JP5646129B2 - 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 present inventors have found that by blending arbutin together with adapalene, the permeability of adapalene to keratin and skin is improved, and the present invention is completed. It came.

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

  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.

  “Arbutin” is a substance obtained by transferring glucose to hydroquinone by α-bonding or β-bonding, and there are α-type and β-type. In the present invention, any type may be used, or they may be used in combination. The content (formulation) of arbutin is 0.5 to 25 parts by mass with respect to 1 part by mass of adapalene.

  This is because if the content of arbutin is less than 0.5 parts by mass, the permeability of adapalene to the skin is considered to be insufficient. On the other hand, when preparing external preparation using this external preparation composition, if adapalene is contained in the external preparation in an amount exceeding 1.0% by mass, it exceeds 25 parts by mass with respect to 1 part by mass of adapalene. When arbutin is blended, adapalene seems to have sufficient permeability to the skin, but it is not preferable because the blending amount of arbutin becomes too large, resulting in poor solubility.

  Arbutin is known to have a whitening action, and the external preparation composition of the present invention not only enhances adapalene's keratin and skin permeability, but also acne is considered to have a therapeutic effect. Among skin diseases such as wrinkles and stains, it is expected to exhibit excellent effects particularly in the treatment of stains.

  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 preparation can be prepared by dissolving and dispersing adapalene and arbutin in water, lower alcohol, polyhydric alcohol or a mixture thereof. In addition, what is necessary is just to mix | blend surfactant required in order to solubilize, when 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.) 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 of arbutin or a heated oil component and / or an oil phase in which a surfactant is dissolved from a hopper, 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 ointments can be prepared 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 arbutin after heating and melting, and then cooling to room temperature. .

  The external preparation composition of the present invention includes an anti-inflammatory agent, antibacterial agent, bactericidal agent, analgesic agent, local anesthetic agent, tissue repair agent, antipruritic agent, moisturizer, vasoconstrictor, antiallergic agent, cooling agent, oxygen A remover, a vitamin, an ultraviolet absorber, an ultraviolet scattering agent, and the like can be appropriately blended within a range that does not impair 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 4 and Examples 1 to 8 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 8 change the concentration of compounding ingredients other than adapalene by changing their concentrations, 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 liquid agents in which pantothenyl ethyl ether, which is widely used as an active ingredient for external preparations, is blended in various concentrations in the composition of Comparative Example 1, and Examples 1 to 4 are α-arbutin in various concentrations. Examples 5 to 8 are liquids containing β-arbutin at 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 8 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 1-4 (0.5-25 parts by mass α-arbutin with respect to 1 part by mass of adapalene), Examples 5-8 (0.5-25 parts by mass with respect to 1 part by mass of adapalene) β Arbutin) and the 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 migration rate relative to Comparative Example 1 is about 2.9 times in Example 1 (0.5 part by mass of α-arbutin relative to 1 part by mass of adapalene), and Example 2 (2. 5 parts by mass of α-arbutin) increased about 4.4 times, and Example 4 (25 parts by mass of α-arbutin relative to 1 part by mass of adapalene) increased about 8.0 times. In addition, Example 5 (0.5 part by mass of β-arbutin with respect to 1 part by mass of adapalene) is about 2.2 times, Example 6 (2.5 parts by mass of β-arbutin with respect to 1 part by mass of adapalene) ) Was about 4.0 times, and about 8 times in Example 8 (25 parts by mass of β-arbutin relative to 1 part by mass of adapalene), an almost constant value from Example 6.

  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 α-arbutin and β-arbutin have an effect of increasing adapalene's ability to migrate to a silicon film. Since it is considered that there is a correlation between the silicon membrane transferability and the skin permeability, α-arbutin and β-arbutin 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: The liquid agents of Comparative Examples 1 to 4, Examples 1 to 4 and Examples 5 to 8 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) 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. On the other hand, in Example 1 (0.5 part by mass α-arbutin for 1 part by mass of adapalene), 0.9 times, in Example 4 (25 parts by mass of α-arbutin for 1 part by mass of adapalene), 1 1.0 times in Example 5 (0.5 parts by mass of β-arbutin per 1 part by mass of adapalene), Example 8 (25 parts by mass of β-arbutin in 1 part by mass of adapalene) However, even if the concentration of α-arbutin and β-arbutin was increased by 1.0 times, there was no effect of increasing the solubility ratio of adapalene.

  In the liquid preparations of Comparative Examples 2 to 4 containing pantothenyl ethyl ether in which the solubility ratio of adapalene was increased in a concentration-dependent manner, no increase in the migration of adapalene to the silicon film was observed, but an example in which α-arbutin was added In Examples 5 to 8 containing 1-4 and β-arbutin, the solubility ratio of adapalene did not change, but the silicon film migration increased 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, and α-arbutin and β It is considered that adapalene has increased the silicon film transferability by blending arbutin.

  That is, the permeability of adapalene to the stratum corneum and skin is independent of the concentration of adapalene dissolved in the solution, it does not change even if adapalene is present in a dispersed state in the solution, and α-arbutin and β-arbutin Formulation is thought to increase the permeability of adapalene to the keratin and skin.

  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 composition comprising 0.01 to 1.0% by mass of adapalene and 0.5 to 25 parts by mass of arbutin relative to 1 part by mass of the adapalene with respect to the entire external preparation composition. .   The external preparation composition according to claim 1, which is a liquid, lotion, gel, aerosol, cream or aqueous ointment.

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