JP5233149B2 - Adapalene-containing external preparation composition - Google Patents

Description

  The present invention relates to an adapalene-containing external preparation composition excellent in permeability to keratin and skin.

  Adapalene is one of the third-generation synthetic retinoids that are known to penetrate the sebaceous glands and hair follicles and reduce the size of comedones, the first acne rash. Regarding adapalene-containing preparations, there are reports that side effects such as desquamation and burning sensation are few while maintaining the high therapeutic effects of conventional external retinoid agents (see Non-Patent Document 1).

  However, since the skin inherently has a barrier function (stratum corneum) that prevents foreign substances from entering from the outside, sufficient skin permeability cannot be obtained simply by blending a medicinal component into an external preparation. In many cases, sufficient medicinal effects cannot be expressed.

  Then, when an in vitro transdermal absorbability test using a diffusion cell was performed on a gel containing 0.1% adapalene, quick penetration into the hair follicle was confirmed, but adapalene was not treated even 15 hours after administration. It has been reported that only 0.01% of the dose is transferred to the receiver solution (see Non-Patent Document 2), and it is presumed that the permeability to the skin through the stratum corneum is low.

Atsuko Nishijima “Skin Chemistry” 2 (3), p155-159, 2003 J. Allec, et al, Journal of the American Academy of Dermatology, 36 (6): S119-S125 (1997)

  Since adapalene is a retinoid, it is expected to be effective for skin diseases such as acne, keratosis, psoriasis, wrinkles, and spots as well as vitamin A. However, as described above, adapalene has a low permeability to the keratin and skin, and it is considered that it does not exhibit a sufficient therapeutic effect for diseases that occur in the epidermis and dermis.

  Then, this invention makes it a subject to provide the adapalene containing external preparation composition excellent in the permeability | transmittance to a keratin and skin.

  As a result of intensive studies to solve the above-mentioned problems, the inventors of the present invention combined adapalene with ubidecarenone, dipotassium glycyrrhizinate, tocopherol acetate, camphor or menthol, so that adapalene can penetrate into the keratin and skin. As a result, the present invention has been completed.

  That is, an aspect of the present invention is an external preparation composition containing (a) adapalene and (b) at least one of ubidecalenone, dipotassium glycyrrhizinate, tocopherol acetate, camphor and menthol.

  According to the present invention, it is possible to provide an adapalene-containing external preparation composition excellent in permeability to keratin and skin.

  “Adapalene” is a compound having an adamantyl skeleton and a molecular weight of 412.52, which is soluble in tetrahydrofuran but slightly soluble in ethanol and insoluble in water (see THE MERCK INDEX). The content (formulation) of adapalene is 0.01 to 1.0% by mass in the external preparation composition, and 0.05 to 0.5% by mass is preferable from the balance between the effectiveness and safety of adapalene.

  “Ubidecarenone” is a type of coenzyme Q that has energy supply by mitochondrial activation and antioxidant activity by reduced form. Also called ubiquinone, coenzyme Q10. The content (formulation) of ubidecarenone is 0.5 to 25 parts by mass with respect to 1 part by mass of adapalene, and 0.5 to 5 parts by mass is preferable in terms of enhancing the permeability of adapalene to the skin. This is because if the content of ubidecarenone is less than 0.5 parts by mass, the permeability of adapalene to the skin is considered insufficient, and if it exceeds 25 parts by mass, the permeability of adapalene to the skin decreases. The external preparation composition of the present invention containing ubidecarenone is expected not only to enhance adapalene's keratin and skin permeability but also to enhance the anti-wrinkle effect of adapalene.

  “Dipotassium glycyrrhizinate” is an anti-inflammatory agent and has an action of quickly sedating inflammation. The content (formulation) of dipotassium glycyrrhizinate is 0.5 to 25 parts by mass with respect to 1 part by mass of adapalene, and 0.5 to 2.5 in terms of increasing the permeability of adapalene to the skin. Part by mass is preferred. If the content of dipotassium glycyrrhizinate is less than 0.5 parts by mass, it is considered that the permeability of adapalene to the skin is not sufficient, and if it exceeds 25 parts by mass, the permeability of adapalene to the skin decreases instead. is there. The external preparation composition of the present invention containing dipotassium glycyrrhizinate is effective not only for enhancing the permeability of adapalene to the keratin and skin but also for treating keratosis and psoriasis accompanied by inflammatory symptoms. In addition, it is expected to exhibit an excellent therapeutic effect in acne, wrinkles, and skin diseases such as wrinkles that have dry skin, sensitive skin, and atopic skin with itching.

  “Tocopherol acetate” is also called vitamin E, and has blood circulation promoting action, lipid peroxide decomposition action, and antioxidant action. The content (formulation) of tocopherol acetate is 0.5 to 25 parts by mass with respect to 1 part by mass of adapalene, and 2.5 to 25 parts by mass is preferable in terms of increasing the permeability of adapalene to the skin. . If the content of tocopherol acetate is less than 0.5 parts by mass, the penetration of adapalene into the skin is considered insufficient, and if it exceeds 25 parts by mass, there is a concern about the solubility of fat-soluble tocopherol acetate. is there. The external preparation composition of the present invention containing tocopherol acetate not only enhances the penetration of adapalene into the keratin and skin, but also skin such as keratosis, psoriasis, acne, wrinkles and spots with rough skin. Expected to exert excellent therapeutic effects in disease.

  “Camphor” includes d-form and dl-form, both of which are also called camphor and synthetic camphor, respectively. Used as a refreshing agent and local stimulant. The content (formulation) of camphor is 0.5 to 25 parts by mass with respect to 1 part by mass of adapalene, and 0.5 to 15 parts by mass is preferable in terms of enhancing the permeability of adapalene to the skin. This is because if the content of camphor is less than 0.25 parts by mass, the permeability of adapalene to the skin is considered insufficient, and if it exceeds 25 parts by mass, the permeability of adapalene to the skin decreases. In addition, since camphor has the effect of masking itchiness and pain due to a refreshing action, the composition for external use of the present invention not only enhances the penetration of adapalene into the keratin and skin but also itching and pain. It is expected to exhibit excellent therapeutic effects in keratosis with symptoms and skin diseases such as psoriasis, acne, wrinkles and stains.

  “Menthol” includes d-form, l-form and dl-form, all of which have a cooling effect, a local anti-inflammatory effect and an analgesic action. The content (formulation) of menthol is 0.5 to 25 parts by mass with respect to 1 part by mass of adapalene. If the content of menthol is less than 0.5 parts by mass, it is considered that the permeability of adapalene to the skin is insufficient, and if it exceeds 25 parts by mass, irritation to the skin of menthol becomes a problem. Since menthol has an itching and pain masking effect due to a refreshing action and an analgesic action, the external preparation composition of the present invention not only enhances adapalene's keratin and skin penetration, but also itching. Effective for the treatment of keratosis, psoriasis, etc. accompanied by pain and symptom, and exhibits excellent therapeutic effect on acne, wrinkles and skin diseases such as acne, dry skin, sensitive skin, and atopic skin Expected.

  In the present invention, ubidecalenone, dipotassium glycyrrhizinate, tocopherol acetate, camphor and menthol may be used alone or in combination of two or more.

  The adapalene-containing external preparation composition of the present invention is provided as various external preparations such as liquids, lotions, gels, aerosols, creams and aqueous ointments.

  The liquid agent can be prepared by dissolving and dispersing adapalene, ubidecarenone, etc. using water, lower alcohol, polyhydric alcohol or a mixture thereof. If oily components such as ubidecarenone, tocopherol acetate, camphor and menthol cannot be completely dissolved, a surfactant necessary for solubilization may be added. Further, an aerosol agent can be prepared by putting such a liquid agent and an appropriate liquefied gas (liquefied petroleum gas, dimethyl ether, etc.) in an aluminum pressure vessel or the like. Furthermore, it is also possible to prepare a gel agent by blending such a liquid agent with an appropriate gelling agent.

  Creams can also be prepared by conventional methods. For example, adapalene and a surfactant are added to water and a polyhydric alcohol phase, and the mixture is put into a homomixer container and deaerated and heated. A cream agent can be prepared by adding a dissolved phase such as ubidecalenone heated from a hopper or an oil phase in which an oil and a surfactant are dissolved, stirring at high speed (homogenizing), and then cooling to room temperature. Here, an O / W cream can be prepared by using a surfactant having a high HLB, and a W / O cream can be prepared by using a surfactant having a low HLB.

  Aqueous ointment is prepared by taking any amount of polyethylene glycol that is solid at room temperature and polyhydric alcohol that is liquid at room temperature, adding adapalene, ubidecarenone, etc. after heating and melting, and then cooling to room temperature. it can.

  Antibacterial agents, bactericides, analgesics, local anesthetics, tissue repair agents, antipruritics, moisturizers, vasoconstrictors, antiallergic agents, oxygen scavengers, vitamins, ultraviolet absorbers In addition, an ultraviolet scattering agent or the like can be appropriately blended within a range not impairing the effects of the present invention.

  In the external preparation composition of the present invention, various base components that can be blended with pharmaceuticals and quasi drugs can be appropriately blended within a range not impairing the effects of the present invention. Examples of such base components include purified water, solubilizing agents such as lower alcohols and polyhydric alcohols, hydrocarbons, glycerin fatty acid esters, wax components, surfactants, antioxidants, emulsion stabilizers, gelling agents, Examples include extracts from various animals and plants such as pressure-sensitive adhesives, pH adjusters, preservatives, chelating agents, fragrances, pigments, and liquefied gases.

Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples and Test Examples.
Each liquid agent of Comparative Examples 1 to 7 and Examples 1 to 18 shown in Table 1 below is a dispersion of adapalene in which adapalene is blended and stirred for 24 hours. That is, Comparative Example 1 is a liquid agent in which adapalene, ethanol and purified water are mixed. Comparative Examples 2 to 7 and Examples 1 to 18 are ethanol, pH adjuster and purified by changing the concentration of compounding ingredients other than adapalene. A solution prepared by dissolving adapalene after being dissolved in a mixture of water. Comparative Examples 2 to 4 are solutions in which pantothenyl ethyl ether, which is widely used as an active ingredient for external preparations, is mixed with the composition of Comparative Example 1 at various concentrations, and Comparative Example 5 is a blood coagulation effect on the composition of Comparative Example 1. Is a solution containing 2.5 parts by mass of phylloquinone (vitamin K ₁ ) with respect to 1 part by mass of adapalene, and Comparative Examples 6 to 7 are menadione having the composition of Comparative Example 1 having a P. acnes growth inhibitory effect. (Vitamin K ₃ ) is a solution containing 0.5 and 2.5 parts by mass with respect to 1 part by mass of adapalene. Examples 1 to 4 are ubidecarenone, Examples 5 to 7 are dipotassium glycyrrhizinate. Examples 8 to 10 are tocopherol acetates, Examples 11 to 15 are camphors, and Examples 16 to 18 are liquids containing menthol in various concentrations. In addition, as a pH adjuster, sodium hydroxide, potassium dihydrogen phosphate, and dilute hydrochloric acid were used, and pH of each liquid agent was adjusted to about 8.

Test Example 1 Silicon film transferability test of adapalene Premise: According to Tanaka et al., Transferability test using silicon film in open system is said to be suitable for evaluation of transdermal absorbability of topically administered preparations ( S. Tanaka, et al., International Journal of Pharmaceutics, 27: 29-38 (1985)), the permeability to the stratum corneum was evaluated by a silicon membrane transfer test. Further, by using a silicon film, it is possible to eliminate the influence of pores through which adapalene easily permeates, so that it is considered that adapalene's ability to move to the keratin can be simply evaluated.

  Method: A gauze for uniformly applying the liquid agents of Comparative Examples 1 to 7 and Examples 1 to 18 is placed on a silicon rubber film (2.5 cm × 2.5 cm × 0.5 mm), and each liquid agent is spread throughout. 150 μL each was applied and immediately put into a thermostat (about 35 ° C., humidity control). After 1 hour, the silicon rubber film was taken out of the thermostat, the liquid on the surface was thoroughly washed with water, and the moisture was wiped off well. This was left in methanol overnight, and adapalene was completely extracted from the silicon film with an ultrasonic generator, and the content of adapalene in the extract was measured by liquid chromatography. The adapalene migration of each liquid agent was determined as a migration rate value when the silicon migration rate of Comparative Example 1 was 1.

  Results: Examples 1 to 4 (0.5 to 25 parts by mass of ubidecarenone to 1 part by mass of adapalene), Examples 5 to 7 (0.5 to 25 parts by mass of glycyrrhizin to 1 part by mass of adapalene) Acid dipotassium), Examples 8 to 10 (0.5 to 25 parts by mass of tocopherol acetate to 1 part by mass of adapalene), Examples 11 to 15 (0.5 to 25 to 1 part by mass of adapalene) FIG. 1 shows the results of the silicon film migration test in Comparative Examples 1 to 7, and Examples 16 to 18 (0.5 to 25 parts by mass of menthol with respect to 1 part by mass of adapalene). In addition, it was judged that the relative transition rate was 1.4 times or more and there was an effect.

  The migration rate relative to Comparative Example 1 was about 2.8 times in Example 1 (0.5 parts by mass of ubidecalenone relative to 1 part by mass of adapalene), and Example 2 (2.5 parts per 1 part by mass of adapalene). The concentration increased in a concentration-dependent manner by about 4.3 times in terms of mass part of ubidecarenone) and about 5.4 times in Example 3 (5 parts by mass of ubidecalenone relative to 1 part by mass of adapalene). The adapalene migration in Example 4 (25 parts by mass of ubidecalenone relative to 1 part by mass of adapalene) was lower than that in Example 3, but still showed a migration rate of about 1.6 times. Moreover, about 2.8 times in Example 5 (0.5 mass part dipotassium glycyrrhizinate with respect to 1 mass part of adapalene), Example 6 (2.5 mass parts with respect to 1 mass part of adapalene) (Dipotassium glycyrrhizinate) increased in a concentration-dependent manner about 3.3 times. The adapalene transferability in Example 7 (25 parts by mass of dipotassium glycyrrhizinate relative to 1 part by mass of adapalene) was lower than that in Example 6, but still showed a transfer rate of about 2.5 times. . In Example 8 (0.5 parts by mass of tocopherol acetate to 1 part by mass of adapalene), about 1.5 times in Example 9 (2.5 parts by mass of tocopherol acetate to 1 part by mass of adapalene) The concentration increased about 6.1 times in Example 10 (25 parts by mass of tocopherol acetate to 1 part by mass of adapalene), about 19.4 times. Example 11 (0.5 parts by mass camphor with respect to 1 part by mass of adapalene) is about 2.4 times, and Example 13 (5 parts by mass camphor with respect to 1 part by mass of adapalene) is about 3.1. The silicon film migration increased in a double and concentration dependent manner. The adapalene transferability in Example 14 (15 parts by mass camphor per 1 part by mass of adapalene) and Example 15 (25 parts by mass camphor in 1 part by mass of adapalene) is lower than that in Example 13. However, the migration rate was still about 2.6 times in Example 14 and about 1.8 times in Example 15. About 2.4 times in Example 16 (0.5 part by mass menthol with respect to 1 part by mass of adapalene), about 2.7 in Example 17 (5 parts by mass menthol with respect to 1 part by mass of adapalene) In Example 18 (25 parts by mass of menthol with respect to 1 part by mass of adapalene), the increase effect was almost 2.6 times, regardless of the concentration.

  On the other hand, Comparative Examples 2 to 4 (2.5 to 25 parts by mass of pantothenyl ethyl ether with respect to 1 part by mass of adapalene), Comparative Example 5 (2.5 parts by mass of phylloquinone with respect to 1 part by mass of adapalene) In Comparative Examples 6 to 7 (0.5 to 2.5 parts by mass of menadione with respect to 1 part by mass of adapalene), the migration of adapalene to the silicon film was hardly increased by the drug.

  From the above results, it has been clarified that ubidecarenone, dipotassium glycyrrhizinate, tocopherol acetate, camphor and menthol have an effect of increasing the migration of adapalene to a silicon film. Since it is considered that there is a correlation between the transferability of the silicon film and the skin permeability, ubidecarenone, dipotassium glycyrrhizinate, tocopherol acetate, camphor and menthol are considered to increase the skin permeability of adapalene.

Test Example 2 Influence of Solubility of Adapalene on Silicon Film Mobility Since each of the liquid agents is considered to have increased the silicon film mobility of adapalene depending on the amount of adapalene dissolved in each liquid listed in Table 1. In order to investigate the relationship between the solubility of adapalene and the migration of silicon film, the saturation solubility of adapalene in each solution was measured.

  Method: Filter the liquids of Comparative Examples 1-7, Examples 1-4, Examples 5-7, Examples 8-10, Examples 11-15 and Examples 16-18 listed in Table 1, and in the filtrate The amount of adapalene was quantified using liquid chromatography. The saturation solubility of each solution was determined as the solubility ratio when the solubility of Comparative Example 1 was 1.

Results: The results are shown in FIG.
Comparative Example 2 (2.5 parts by mass of pantothenyl ethyl ether with respect to 1 part by mass of adapalene) 1.5 times, Comparative Example 4 (25 parts by mass of pantothenyl ethyl ether with respect to 1 part by mass of adapalene) Then, the solubility ratio of adapalene increased about 3 times depending on the concentration of pantothenyl ethyl ether, which is a solubilizing agent for adapalene. In Comparative Example 5 (2.5 parts by mass of phylloquinone relative to 1 part by mass of adapalene), 1.6 times, in Comparative Example 6 (0.5 parts by mass of menadione relative to 1 part by mass of adapalene), 1.1 times. In Comparative Example 7 (2.5 parts by mass of menadione with respect to 1 part by mass of adapalene), there was an effect of slightly increasing the solubility ratio of adapalene by 1.3 times in phylloquinone _and menadione. In Example 8 (0.5 parts by mass of tocopherol acetate to 1 part by mass of adapalene), 2.3 times in Example 10 (25 parts by mass of tocopherol acetate to 1 part by mass of adapalene), 2.3 In Example 12 (2.5 parts by mass camphor per 1 part by weight of adapalene), 1.3 times in Example 15 “(25 parts by weight camphor per 1 part by weight of adapalene). 2 times, 1.9 times in Example 17 (5 parts by weight menthol for 1 part by weight of adapalene), 3.0 times in Example 18 (25 parts by weight menthol for 1 part by weight of adapalene) And tocopherol acetate, camphor and menthol increased the solubility ratio of adapalene, whereas in Example 1 (0.5 parts by weight of ubidecarenone relative to 1 part by weight of adapalene), 0.9 times, Example 4 (adapa 1.0 times for 25 parts by weight of ubidecalenone relative to 1 part by weight of water, 0.8 times for Example 5 (0.5 parts by weight of dipotassium glycyrrhizinate for 1 part by weight of adapalene) In Example 7 (25 parts by mass of dipotassium glycyrrhizinate relative to 1 part by mass of adapalene), the ratio was 0.7 times, and ubidecarenone and dipotassium glycyrrhizinate had no effect of increasing the solubility ratio of adapalene.

  In the liquid preparations of Comparative Examples 2 to 7 in which pantothenyl ethyl ether, phylloquinone and menadione having an increased solubility ratio of adapalene were added, no increase in the migration of adapalene to the silicon film was observed, but Example 1 in which ubidecarenone was added. In Examples 5 to 7 containing ˜4 and dipotassium glycyrrhizinate, the solubility ratio of adapalene did not change, but the silicon film migration increased substantially in a concentration-dependent manner. Further, in Examples 8 to 10 containing tocopherol acetate, Examples 11 to 15 containing camphor and Examples 16 to 18 containing menthol, the solubility ratio of adapalene was increased, and the silicon film migration was also increased ( (See FIGS. 1 and 2).

  Considering the above, the migration of adapalene to the silicon film is independent of the concentration of adapalene dissolved in the solution, and does not change even when adapalene is present in a dispersed state in the solution, and ubidecarenone, glycyrrhizic acid It is considered that the adapalene migration into the silicon film is increased by the combination of dipotassium, tocopherol acetate, camphor and menthol.

  That is, the permeability of adapalene to the keratin and skin is independent of the concentration of adapalene dissolved in the solution, and it does not change even if adapalene is present in a dispersed state in the solution, and ubidecarenone, dipotassium glycyrrhizinate. It is considered that adapalene's keratin and skin permeability are increased by the combination of tocopherol acetate, camphor and menthol.

  According to the present invention, there are provided various external preparations containing adapalene and effective for acne, keratosis, psoriasis, wrinkles and stains, lotions, gels, aerosols, creams, aqueous ointments and the like. There is expected.

It is a graph which shows the silicon film transfer rate of adapalene. It is a graph which shows the solubility ratio of adapalene.

Claims (2)

(A) 0.01-1.0 mass% adapalene with respect to the whole external preparation composition , and (b) 0.5-25 mass parts dipotassium glycyrrhizinate with respect to 1 mass part of this adapalene , An external preparation composition comprising at least one of tocopherol acetate, camphor and menthol.   The external preparation composition according to claim 1, which is a liquid, lotion, gel, aerosol, cream or aqueous ointment.

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