JP7165534B2 - Preventive or improving agent for vitiligo - Google Patents

Description

TECHNICAL FIELD The present invention relates to an agent for preventing or improving vitiligo.

Vitiligo is a depigmentation disease of the skin due to the reduction or disappearance of melanocytes. Factors that cause vitiligo include immune disorders, oxidative stress, and chemicals. As a vitiligo-inducing chemical substance, rhododendrol (rhododenol) is known in addition to monobenzone, which is used to reduce uneven skin color in vitiligo patients. On the other hand, the detailed mechanism by which these factors cause the reduction or disappearance of melanocytes in vitiligo has not been elucidated.

Conventionally, topical adrenocorticosteroids have been most widely used for the treatment of vitiligo, and other drugs such as active vitamin D3 topical preparations, tacrolimus ointment, and ultraviolet therapy have been used. A similar treatment has been attempted for rhododendrol-induced vitiligo, but the effect was only about 40% of patients prescribed topical steroids. have been reported, which is not sufficient. US Pat. No. 4,800,003 discloses that active ingredients comprising one or more compounds from the group of osmolytes or their precursors and derivatives very specifically improve the homeostasis of aged skin and improve the epidermal barrier to water. It is described that stimulating the skin's own metabolism of lipids and proteins that must be constantly regenerated in order to maintain , and that topical application of the active ingredient can treat and prevent various skin conditions, including vitiligo. However, Patent Document 1 does not report that the active ingredient actually has those physiological effects.

On the other hand, Patent Documents 2 and 3 describe the use of an apoptosis inhibitor containing a lanostane-type triterpenoid derivative or a plant extract as an active ingredient for the prevention or improvement of vitiligo and gray hair.

Japanese Patent Publication No. 2004-536838 JP-A-2005-068061 Japanese Patent Application Laid-Open No. 2002-080382

The present invention provides a substance capable of preventing or improving vitiligo and gray hair.

The present inventors have found that a series of substances known as chemical chaperones inhibit the decrease in cell viability of melanocytes caused by rhododendrol, and therefore, the substances reduce vitiligo and gray hair caused by the reduction of melanocytes. We have found that it can be prevented or ameliorated.

Accordingly, the present invention provides a vitiligo preventive or ameliorating agent containing a chemical chaperone as an active ingredient.
The present invention also provides an agent for preventing or improving gray hair containing a chemical chaperone as an active ingredient.
The present invention also provides a melanocyte injury or death inhibitor containing a chemical chaperone as an active ingredient.

The active ingredient of the present invention has an effect of suppressing injury or death of melanocytes caused by factors such as chemical substances that cause vitiligo, and is useful for preventing or improving vitiligo and gray hair.

Effect of test substances on melanocyte cell viability in the presence of rhododendrol. Concentrations in the figure represent final concentrations in culture.

As used herein, the term "chemical chaperone" refers to a low-molecular-weight compound involved in the formation and stabilization of higher-order protein structures. Chemical chaperones are roughly divided into two groups: osmolytes and bile acids. Osmotic pressure regulators include amino acids and derivatives thereof, methylamine and derivatives thereof, polyhydric alcohols and the like (Prion, 8(2): 197-202, 2014). Amino acids and derivatives thereof include free amino acids or salts thereof, taurine, and the like. Methylamine and its derivatives include trimethylamine-N-oxide (TMAO), betaine, carnitine chloride, and the like. Polyhydric alcohols include myoinositol and trehalose. Bile acids include ursodeoxycholic acid (UDCA), tauroursodeoxycholic acid (TUDCA), and the like. Moreover, you may use the salt of a bile acid as a bile acid. The salt may be a physiologically acceptable salt.

The chemical chaperone used as an active ingredient in the present invention may be any one of the chaperones listed above or a combination of two or more thereof. Preferably, the chemical chaperone used as an active ingredient in the present invention is at least one selected from the group consisting of osmotic agents, bile acids and salts thereof, and the osmotic agents are preferably , amino acids and derivatives thereof, methylamine and derivatives thereof, and polyhydric alcohols. More preferably, the chemical chaperone used as an active ingredient in the present invention is taurine, trimethylamine-N-oxide, betaine, carnitine chloride, myoinositol, trehalose, ursodeoxycholic acid and salts thereof, and tauroursodeoxycholic acid and It is at least one selected from the group consisting of salts thereof.

The chemical chaperones described above have the effect of suppressing the decrease in cell viability of melanocytes in the presence of rhododendrol, as shown in the Examples below. If the survival rate of melanocytes is improved, the decrease or disappearance of melanocytes can be suppressed, and the onset of vitiligo and gray hair can be prevented or improved.

Therefore, the present invention provides an agent for suppressing injury or death of melanocytes, an agent for preventing or improving vitiligo, and an agent for preventing or improving gray hair (hereinafter collectively referred to as the agent of the present invention). These agents of the present invention contain chemical chaperones as active ingredients.

The injury or death of melanocytes suppressed by the agent of the present invention is injury or death of melanocytes due to oxidative stress caused by active oxygen, radicals, etc. generated in vivo. exposure and UV irradiation. Preferably, the melanocyte injury or death inhibited by the agents of the present invention is chemical-induced injury or death. Such chemical substances include, for example, rhododendrol, monobenzone, and the like. More preferably, the agent of the present invention inhibits rhododendrol-induced melanocyte injury or death.

Preferably, vitiligo to be prevented or ameliorated by the agent of the present invention is chemical-induced vitiligo. Such chemical substances include, for example, rhododendrol, monobenzone, and the like. More preferably, the agents of the present invention prevent or ameliorate rhododendrol-induced vitiligo. For example, the agents of the present invention suppress the development of rhododendrol-induced vitiligo. Also for example, agents of the present invention improve the color of skin with rhododendrol-induced vitiligo. Alternatively, agents of the present invention can alleviate vitiligo and excessive skin depigmentation caused by application of monobenzone and the like.

The agent of the present invention may contain only a chemical chaperone as an active ingredient, or as long as the function of the chemical chaperone is not lost, further suppresses injury or death of melanocytes, or prevents or improves vitiligo or gray hair. It may contain other active ingredients for, for example, an apoptosis inhibitor, a melanin production promoter, and the like. For example, the agent of the present invention can be a composition for suppressing injury or death of melanocytes, preventing or improving vitiligo, or preventing or improving gray hair. Alternatively, the agent of the present invention can be used as an active ingredient for imparting the function to a composition for suppressing injury or death of melanocytes, preventing or improving vitiligo, or preventing or improving gray hair. .

Examples of compositions for suppressing injury or death of melanocytes, preventing or improving vitiligo, or preventing or improving gray hair provided by the present invention include pharmaceuticals, quasi-drugs, and cosmetics. The composition contains a chemical chaperone as an active ingredient. Furthermore, the composition may optionally contain other ingredients (e.g., pharmaceutically or cosmetically acceptable carriers, other effective ingredients, other pharmacological ingredients, cosmetic ingredients, etc.).

The composition may be administered in any form, and may be either oral administration or parenteral administration. Dosage forms for oral administration include solid formulations such as tablets, granules, powders and capsules, as well as liquid formulations such as elixirs, syrups and suspensions. Dosage forms for parenteral administration include preparations for external use on the skin, transdermal, transmucosal, nasal, enteral, injection, suppository, injection, inhalation, patch and the like.

Preferably, the composition is in the form of an external skin preparation, and more specifically, it can be in various forms such as ointments, emulsions, creams, milky lotions, lotions, gels, and aerosols. Preferable examples of the cosmetics include face or body cleansers, head (hair or scalp) cleansers (e.g., shampoos, rinses, conditioners, etc.), and face, body, or head cosmetics. (for example, lotions, gels, creams, packs, etc.), make-up cosmetics, hair coloring or gray hair dyeing, and the like.

The composition contains a chemical chaperone, which is an active ingredient, and optionally other ingredients described above (pharmaceutically or cosmetically acceptable carriers, other active ingredients mentioned above, other pharmacological ingredients, cosmetic ingredients, etc. ), it can be produced according to a conventional method. Examples of the pharmaceutically or cosmetically acceptable carrier include various oils, surfactants, gelling agents, buffers, preservatives, antioxidants, solvents, dispersants, chelating agents, thickeners, Examples include ultraviolet absorbers, emulsion stabilizers, pH adjusters, pigments, and fragrances. Examples of other pharmacological ingredients or cosmetic ingredients include plant extracts, bactericides, moisturizing agents, anti-inflammatory agents, antibacterial agents, keratolytic agents, cooling agents, antiseborrheic agents, cleansers, makeup ingredients, and the like. mentioned.

In the agent and composition of the present invention, the content of the chemical chaperone, which is an active ingredient, varies depending on the form of the agent used for administration, so it cannot be generalized. , preferably 0.001% by mass or more, more preferably 0.005% by mass or more, still more preferably 0.01% by mass or more, and preferably 50% by mass or less, more preferably 20% by mass or less and more preferably 10% by mass or less. Alternatively, the content of the chemical chaperone in the external preparation for skin of the present invention is preferably 0.001 to 50% by mass, more preferably 0.005 to 20% by mass, and still more preferably 0.01 to 10% by mass. be. When the active ingredient is in the form of a salt (for example, bile salt), the content thereof shall be converted to the content of the corresponding free form (for example, free bile acid).

Subjects to which the agent of the present invention is applied include humans and non-human animals for which suppression of melanocyte apoptosis, prevention or improvement of vitiligo, or prevention or improvement of gray hair is desired. Non-human animals include non-human mammals, and non-human mammals include, for example, apes, other primates, mice, rats, hamsters, horses, cows, pigs, sheep, goats, dogs, cats, and companion animals.

The agents of the invention may be used for therapeutic purposes or for non-therapeutic purposes. Examples of therapeutic uses include use for vitiligo patients. Examples of non-therapeutic uses include cosmetic uses for the prevention or reduction of vitiligo and gray hair.

EXAMPLES The present invention will be specifically described below with reference to examples.

Commercially available human epidermis-derived normal melanocytes were suspended in MCDB153HAA medium containing Human Melanocyte Growth Supplement (HMGS; Life Technologies) at 2.0×10 ⁵ cells/mL, and added to a 24-well or 96-well culture plate at 0.5 or Seeded at 0.1 mL/well. After culturing the cells for 2 days at 37° C. and 5% CO ₂ , various concentrations of rhododendrol (Tokyo Chemical Industry Co., Ltd.) and test substances were added to the cultures. After 24 hours, cell viability was assessed. The following compounds were used as test substances and diluted to a predetermined concentration in the medium: taurine (Sigma-Aldrich), trimethylamine-N-oxide (TMAO) (Sigma-Aldrich), betaine (Sigma-Aldrich). Co.), carnitine chloride (Kongo Chemical Co.), myoinositol (Sigma-Aldrich Co.), trehalose (Treh) (Sigma-Aldrich Co.), ursodeoxycholic acid (UDCA) (Sigma-Aldrich Co.), and tauroursodeoxycholic acid (TUDCA). ) (Merck Millipore). Measurement of cell viability was performed by the WST-8 method. That is, after washing the cells once with Hepes buffer, Hepes buffer mixed with 1/10 amount of Cell count reagent SF (Nacalai tesque) was added and incubated at 37°C. The fluorescence value (Excitation/Emission=560/590 nm) in the resulting reaction solution was measured with a plate reader.

FIG. 1 shows the measurement results of cell viability. In the absence of test substance, rhododendrol (RD) at concentrations of 0.1 mM or higher reduced melanocyte cell viability by 50% or less compared to no rhododendrol. On the other hand, this decrease in cell viability due to rhododendrol was suppressed by the addition of the test substance. In particular, effects on cell viability were clearly observed for 100 mM taurine, 100 mM TMAO, 100 mM betaine, 10 mM carnitine chloride, 50-150 mM myoinositol, 100 mM trehalose, 1 mM UDCA, and 1-3 mM TUDCA. These results indicated that the test substance inhibited rhododendrol-induced melanocyte damage and loss.

Claims (1)

effective at least one chemical chaperone selected from the group consisting of taurine, trimethylamine-N-oxide, betaine, carnitine chloride, myoinositol, trehalose, ursodeoxycholic acid and its salts, and tauroursodeoxycholic acid and its salts An agent for preventing or improving rhododendrol- induced vitiligo as a component.

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