive to obtain novel therapies which are effective for skin lesions and which can be applied singly and improve patient adherence compliance, as a stable composition providing good cosmetic properties.

On the other hand, in the case of a composition comprising both benzoyl peroxide and retinoids, it is difficult to be particularly sensitive to natural oxidation, visible light and ultraviolet rays, and because benzoyl peroxide is a strong oxidizing agent, the chemical compatibility of these compounds in the same formulation Has a number of stability problems.

As a related study, a study of the stability of complex agents including retinoids has been performed on compositions that combine a retinoid (tretinoin or adapalene) component with a benzoyl peroxide component (B. Martin et al., Br. J. Dermatol. ) 139, (suppl. 52), 8-11). According to this, the presence of the benzoyl peroxide-type formulation caused very rapid degradation of the oxidation-sensitive retinoid, 50% of the tretinoin was degraded within 2 hours, and 95% was degraded within 24 hours. The results demonstrate that benzoyl peroxide decomposes and gradually releases benzoic acid as the final product, degrading the oxidation-sensitive retinoid over time. However, it has been shown that any degradation of adapalene is not measured for 24 hours in a composition using adapalene as a retinoid-based drug.

U.S. Patent No. 4,497,794 (registered on Feb. 5, 1985) U.S. Patent No. 5,767,098 (registered on June 16, 1998) U.S. Patent No. 5,733,886 (registered on March 31, 1998) U.S. Patent No. 5,466,446 (registered on November 14, 1995)

Cunliffe W. J., J. Dermatol. Treat., 2000, 11 (suppl.2), S13-S14 B. Martin et al., Br. J. Dermatol. (1998) 139, (suppl. 52), 8-11

In order to solve the above problems, the present inventors have made efforts to produce a composition which is stable, less irritating and advantageous for skin penetration. Among the retinoid-based naphthoic acid derivatives, adapalene, benzoyl peroxide and a cream gel The present inventors have completed the present invention by confirming the physicochemical stability of the composition, the improvement of the skin permeability and the effect of decreasing the skin irritation through experiments.

Accordingly, an object of the present invention is to provide a pharmaceutical composition for treating acne with improved bioavailability.

In order to accomplish the above object, the present invention provides a pharmaceutical composition comprising adapalene, benzoyl peroxide and pseudoceramide,

And at least one selected from the group consisting of oils, aliphatic alcohols and fatty acid esters.

The pseudoceramide may be myristoyl / palmitoyl oxostearamide / arachamide MEA, dihydroxyisopropyl palmoylpalmamide, or a mixture thereof.

The oil may be at least one selected from the group consisting of liquid paraffin, squalane, castor oil and wheat germ oil.

The aliphatic alcohol is preferably selected from the group consisting of octyldodecanol, cetyl alcohol, decyl alcohol, lauryl alcohol, myristyl alcohol, stearyl alcohol, oleyl alcohol, linoleyl alcohol, linolenyl alcohol, cetearyl alcohol and behenyl alcohol And the like.

The fatty acid ester is selected from the group consisting of isopropyl myristate, sucrose fatty acid ester, sorbitan fatty acid ester, propylene glycol fatty acid ester, polyoxyethylene fatty acid ester, glycerin fatty acid ester, glycerin acetic acid fatty acid ester, glycerin lactic acid fatty acid ester, glycerin citric acid fatty acid ester, Fatty acid esters, glycerin diacetyl tartaric acid fatty acid esters, and polyglycerin fatty acid esters.

The pseudoceramide may include 10 to 200 parts by weight based on 100 parts by weight of adapalene.

The oil may include 50 to 500 parts by weight based on 100 parts by weight of adapalene.

The fatty acid ester may be 100 to 10,000 parts by weight based on 100 parts by weight of adapalene.

The aliphatic alcohol may be 100 to 10,000 parts by weight based on 100 parts by weight of the adalparene.

The pharmaceutical composition according to the present invention is excellent in skin affinity as it contains pseudamide ceramides which are very similar to natural ceramides and contains a multilamellar emulsion which is very similar to the lamellar structure of the epidermal keratinocyte lipid structure, The moisturizing power for the user, feeling of use, and skin usability such as formation of a skin protective film.

In addition, the pharmaceutical composition according to the present invention is non-toxic and has excellent therapeutic effect on acne lesions without inducing skin irritation.

FIG. 1 is a photograph showing the results of Experimental Example 2 in which the presence or absence of phase separation in the formulation according to the present invention and Comparative Example was observed.
Fig. 2 is a photograph showing the results of Experimental Example 7 comparing the particle diagrams of the formulation according to the present invention and the comparative example.
Fig. 3 shows the results of Experimental Example 8 comparing the skin permeation amount of benzoyl peroxide of the formulation of the present invention and the comparative example.
Fig. 4 shows the results of Experimental Example 8 comparing the permeation amount of the adapalain skin of the preparation according to the present invention and the comparative example.
FIG. 5 shows the composition of the test drug administration compartment according to Experimental Example 9 for confirming the skin irritation of the formulation according to the present invention and the comparative example.
6 is a photograph showing the results of Experimental Example 11 for confirming whether or not the lamellar structure of the formulation according to the present invention and the comparative example is a structure.

Hereinafter, the present invention will be described in detail. Prior to this, terms and words used in the present specification and claims should not be construed as limited to ordinary or dictionary terms, and the inventor should appropriately interpret the concepts of the terms appropriately It should be interpreted in accordance with the meaning and concept consistent with the technical idea of the present invention based on the principle that it can be defined. Therefore, the constitutions described in the embodiments described herein are merely the most preferred embodiments of the present invention, and are not intended to represent all of the technical ideas of the present invention. Therefore, various equivalents which can be substituted at the time of application It should be understood that variations can be made.

The present invention includes adapalene, benzoyl peroxide and pseudoceramide,

And at least one selected from the group consisting of oils, aliphatic alcohols and fatty acid esters.

The pharmaceutical composition of the present invention can be formed in the form of a cream gel, wherein the active ingredient is present in a dispersed form.

The term " dispersed form " according to the present invention means an active ingredient in the form of solid particles suspended in a given carrier.

Here, the reason for being present as an active ingredient in the form of a solid particle is to exclude an environment in which a hydration reaction, which is the most unstable cause in the formulation using water, can sufficiently take place. If the active ingredient is present in a dissolved state, the hydration reaction and the oxidation reaction are accelerated due to the state in which the molecular structure can have a loose reactivity, so that the active ingredient is maintained in a solid state to improve the stability. This prevents the generation of harmful impurities and reduces the production of toxic substances harmful to the human body, so that it can be manufactured as safe medicines.

Preferably, at least 80% of the particles have a diameter of less than 25 占 퐉, at least 99% of the particles may have a diameter of less than 100 占 퐉, more preferably at least 90% of the particles have a diameter Diameters less than 25 microns, and more than 99% of the particles may be less than 100 microns in diameter.

The pharmaceutical composition contains pseudoceramide, which is a substance having similar structure and potency to natural ceramide, which is a lipid component of dermal keratocyte, and thus has an excellent skin-affinity.

The pseudoceramide may be myristoyl / palmitoyl oxostearamide / arachamide MEA, dihydroxyisopropyl palmoylpalmamide, or a mixture thereof.

The oil may be at least one selected from the group consisting of liquid paraffin, squalane, castor oil and wheat germ oil.

The liquid paraffin is also referred to as liquid paraffin, petrolatum oil, and white oil, and refers to a relatively hard lubricant distillate. It is known to be used as a lubricant for a cosmetic raw material, a precision machine, a refrigerator, and a sulfuric acid pump bearing.

It can be obtained by re-distilling oil fractions with a high boiling point (distillate: 330 ~ 390 ℃) and filtering and separating the residue after washing and discoloring. It is soluble in ether, chloroform, carbon disulfide, It has a property that it does not dissolve in alcohol and the like.

The aliphatic alcohol is preferably selected from the group consisting of octyldodecanol, cetyl alcohol, decyl alcohol, lauryl alcohol, myristyl alcohol, stearyl alcohol, oleyl alcohol, linoleyl alcohol, linolenyl alcohol, cetearyl alcohol and behenyl alcohol , And preferably at least one of octyldodecanol, myristyl alcohol, cetyl alcohol, and decyl alcohol.

The fatty acid ester is selected from the group consisting of isopropyl myristate, sucrose fatty acid ester, sorbitan fatty acid ester, propylene glycol fatty acid ester, polyoxyethylene fatty acid ester, glycerin fatty acid ester, glycerin acetic acid fatty acid ester, glycerin lactic acid fatty acid ester, glycerin citric acid fatty acid ester, Fatty acid esters, glycerin diacetyl tartaric acid fatty acid esters and polyglycerin fatty acid esters, and preferably at least one of isopropyl myristate, propylene glycol fatty acid esters and glycerin fatty acid esters.

The pseudoceramide may include 10 to 200 parts by weight based on 100 parts by weight of adapalene.

More specifically, the pseudoceramide may include 10 to 200 parts by weight, preferably 20 to 100 parts by weight, more preferably 30 to 80 parts by weight, based on 100 parts by weight of adapalene .

If the pseudoceramide is contained in an amount of less than 10 parts by weight based on 100 parts by weight of adapalene, the skin affinity may be decreased, and if it exceeds 200 parts by weight, the total weight of the composition may be unnecessarily increased.

The oil may include 50 to 500 parts by weight based on 100 parts by weight of adapalene.

More specifically, the oil may include 50 to 500 parts by weight, preferably 100 to 400 parts by weight, more preferably 150 to 350 parts by weight, based on 100 parts by weight of adapalene. have.

The fatty acid ester may be 100 to 10,000 parts by weight based on 100 parts by weight of adapalene.

More specifically, the fatty acid ester may include 100 to 10,000 parts by weight, and preferably 100 to 1,000 parts by weight, based on 100 parts by weight of the adalparene.

The aliphatic alcohol may be 100 to 10,000 parts by weight based on 100 parts by weight of the adalparene.

More specifically, the aliphatic alcohol may include 100 to 10,000 parts by weight, and preferably 100 to 2,000 parts by weight, based on 100 parts by weight of adapalene.

If one or more of the above oils, fatty acid esters and aliphatic alcohols are included in excess of the respective ranges described above, stable emulsion formulations are not produced and excessive drug penetration can lead to adverse drug reactions. In addition, when the amount of each component is less than the above-described ranges, the amount of the oil phase corresponding to the amount of the water-soluble medium does not correspond to the amount of the emulsion.

The pharmaceutical composition may comprise a surfactant or an auxiliary surfactant.

The surfactant or co-surfactant may be used to form a stable emulsion by controlling the interfacial tension between the water-soluble medium and the water-insoluble medium. The surfactant or the co-surfactant may be contained in an amount of 30 to 80 parts by weight based on 100 parts by weight of the adapalene.

If the surfactant or co-surfactant is contained in an amount exceeding 80 parts by weight, it may cause irritation to the skin due to toxicity and may cause an excessive amount of the drug to penetrate into the skin tissue, resulting in adverse reaction of the drug. In addition, when the amount is less than 30 parts by weight, an emulsion formulation can not be formed.

The surfactant or cosurfactant is not particularly limited, but it may be at least one selected from the group consisting of sodium docusate, glyceryl monooleate, polyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester (polysorbate = Tween), sodium lauryl sulfate, sorbic acid , Sorbitan fatty acid esters, polypolysglyceryl-10, dipalmitate, polyglyceryl-10 distearate, polyglyceryl-10 stearate, polyglyceryl-10 oleate, sorbitan palmitate, sorbitan stearate But may be any one or more selected from the group consisting of sorbitan isostearate, sorbitol oleate, glyceryl stearate, glyceryl oleate, hydrogenated lecithin and hydrogenated palm glyceride.

The pharmaceutical composition contains a lamellar emulsion, which is very similar to the lamellar structure of the epidermal keratocyte, and exhibits improved skin usability such as safety, skin moisturizing effect, and skin barrier formation.

The pharmaceutical composition may be used for prevention or treatment of skin lesions associated with keratinization diseases related to cell differentiation and proliferation.

In particular, it is possible to use secondary acne like acne, acne vulgaris, acne vulgaris, acne vulgaris acne, crystalline cystic acne, polymorphic acne, strawberry acne, acne acne, senile acne or sunburn acne, drug properties acne or occupational acne Prevention or treatment.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .

EXAMPLES 1 TO 3 Gel compositions comprising adapalene, benzoyl peroxide, propylene glycol, light liquid paraffin, octyldodecanol and isopropyl myristate

Purified water, sodium edetate hydrate, docusate sodium, carbomer 940 is swollen at 80 캜 (solution 1). Propylene glycol, adapalene and benzoyl peroxide are dispersed for 30 minutes (solution 2). Myristoyl palmitoyloxostearamide arachamide miei, hard liquid paraffin, octyldodecanol, isopropyl myristate, and butylenehydroxytoluene are stirred for 30 minutes (solution 3). Solution 1 is slowly added to Solution 3, and the solution is cooled to 50 ° C or less. Solution 2 and sodium hydroxide are added. After stirring for 10 minutes, the solution is packed in a tube.

Ingredients (g) Example 1 Example 2 Example 3 Adapalene 1.0 1.0 1.0 Benzoyl peroxide 33.3 33.3 33.3 Propylene glycol 40.0 80.0 30.0 Sodium edetate hydrate 5.0 5.0 5.0 Docusate sodium 0.6 0.6 0.6 Carbomer 940 14.0 14.0 14.0 Sodium hydroxide 1.5 1.5 1.5 Myristyl palmitoyl oxostearamide, arachamide < RTI ID = 0.0 > 0.5 0.5 0.5 Hard liquid paraffin 22.0 31.5 15.0 Octyldodecanol 2.5 20.0 1.5 Isopropyl myristate 1.2 10.0 1.0 Butylenehydroxytoluene 0.2 0.2 0.2 Purified water 878.2 802.4 896.4

EXAMPLES 4-5: Gel compositions comprising adapalene, benzoyl peroxide, propylene glycol, octyldodecanol and isopropyl myristate

Purified water, sodium edetate hydrate, docusate sodium, carbomer 940 is swollen at 80 캜 (solution 1). Propylene glycol, adapalene and benzoyl peroxide are dispersed for 30 minutes (solution 2). Myristoyl palmitoyloxostearamide arachamide miechi, octyldodecanol, isopropyl myristate, and butylenehydroxytoluene are stirred for 30 minutes (solution 3). Solution 1 is slowly added to Solution 3, and the solution is cooled to 50 ° C or less. Solution 2 and sodium hydroxide are added. After stirring for 10 minutes, the solution is packed in a tube.

EXAMPLES 6 to 7 Gels comprising adapalene, benzoyl peroxide, propylene glycol, light liquid paraffin and isopropyl myristate

Purified water, sodium edetate hydrate, docusate sodium, carbomer 940 is swollen at 80 캜 (solution 1). Propylene glycol, adapalene and benzoyl peroxide are dispersed for 30 minutes (solution 2). Myristoyl palmitoyloxostearamide arachamide mie, hard liquid paraffin, isopropyl myristate and butylenehydroxytoluene are stirred for 30 minutes (solution 3). Solution 1 is slowly added to Solution 3, and the solution is cooled to 50 ° C or less. Solution 2 and sodium hydroxide are added. After stirring for 10 minutes, the solution is packed in a tube.

EXAMPLES 8 to 9: Gelatin containing adapalene, benzoyl peroxide, propylene glycol, light liquid paraffin and octyldodecanol

Purified water, sodium edetate hydrate, docusate sodium, carbomer 940 is swollen at 80 캜 (solution 1). Propylene glycol, adapalene and benzoyl peroxide are dispersed for 30 minutes (solution 2). Myristoyl palmitoyloxostearamide arachamide mie, hard liquid paraffin, octyldodecanol, and butylenehydroxytoluene are stirred for 30 minutes (solution 3). Solution 1 is slowly added to Solution 3, and the solution is cooled to 50 ° C or less. Solution 2 and sodium hydroxide are added. After stirring for 10 minutes, the solution is packed in a tube.

EXAMPLES 10-11: Gelatin containing adapalene, benzoyl peroxide, light liquid paraffin, octyldodecanol and isopropyl myristate

Purified water, sodium edetate hydrate, docusate sodium, carbomer 940 is swollen at 80 캜 (solution 1). Purified water, adalphalene and benzoyl peroxide are dispersed for 30 minutes (solution 2). Myristoyl palmitoyloxostearamide arachamide miei, hard liquid paraffin, octyldodecanol, isopropyl myristate, and butylenehydroxytoluene are stirred for 30 minutes (solution 3). Solution 1 is slowly added to Solution 3, and the solution is cooled to 50 ° C or less. Solution 2 and sodium hydroxide are added. After stirring for 10 minutes, the solution is packed in a tube.

Ingredients (g) Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Example 11 Adapalene 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 Benzoyl peroxide 33.3 33.3 33.3 33.3 33.3 33.3 33.3 33.3 Propylene glycol 80.0 30.0 80.0 30.0 80.0 30.0 - - Sodium edetate hydrate 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 Docusate sodium 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6 Carbomer 940 14.0 14.0 14.0 14.0 14.0 14.0 14.0 14.0 Sodium hydroxide 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 Myrtle palmy toil
Oxostearamide
Arakamide Miai 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Hard liquid paraffin - - 31.5 15.0 31.5 15.0 31.5 15.0 Octyldodecanol 20.0 1.5 - - 20.0 1.5 20.0 1.5 Isopropyl
Miri State 10.0 1.0 10.0 1.0 - - 10.0 1.0 Butylenehydroxytoluene 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 Purified water 833.9 911.4 822.4 897.9 812.4 897.4 882.4 926.4

Examples 12-13: Gelatin containing adapalene, benzoyl peroxide, propylene glycol and isopropyl myristate

Purified water, sodium edetate hydrate, docusate sodium, carbomer 940 is swollen at 80 캜 (solution 1). Propylene glycol, adapalene and benzoyl peroxide are dispersed for 30 minutes (solution 2). Myristoyl palmitoyloxostearamide arachamide m-is, isopropyl myristate, and butylene hydroxytoluene are stirred for 30 minutes (solution 3). Solution 1 is slowly added to Solution 3, and the solution is cooled to 50 ° C or less. Solution 2 and sodium hydroxide are added. After stirring for 10 minutes, the solution is packed in a tube.

EXAMPLES 14-15: Gels comprising adapalene, benzoyl peroxide, propylene glycol and octyldodecanol

Purified water, sodium edetate hydrate, docusate sodium, carbomer 940 is swollen at 80 캜 (solution 1). Propylene glycol, adapalene and benzoyl peroxide are dispersed for 30 minutes (solution 2). Myristoyl palmitoyloxostearamide arachamide miechi, octyldodecanol, and butylenehydroxytoluene are stirred for 30 minutes (solution 3). Solution 1 is slowly added to Solution 3, and the solution is cooled to 50 ° C or less. Solution 2 and sodium hydroxide are added. After stirring for 10 minutes, the solution is packed in a tube.

EXAMPLES 16-17: Gels comprising adapalene, benzoyl peroxide, propylene glycol and light liquid paraffin

Purified water, sodium edetate hydrate, docusate sodium, carbomer 940 is swollen at 80 캜 (solution 1). Propylene glycol, adapalene and benzoyl peroxide are dispersed for 30 minutes (solution 2). Myristoyl palmitoyloxostearamide arachamide mie, hard liquid paraffin, and butylenehydroxytoluene are stirred for 30 minutes (solution 3). Solution 1 is slowly added to Solution 3, and the solution is cooled to 50 ° C or less. Solution 2 and sodium hydroxide are added. After stirring for 10 minutes, the solution is packed in a tube.

EXAMPLES 18-19: A gel containing adapalene, benzoyl peroxide, octyldodecanol and isopropyl myristate

Purified water, sodium edetate hydrate, docusate sodium, carbomer 940 is swollen at 80 캜 (solution 1). Purified water, adalphalene and benzoyl peroxide are dispersed for 30 minutes (solution 2). Myristoyl palmitoyloxostearamide arachamide m-is, isopropyl myristate, and butylene hydroxytoluene are stirred for 30 minutes (solution 3). Solution 1 is slowly added to Solution 3, and the solution is cooled to 50 ° C or less. Solution 2 and sodium hydroxide are added. After stirring for 10 minutes, the solution is packed in a tube.

EXAMPLES 20-21 Gels comprising adapalene, benzoyl peroxide, light liquid paraffin and isopropyl myristate

Purified water, sodium edetate hydrate, docusate sodium, carbomer 940 is swollen at 80 캜 (solution 1). Purified water, adalphalene and benzoyl peroxide are dispersed for 30 minutes (solution 2). Myristoyl palmitoyloxostearamide arachamide mie, hard liquid paraffin, and butylenehydroxytoluene are stirred for 30 minutes (solution 3). Solution 1 is slowly added to Solution 3, and the solution is cooled to 50 ° C or less. Solution 2 and sodium hydroxide are added. After stirring for 10 minutes, the solution is packed in a tube.

EXAMPLES 22-23 Gels comprising adapalene, benzoyl peroxide, light liquid paraffin and octyldodecanol

Purified water, sodium edetate hydrate, docusate sodium, carbomer 940 is swollen at 80 캜 (solution 1). Purified water, adalphalene and benzoyl peroxide are dispersed for 30 minutes (solution 2). Myristoyl palmitoyloxostearamide arachamide mie, hard liquid paraffin, octyldodecanol, and butylenehydroxytoluene are stirred for 30 minutes (solution 3). Solution 1 is slowly added to Solution 3, and the solution is cooled to 50 ° C or less. Solution 2 and sodium hydroxide are added. After stirring for 10 minutes, the solution is packed in a tube.

Ingredients (g) Example 12 Example 13 Example 14 Example 15 Example 16 Example 17 Adapalene 1.0 1.0 1.0 1.0 1.0 1.0 Benzoyl peroxide 33.3 33.3 33.3 33.3 33.3 33.3 Propylene glycol 80.0 30.0 80.0 30.0 80.0 30.0 Sodium edetate hydrate 5.0 5.0 5.0 5.0 5.0 5.0 Docusate sodium 0.6 0.6 0.6 0.6 0.6 0.6 Carbomer 940 14.0 14.0 14.0 14.0 14.0 14.0 Sodium hydroxide 1.5 1.5 1.5 1.5 1.5 1.5 Myrtle palmy toil
Oxostearamide
Arakamide Miai 0.5 0.5 0.5 0.5 0.5 0.5 Hard liquid paraffin - - - - 31.5 15.0 Octyldodecanol - - 20.0 1.5 - - Isopropyl
Miri State 10.0 1.0 - - - - Butylenehydroxytoluene 0.2 0.2 0.2 0.2 0.2 0.2 Purified water 853.9 912.9 843.9 912.4 832.4 898.9 Ingredients (g) Example 18 Example 19 Example 20 Example 21 Example 22 Example 23 Adapalene 1.0 1.0 1.0 1.0 1.0 1.0 Benzoyl peroxide 33.3 33.3 33.3 33.3 33.3 33.3 Propylene glycol - - - - - - Sodium edetate hydrate 5.0 5.0 5.0 5.0 5.0 5.0 Docusate sodium 0.6 0.6 0.6 0.6 0.6 0.6 Carbomer 940 14.0 14.0 14.0 14.0 14.0 14.0 Sodium hydroxide 1.5 1.5 1.5 1.5 1.5 1.5 Myrtle palmy toil
Oxostearamide
Arakamide Miai 0.5 0.5 0.5 0.5 0.5 0.5 Hard liquid paraffin - - 31.5 15.0 31.5 15.0 Octyldodecanol 20.0 1.5 - - 20.0 1.5 Isopropyl
Miri State 10.0 1.0 10.0 1.0 - - Butylenehydroxytoluene 0.2 0.2 0.2 0.2 0.2 0.2 Purified water 913.9 941.4 902.4 927.9 892.4 927.4

Examples 24-25: Gelatin containing adapalene, benzoyl peroxide, propylene glycol

Purified water, sodium edetate hydrate, docusate sodium, carbomer 940 is swollen at 80 캜 (solution 1). Propylene glycol, adapalene and benzoyl peroxide are dispersed for 30 minutes (solution 2). Myristoyl palmitoyloxostearamide arachamide, and butylenehydroxytoluene are stirred for 30 minutes (solution 3). Solution 1 is slowly added to Solution 3, and the solution is cooled to 50 ° C or less. Solution 2 and sodium hydroxide are added. After stirring for 10 minutes, the solution is packed in a tube.

Examples 26-27: A gel containing adapalene, benzoyl peroxide, isopropyl myristate

Purified water, sodium edetate hydrate, docusate sodium, carbomer 940 is swollen at 80 캜 (solution 1). Purified water, adalphalene and benzoyl peroxide are dispersed for 30 minutes (solution 2). Myristoyl palmitoyloxostearamide arachamide m-is, isopropyl myristate, and butylene hydroxytoluene are stirred for 30 minutes (solution 3). Solution 1 is slowly added to Solution 3, and the solution is cooled to 50 ° C or less. Solution 2 and sodium hydroxide are added. After stirring for 10 minutes, the solution is packed in a tube.

Examples 28 to 29: Gelatin containing adapalene, benzoyl peroxide, octyldodecanol

Purified water, sodium edetate hydrate, docusate sodium, carbomer 940 is swollen at 80 캜 (solution 1). Purified water, adalphalene and benzoyl peroxide are dispersed for 30 minutes (solution 2). Myristoyl palmitoyloxostearamide arachamide miechi, octyldodecanol, and butylenehydroxytoluene are stirred for 30 minutes (solution 3). Solution 1 is slowly added to Solution 3, and the solution is cooled to 50 ° C or less. Solution 2 and sodium hydroxide are added. After stirring for 10 minutes, the solution is packed in a tube.

Examples 30 to 31: Gelatin containing adapalene, benzoyl peroxide, light liquid paraffin

Purified water, sodium edetate hydrate, docusate sodium, carbomer 940 is swollen at 80 캜 (solution 1). Purified water, adalphalene and benzoyl peroxide are dispersed for 30 minutes (solution 2). Myristoyl palmitoyloxostearamide arachamide, and butylenehydroxytoluene are stirred for 30 minutes (solution 3). Solution 1 is slowly added to Solution 3, and the solution is cooled to 50 ° C or less. Solution 2 and sodium hydroxide are added. After stirring for 10 minutes, the solution is packed in a tube.

Ingredients (g) Example 24 Example 25 Example 26 Example 27 Example 28 Example 29 Example 30 Example 31 Adapalene 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 Benzoyl peroxide 33.3 33.3 33.3 33.3 33.3 33.3 33.3 33.3 Propylene glycol 80.0 30.0 - - - - - - Sodium edetate hydrate 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 Docusate sodium 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6 Carbomer 940 14.0 14.0 14.0 14.0 14.0 14.0 14.0 14.0 Sodium hydroxide 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 Myrtle palmy toil
Oxostearamide
Arakamide Miai 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Hard liquid paraffin - - - - - - 31.5 15.0 Octyldodecanol - - - - 20.0 1.5 - - Isopropyl
Miri State - - 10.0 1.2 - - - - Butylenehydroxytoluene 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 Purified water 863.9 913.9 933.9 942.9 923.9 942.4 912.4 928.9

Comparative Example 1: Gelatin containing adapalene, benzoyl peroxide, glycerin and purified water

Purified water, Cymel gel 600PHA, and docusate sodium are swollen at 80 캜 (solution 1). 1 g of glycerin, adalphalene and 33.3 g of benzoyl peroxide (25 g in the form of benzoyl peroxide) are dispersed for 30 minutes (solution 2). Solution 2 is slowly added to solution 1, cooled to 50 ° C or lower, and then packed in a tube.

Comparative Example 2: Gelatin containing adapalene, benzoyl peroxide, propylene glycol and purified water

Purified water, Cymel gel 600PHA, and docusate sodium are swollen at 80 캜 (solution 1). 1 g of propylene glycol, adarenaline, and 33.3 g of benzoyl peroxide (25 g in the form of benzoyl peroxide) are dispersed for 30 minutes (solution 2). Solution 2 is slowly added to solution 1, cooled to 50 ° C or lower, and then packed in a tube.

Comparative Example 3: A gel containing adapalene, benzoyl peroxide, glycerin and poloxamer 124

Purified water, Cymel gel 600PHA, docusate sodium, and Poloxamer 124 are swollen at 80 캜 (solution 1). 1 g of glycerin, adalphalene and 33.3 g of benzoyl peroxide (25 g in the form of benzoyl peroxide) are dispersed for 30 minutes (solution 2). Solution 2 is slowly added to solution 1, cooled to 50 ° C or lower, and then packed in a tube.

Comparative Example 4: Gelatin containing adapalene, benzoyl peroxide, propylene glycol and poloxamer 124

Purified water, Cymel gel 600PHA, docusate sodium, and Poloxamer 124 are swollen at 80 캜 (solution 1). 1 g of propylene glycol, adarenaline, and 33.3 g of benzoyl peroxide (25 g in the form of benzoyl peroxide) are dispersed for 30 minutes (solution 2). Solution 2 is slowly added to solution 1, cooled to 50 ° C or lower, and then packed in a tube.

Comparative Example 5: Gelatin containing adapalene, benzoyl peroxide, glycerin, propylene glycol and poloxamer 124

Purified water, Cymel gel 600PHA, docusate sodium, and Poloxamer 124 are swollen at 80 캜 (solution 1). 1 g of propylene glycol, glycerin, adalphalene and 33.3 g of benzoyl peroxide (25 g in the form of benzoyl peroxide) are dispersed for 30 minutes (solution 2). Solution 2 is slowly added to solution 1, cooled to 50 ° C or lower, and then packed in a tube.

Ingredients (g) Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Adapalene One One One One One Benzoyl peroxide 33.3 33.3 33.3 33.3 33.3 glycerin 80 - 80 - 40 Propylene glycol - 80 - 80 40 Poloxamer 124 - - 2 2 2 Simeulgel 600PHA 4 4 4 4 4 Docusate sodium 0.5 0.5 0.5 0.5 0.5 Purified water 881.2 881.2 879.2 879.2 879.2

Comparative Example 6: A commercially available E product (Gelled)

Experimental Example 1: Preparation Interaction Test

Interaction tests were conducted to confirm the incompatibility of the main ingredients adapalene, benzoyl peroxide and various excipients used in the formulation. Each of the excipients and the main components were mixed at a ratio of 50:50, and the accelerated test was conducted at 40 ° C. and 75% RH. The control was also conducted under the same conditions and the absorption spectrum of near infrared was analyzed.

Experimental Example 2: Phase separation

The formulations prepared in the above Examples and Comparative Examples were placed in a container and stored at 40 DEG C and 70% RH for 1 week to observe the phase separation of the preparation. The results are shown in Table 6 and FIG.

Name of sample Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Phase separation - - - - - - - - - - Name of sample Example 11 Example 12 Example 13 Example 14 Example 15 Example 16 Example 17 Example 18 Example 19 Example 20 Phase separation - - - - - - - - - - Name of sample Example 21 Example 22 Example 23 Example 24 Example 25 Example 26 Example 27 Example 28 Example 29 Example 30 Phase separation - - - - - - - - - - Name of sample Example 31 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Phase separation - + + + + + + -: No phase separation
+: With phase separation

As shown in Table 6 and FIG. 1, the phase separation phenomenon was observed in the preparations of Comparative Examples 1 to 4, and it was confirmed that the phase separation did not appear at all in the formulation of the Example.

Experimental Example 3: Deposition

The preparations prepared in the above Examples and Comparative Examples were placed in a container and stored at 25 DEG C and 60% RH for 1 week to examine the presence or absence of precipitation of the main components. 7 and Table 8, respectively.

Adapalene content (%) Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Early Prize 101.3 101.2 99.5 99.9 100.0 99.7 99.3 100.3 99.1 99.3 medium 101.1 99.7 100.4 100.7 100.7 100.2 100.0 99.9 100.4 101.1 Ha 100.5 101.0 99.0 101.8 100.6 101.9 99.3 101.4 101.9 100.2 Deviation(%) 0.4 0.8 0.7 1.0 0.4 1.2 0.4 0.8 1.4 0.9 One
week
after Prize 101.5 101.5 101.1 101.0 101.1 99.3 99.6 100.6 99.7 101.1 medium 99.8 100.6 101.8 100.2 99.6 100.1 100.7 101.2 100.0 100.6 Ha 101.9 99.1 100.4 100.3 101.3 100.4 99.0 99.1 99.8 101.7 Deviation(%) 1.1 1.2 0.7 0.4 0.9 0.6 0.9 1.1 0.2 0.6 Adapalene content (%) Example 11 Example 12 Example 13 Example 14 Example 15 Example 16 Example 17 Example 18 Example 19 Example 20 second
group Prize 100.1 99.2 99.6 99.0 100.2 101.4 101.4 99.4 100.7 100.1 medium 99.5 100.9 100.0 100.8 101.5 100.4 99.2 99.0 100.4 101.9 Ha 99.6 99.7 99.8 101.3 99.5 99.3 99.7 99.2 101.3 100.9 Deviation(%) 0.3 0.9 0.2 1.2 1.0 1.1 1.2 0.2 0.5 0.9 One
week
after Prize 101.9 100.4 101.0 99.0 99.0 99.9 101.0 99.1 101.0 100.4 medium 101.4 99.6 99.3 101.2 101.1 101.9 99.9 101.7 99.3 99.6 Ha 100.5 101.7 101.7 101.0 100.5 100.2 99.3 99.6 101.7 101.7 Deviation(%) 0.7 1.1 1.2 1.2 1.1 1.1 0.9 1.4 1.2 1.1 Adapalene content (%) Example 21 Example 22 Example 23 Example 24 Example 25 Example 26 Example 27 Example 28 Example 29 Example 30 second
group Prize 100.3 101.3 100.5 101.2 100.9 101.3 101.7 101.6 101.2 101.2 medium 100.7 99.0 101.7 101.3 101.2 100.4 100.7 100.6 100.9 101.2 Ha 100.9 101.1 100.4 100.0 99.2 101.2 101.8 100.9 100.3 99.1 Deviation(%) 0.3 1.3 0.7 0.7 1.1 0.5 0.6 0.5 0.5 1.2 One
Later Prize 101.9 99.9 99.9 101.8 100.5 100.0 99.1 101.5 100.7 100.6 medium 100.5 100.8 101.7 100.1 100.2 101.7 99.1 101.3 101.6 99.8 Ha 100.3 101.5 101.0 99.6 100.6 99.7 101.1 100.6 100.6 101.7 Deviation(%) 0.9 0.8 0.9 1.2 0.2 1.1 1.2 0.5 0.6 1.0 Adapalene content (%) Example 31 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Early Prize 99.4 100.9 101.0 101.3 98.3 98.9 98.2 medium 101.4 99.6 98.6 100.3 98.9 99.3 102.1 Ha 101.0 98.6 99.8 100.8 99.8 101.3 101.7 Deviation(%) 1.1 1.2 1.2 0.5 0.8 1.3 2.1 One
Later Prize 102.6 101.4 97.1 98.7 96.7 98.5 99.0 medium 99.5 98.1 99.6 101.2 101.0 98.3 98.0 Ha 100.3 102.7 102.9 101.5 101.8 100.9 102.4 Deviation(%) 1.6 2.4 2.9 1.5 2.7 1.4 2.3

Peroxide
Benzoyl
content(%) Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Early Prize 100.9 101.3 100.9 101.1 100.2 101.8 99.3 101.5 100.9 101.0 medium 99.2 100.1 101.2 101.0 100.4 99.4 101.4 101.6 100.8 100.3 Ha 100.9 101.3 100.3 101.8 99.4 99.2 99.5 99.2 100.9 100.4 Deviation(%) 1.0 0.7 0.5 0.4 0.5 1.4 1.2 1.4 0.1 0.4 One
week
after Prize 100.7 99.0 99.7 99.1 99.7 99.2 99.1 101.9 101.6 101.0 medium 99.3 100.1 100.5 100.6 101.9 99.0 99.3 101.9 101.6 99.9 Ha 99.2 100.8 101.4 100.9 99.5 99.9 101.5 99.1 100.6 100.8 Deviation(%) 0.8 0.9 0.9 1.0 1.3 0.5 1.3 1.6 0.6 0.6 Peroxide
Benzoyl
content(%) Example 11 Example 12 Example 13 Example 14 Example 15 Example 16 Example 17 Example 18 Example 19 Example 20 second
group Prize 100.4 99.9 100.5 100.5 99.7 99.5 100.7 100.7 101.1 99.6 medium 101.8 99.3 99.8 101.9 100.5 99.6 99.9 100.2 100.2 99.4 Ha 99.7 100.9 100.5 101.7 99.6 100.0 101.4 99.7 101.8 100.4 Deviation(%) 1.1 0.8 0.4 0.8 0.5 0.3 0.8 0.5 0.8 0.5 One
week
after Prize 101.2 101.9 100.8 100.3 100.7 100.7 101.6 100.9 101.6 101.9 medium 99.1 100.8 99.6 99.9 99.8 99.1 101.9 100.9 101.7 99.2 Ha 101.5 101.4 99.8 101.6 100.3 99.0 101.8 99.8 99.8 101.0 Deviation(%) 1.3 0.6 0.6 0.9 0.5 1.0 0.2 0.6 1.1 1.4 Peroxide
Benzoyl
content(%) Example 21 Example 22 Example 23 Example 24 Example 25 Example 26 Example 27 Example 28 Example 29 Example 30 second
group Prize 100.7 99.6 100.7 100.0 99.0 100.1 101.7 100.2 99.4 101.7 medium 101.6 100.2 101.3 99.8 101.3 100.7 99.5 99.7 101.4 100.6 Ha 100.1 99.2 100.9 101.2 101.6 101.6 99.7 100.3 101.3 101.7 Deviation(%) 0.8 0.5 0.3 0.8 1.4 0.8 1.2 0.3 1.1 0.6 One
Later Prize 99.0 100.5 100.8 100.0 101.2 101.6 101.3 100.5 99.3 100.2 medium 99.8 99.8 100.2 100.3 100.8 101.9 100.4 101.8 99.8 99.6 Ha 99.3 100.6 100.0 101.1 100.7 100.6 99.2 99.7 99.2 99.0 Deviation(%) 0.4 0.4 0.4 0.6 0.3 0.7 1.1 1.1 0.3 0.6 Peroxide
Benzoyl
content(%) Example 31 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Early Prize 100.8 100.0 99.7 98.4 101.0 98.5 98.0 medium 100.6 99.2 101.3 99.6 98.9 100.9 100.7 Ha 99.2 98.4 101.9 98.7 98.7 100.6 99.9 Deviation(%) 0.9 0.8 1.1 0.6 1.3 1.3 1.4 One
Later Prize 99.1 98.0 97.7 98.2 98.9 97.1 97.9 medium 99.8 99.0 99.6 99.5 102.7 98.9 100.2 Ha 101.8 102.1 101.9 101.9 99.2 102.8 101.2 Deviation(%) 1.4 2.1 2.1 1.9 2.1 2.9 1.7

As shown in Tables 7 and 8, the formulation of the present invention can prevent sedimentation of adapalene and benzoyl peroxide, and thus the uniformity of contents can be expected.

Experimental Example 4: Evaluation of room temperature versus acceleration stability

In order to evaluate the physicochemical stability of the gel, the following accelerating content stability test was carried out.

The accelerated content stability test was carried out by placing the preparations of the above Examples and Comparative Examples in a container at the time of an accelerated stability test and then measuring the change in content after 2 months at 40 DEG C and 75% RH. At this time, about 1 of the contents was placed in a suitable container having a capacity of 20 to 40 mL, and the mixture was thoroughly shaken to prepare a sample.

Adapalene and benzoyl peroxide were dispersed from the preparation in tetrahydrofuran, and then extracted as a mobile phase and quantified by HPLC.

Adapalene content (%) Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Early 100.2 99.9 99.4 99.6 100.1 100.3 100.6 100.7 99.4 100.6 Two months later 99 100.4 99.3 99.6 100.9 99.4 99.2 100.9 100.8 99.3 Adapalene content (%) Example 11 Example 12 Example 13 Example 14 Example 15 Example 16 Example 17 Example 18 Example 19 Example 20 Early 99.2 100.2 99.7 99.3 99.5 100.1 100.5 100.7 99 100.2 Two months later 99.4 99.5 100.1 99.6 99.2 99.2 100.2 99.3 99.4 100.3 Adapalene content (%) Example 21 Example 22 Example 23 Example 24 Example 25 Example 26 Example 27 Example 28 Example 29 Example 30 Early 100.6 100.8 100.4 100 99.2 99.4 100.8 99.1 99.9 100.9 Two months later 99.2 99.4 99.9 99.4 99.6 99.7 99.8 100.2 99.4 100.1 Adapalene content (%) Example 31 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Early 99.8 99.8 98.2 98.5 98.9 99.2 99.9 Two months later 99.1 97.2 96.4 97.1 97.2 98.1 97.9

Peroxide
Benzoyl
content(%) Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Early 100.3 99.1 100.5 99.5 100.1 100.8 100.2 100.2 99.0 99.9 Two months later 100.2 100.0 100.6 99.2 99.6 100.0 99.9 100.4 99.0 99.3 Peroxide
Benzoyl
content(%) Example 11 Example 12 Example 13 Example 14 Example 15 Example 16 Example 17 Example 18 Example 19 Example 20 Early 99.1 100.8 99.7 100.0 100.2 99.4 99.2 100.6 100.7 100.3 Two months later 99.7 99.4 99.0 100.9 99.0 100.3 99.5 99.8 99.3 99.2 Peroxide
Benzoyl
content(%) Example 21 Example 22 Example 23 Example 24 Example 25 Example 26 Example 27 Example 28 Example 29 Example 30 Early 100.9 99.0 100.4 99.6 99.2 100.6 100.8 100.1 100.8 100.1 Two months later 99.1 99.6 100.9 99.9 100.6 99.3 100.6 100.5 99.3 100.9 Peroxide
Benzoyl
content(%) Example 31 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Early 100.2 99.1 98.1 98.9 98.1 98.9 99.4 Two months later 100.4 97.0 97.1 96.4 96.9 97.4 98.0

As shown in Table 9 and Table 10, the preparation of the present invention can prevent the lowering of the content due to the interaction of adapalene and benzoyl peroxide, and can expect a sufficient effective effect of the active ingredient.

Experimental Example 5: Viscous Comparative Test

The preparation prepared in the above Examples and Comparative Examples was placed in a container and a viscosity comparison test of the samples stored at 40 ° C. and 75% RH for one week was carried out. The results are shown in Table 11 below.

Viscosity
(25 DEG C / cP) Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Early
(cloth) 901 1129 937 957 944 971 956 901 923 969 After 1 week
(cloth) 898 1044 915 943 928 954 899 874 914 953 Viscosity
(25 DEG C / cP) Example 11 Example 12 Example 13 Example 14 Example 15 Example 16 Example 17 Example 18 Example 19 Example 20 Early
(cloth) 891 858 904 897 914 903 881 849 937 919 After 1 week
(cloth) 893 841 897 869 907 883 895 821 899 901 Viscosity
(25 DEG C / cP) Example 21 Example 22 Example 23 Example 24 Example 25 Example 26 Example 27 Example 28 Example 29 Example 30 Early
(cloth) 909 913 941 963 947 936 987 974 912 898 After 1 week
(cloth) 911 896 946 958 916 943 961 961 926 903 Viscosity
(25 DEG C / cP) Example 31 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Early
(cloth) 876 675 711 744 698 754 773 After 1 week
(cloth) 861 693 704 723 655 749 754

Experimental Example 6: Comparison of pH

The pH of the samples stored for 1 week at 25 ° C and 60% RH was measured and the results are shown in Table 12 below.

pH Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Early 4.5 4.5 4.6 4.7 4.5 4.5 4.5 4.5 4.6 4.5 Two months later 4.4 4.5 4.4 4.5 4.5 4.5 4.4 4.4 4.5 4.5 pH Example 11 Example 12 Example 13 Example 14 Example 15 Example 16 Example 17 Example 18 Example 19 Example 20 Early 4.5 4.5 4.5 4.4 4.5 4.5 4.5 4.5 4.6 4.5 Two months later 4.5 4.4 4.4 4.4 4.3 4.4 4.5 4.4 4.4 4.4 pH Example 21 Example 22 Example 23 Example 24 Example 25 Example 26 Example 27 Example 28 Example 29 Example 30 Early 4.5 4.6 4.5 4.5 4.5 4.5 4.6 4.5 4.4 4.5 Two months later 4.4 4.5 4.4 4.5 4.5 4.5 4.5 4.5 4.4 4.5 pH Example 31 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Early 4.5 4.1 4.3 4.0 4.3 4.2 4.2 Two months later 4.4 3.4 3.1 3.8 3.5 3.8 3.7

As shown in Table 12, the formulation of the present invention can maintain stability of adapalene and benzoyl peroxide at stable pH.

Experimental Example 7: Particle size comparison

The preparations prepared in the above Examples and Comparative Examples were placed in a slide glass, and the particle size of the sample was also subjected to a comparative test. The results are shown in Table 13 below.

Particle size Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 (탆) 78 80 88 83 82 77 85 82 84 86 Particle size Example 11 Example 12 Example 13 Example 14 Example 15 Example 16 Example 17 Example 18 Example 19 Example 20 (탆) 88 85 83 84 89 87 81 84 82 84 Particle size Example 21 Example 22 Example 23 Example 24 Example 25 Example 26 Example 27 Example 28 Example 29 Example 30 (탆) 85 84 88 82 84 83 83 89 90 83 Particle size Example 31 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 (탆) 80 115 108 111 107 109 113

As shown in Table 13 and FIG. 2, the formulation of the present invention can reduce the particle size of adapalene and benzoyl peroxide, and thus, favorable results in the sense of foreign body and coating can be expected.

Experimental Example 8: Comparison of skin permeation test

The drug permeation test of the pharmaceutical preparations of the comparative examples and the examples was carried out by the following test method to confirm how much drug permeates through HPLC. The results are shown in FIG. 3, FIG. 4 and Tables 13 and 14.

Experimental Method

 <Skin penetration test conditions>

  - Using Franz diffusion cell and mini pig skin

  - Recipient phase: PBS · Tetrahydrofurane (5.5)

  - Recipient volume: 12mL

  - Temperature: 32 ℃

  - 4 mL sampling, 2 mL filter

  - Sampling time: 12 hours, 24 hours

Peroxide
Benzoyl
Skin permeability
(ug / cm ²⁾ Example 1 Example 6 Example 10 Example 14 Example 18 Example 22 Example 26 Example 30 Comparative Example 1 Comparative Example 3 Comparative Example 6 12 hours 3.3 3.4 4.6 3.1 3.8 4.2 2.6 3.5 1.1 0.7 1.5 24 hours 7.6 6.2 6.4 7.3 6.4 6.4 7.3 5.1 1.8 2.6 3.2

Adapalene
Skin permeability
(ug / cm ²⁾ Example 1 Example 6 Example 10 Example 14 Example 18 Example 22 Example 26 Example 30 Comparative Example 1 Comparative Example 3 Comparative Example 6 12 hours 1.9 2.1 1.9 1.7 1.4 2.3 1.7 1.3 0.1 0.1 0.1 24 hours 5.0 4.4 3.8 4.1 4.1 3.2 3.6 3.1 1.7 1.5 1.2

Experimental Example 9: Animal Test (skin irritation test)

The drug skin irritation test of the preparations of the comparative examples and the examples was carried out by the following test method to determine how much skin irritation there was, and the results are shown in Tables 16 and 17 below.

Method of administration

(1) Routes of administration

Transdermal administration

(2) Reason for selection of route of administration

To evaluate the safety of the test substance by skin exposure, transdermal administration should be used.

(3) Composition of the administration compartment

 The site of administration is the two sites on the right and left sides, total of four sites (approximately 2.5 x 2.5 cm in one site) with the symmetry axis of the epigastric portion of the epilated rabbit. Two of them are designated as non-specific areas, and the other two areas are designated as non-specific areas. Using the 18G needle, the abrasion area was used to create a # -shaped abrasion that only damaged the epidermis and did not damage the dermis and did not bleed. The site of administration is shown in FIG.

(4) Administration method and administration frequency

 The test substances 1 and 2 and the control substance were uniformly applied to a 2.5 × 2.5 cm patch (PIP Co., Ltd., Japan) in 0.5 mL each using a 1 mL syringe, Respectively. Only one patch is applied to the untreated control area of the non-treatment area and the scratch area, respectively. The entire administration site was covered with gauze (DaeHan Medical Supply Co., Ltd., Republic of Korea), fixed with a medical transparent bandage (3M Tegaderm Transparent Dressing, Original Frame Style, 3M Co., Ltd., USA) With a soft cloth tape liner (width 10 cm, 3M Co., Ltd., Republic of Korea). Both sides are fixed again with paper tape (Masking Tape, DAESUN Com., Republic of Korea) and covered for 24 hours. After 24 hours, remove the patches and remove remaining residue with gauze and dry gauze moistened with warm water and appropriate solvent. Administration proceeds under light-shielding conditions.

(5) Judgment of skin reaction

After 24 hours (30 minutes after the removal of the test material), the change of the erythema of the applied local area was visually observed and scored according to the skin reaction standard

The skin reaction evaluation criteria were evaluated according to the degree of erythema according to Table 16, and the results are shown in Table 17.

reaction Degree No erythema 0 Very light erythema (barely visible to the naked eye) One A clear erythema 2 Some severe erythema 3 Severe erythema (blushing redness) and mild degree of scar formation (deep injury) 4

Degree of erythema Example 1 Example 6 Comparative Example 1 grade 2 3 3

Experimental Example 10: Animal test (intraocular stimulation test)

The drug mucosal irritation test of the pharmaceutical preparations of the comparative examples and the examples was carried out by the following test method to determine how much irritation there was, and the results are shown in Table 18 below.

Method of administration

(1) Routes of administration

Instillation

(2) Reason for selection of route of administration

In order to evaluate the safety of the test substance by internal exposure, it should be administered as an eye drop.

(3) Method and frequency of administration

- Biasian.

 Pull the eyelid (lower eyelid) away from the eyeballs to form a cup shape under the right eye of the rabbit. Do not apply 0.1 mL of the test substance stock to the conjunctival sac 1 time using a 1 mL syringe. Maintain the wound state for about 1 second to prevent the loss of the test material. The left eye should be in the untreated control.

- Face wash.

 In the same manner as in the case of Bissau's eye, 0.1 mL of the test substance solution was not spotted once in the conjunctival sac of the right eye. After about 30 seconds, the eye was stimulated with about 20 mL of physiological saline (Choongwae Pharma Corp., Republic of Korea) Washing at a rate that does not give. The left eye also performs the same cleansing as the right eye, and it is done in the cleansing contrast.

Degree of stimulation Example 1 result Irritant

Experimental Example 11: Identification of lamellar structure

The drugs of the preparations of the comparative examples and the examples were photographed with a polarizing microscope by the following experimental method to confirm whether or not the lamellar structure was present on the formulation. The results are shown in Table 19 and FIG.

Name of sample Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Phase separation + + + + + + + + + + Name of sample Example 11 Example 12 Example 13 Example 14 Example 15 Example 16 Example 17 Example 18 Example 19 Example 20 Phase separation + + + + + + + + + + Name of sample Example 21 Example 22 Example 23 Example 24 Example 25 Example 26 Example 27 Example 28 Example 29 Example 30 Phase separation + + + + + + + + + + Name of sample Example 31 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Phase separation + - - - - - - +: With lamellar structure
-: No lamellar structure

As shown in Table 19 and FIG. 6, it was confirmed that the lamellar structure did not appear in the preparations of Comparative Examples 1 to 6, and that the lamellar structure of the preparation of Example was exhibited.

Claims (9)

Adapalene, benzoyl peroxide and pseudoceramide,
Oils, aliphatic alcohols and fatty acid esters,
The pseudoceramide may be selected from the group consisting of myristoyl / palmitoyl oxostearamide / arachamide MEA, dihydroxyisopropyl palmoylpalmamide or a mixture thereof,
Wherein the pseudoceramide comprises 10 to 200 parts by weight per 100 parts by weight of adapalene.
delete The method according to claim 1,
Wherein the oil is at least one selected from the group consisting of liquid paraffin, squalane, castor oil and wheat germ oil.
The method according to claim 1,
The aliphatic alcohol is preferably selected from the group consisting of octyldodecanol, cetyl alcohol, decyl alcohol, lauryl alcohol, myristyl alcohol, stearyl alcohol, oleyl alcohol, linoleyl alcohol, linolenyl alcohol, cetearyl alcohol and behenyl alcohol And a pharmaceutically acceptable carrier.
The method according to claim 1,
The fatty acid ester is selected from the group consisting of isopropyl myristate, sucrose fatty acid ester, sorbitan fatty acid ester, propylene glycol fatty acid ester, polyoxyethylene fatty acid ester, glycerin fatty acid ester, glycerin acetic acid fatty acid ester, glycerin lactic acid fatty acid ester, glycerin citric acid fatty acid ester, A fatty acid ester, a glycerine diacetyl tartaric acid fatty acid ester, and a polyglycerin fatty acid ester.
delete The method according to claim 1,
Wherein the oil comprises 50 to 3,150 parts by weight of 100 parts by weight of adapalene.
The method according to claim 1,
Wherein the fatty acid ester comprises 100 to 10,000 parts by weight per 100 parts by weight of adapalene.
The method according to claim 1,
Wherein the aliphatic alcohol comprises 100 to 10,000 parts by weight per 100 parts by weight of adapalene.

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