JP5109383B2 - 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 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 problems, the present inventors have found that by adding isopropylmethylphenol together with adapalene, the permeability of adapalene to the keratin and skin is improved, and the present invention has been completed. It came to do.

  That is, the aspect of this invention is an external preparation composition characterized by containing adapalene and isopropylmethylphenol.

  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 tetrohydrofuran 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.

  “Isopropylmethylphenol” is a component that is widely used in pharmaceuticals and cosmetics as a bactericidal agent. The content (formulation) of isopropylmethylphenol 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 increased in terms of increasing the permeability of adapalene to the skin. preferable.

  If the content of isopropylmethylphenol 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, the permeability of adapalene to the skin is considerably reduced. is there.

  In addition, since isopropylmethylphenol has a bactericidal action and has an effect of preventing secondary infection in acne and inflamed skin, the composition for external use of the present invention simply enhances the permeability of adapalene to the keratin and skin. In addition, it is expected to exert an excellent therapeutic effect on skin diseases such as acne, keratosis, psoriasis, or skin diseases such as wrinkles and stains that are associated with secondary infections. The

  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 and isopropylmethylphenol in water, lower alcohol, polyhydric alcohol or a mixture thereof. In addition, what is necessary is just to mix | blend the surfactant required for solubilization, when isopropylmethylphenol and an oil component cannot be melt | dissolved completely. Further, an aerosol agent can be prepared by putting such a liquid agent and an appropriate liquefied gas (liquefied petroleum gas, dimethyl ether, etc.) into an aluminum pressure vessel. 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 of isopropylmethylphenol 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 made by taking any amount of polyethylene glycol that is solid at room temperature and polyhydric alcohol that is liquid at room temperature, adding and dispersing adapalene and isopropylmethylphenol after heating and melting, and then cooling to room temperature. Can be prepared.

  The external preparation composition of the present invention includes antibacterial agents, anti-inflammatory agents, analgesics, antihistamines, tissue repair agents, antipruritic agents, moisturizers, vasoconstrictors, antiallergic agents, local anesthetics, oxygen scavengers, and cooling agents. An agent, a vitamin, an ultraviolet absorber, an ultraviolet scattering agent, and 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 in pharmaceuticals and quasi drugs can be appropriately contained 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 4 and Examples 1 to 4 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, and Comparative Examples 2 to 4 and Examples 1 to 4 have different concentrations of compounding ingredients other than adapalene, ethanol, pH adjuster and purification. A solution prepared by dissolving adapalene after being dissolved in a mixture of water. Comparative Examples 2 to 4 are solutions prepared by blending pantothenyl ethyl ether with various concentrations in the composition of Comparative Example 1, and Examples 1 to 4 are solutions obtained by blending isopropylmethylphenol with 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 4 and Examples 1 to 3 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 from the thermostatic chamber, the liquid residue 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 migration of adapalene in each liquid agent to the silicon film was determined as a migration rate value when the silicon membrane migration rate of Comparative Example 1 was 1.

  Results: Examples 1 to 4 (0.5 to 25 parts by mass of isopropylmethylphenol with respect to 1 part by mass of adapalene) and silicon film migration test results in Comparative Examples 1 to 4 are shown in FIG. In addition, it was judged that the relative transition rate was 1.4 times or more and there was an effect.

  The transfer rate relative to Comparative Example 1 was about 4.7 times in Example 1 (0.5 parts by mass of isopropylmethylphenol relative to 1 part by mass of adapalene), and Example 2 (2 parts per part by mass of adapalene). (5 parts by mass of isopropylmethylphenol) increased in a concentration-dependent manner to about 5.9 times. Although the adapalene transferability in Example 3 (5 parts by mass of isopropylmethylphenol with respect to 1 part by mass of adapalene) was slightly lower than that in Example 2, it was still about 5.1 times that of Example 4 (adapalene). 25 parts by mass of isopropylmethylphenol per 1 part by mass) showed a migration rate of about 1.8 times. Thus, isopropylmethylphenol had an amount suitable for the migration of adapalene (0.5 to 5 parts by mass of isopropylmethylphenol with respect to 1 part by mass of adapalene).

  On the other hand, in Comparative Examples 2 to 4 (2.5 to 25 parts by mass of pantothenyl ethyl ether relative 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 isopropylmethylphenol has an effect of increasing the migration of adapalene to a silicon film. Since it is considered that there is a correlation between the silicon membrane transferability and the skin permeability, isopropylmethylphenol is 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: The liquid agents of Comparative Examples 1 to 4 and Examples 1 to 4 described in Table 1 were filtered, and the amount of adapalene in the filtrate 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) About 3 times, Example 2 (2.5 parts by mass of isopropylmethylphenol with respect to 1 part by mass of adapalene) 1.3 times, Example 3 (5 parts by mass of isopropyl with respect to 1 part by mass of adapalene) Methylphenol) is about 1.7 times, and in Example 4 (25 parts by mass of isopropylmethylphenol with respect to 1 part by mass of adapalene) is about 6 times that of adapalene depending on the concentration of pantothenyl ethyl ether and isopropylmethylphenol. The solubility ratio increased.

  Both compounds increased the concentration ratio of adapalene in a concentration-dependent manner. However, in the liquid preparations of Comparative Examples 2 to 4 containing pantothenyl ethyl ether, no increase in the migration of adapalene to the silicon film was observed, whereas isopropylmethyl In Examples 2 to 4 in which phenol was blended, the silicon film migration increased substantially in a concentration-dependent manner (see FIGS. 1 and 2 above).

  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 if adapalene is present in a dispersed state in the solution. It is considered that the adapalene transferability to the silicon film is increased depending on the concentration of the compound.

  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. It is considered that the permeability of adapalene to keratin and skin increases depending on its concentration.

  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)

An external preparation characterized by containing 0.01 to 1.0% by mass of adapalene and 0.5 to 25 parts by mass of isopropylmethylphenol with respect to 1 part by mass of the adapalene based on the whole external preparation composition. Composition.   The external preparation composition according to claim 1, which is a liquid, lotion, gel, aerosol, cream or aqueous ointment.

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