Composition for preventing or treating malassezia skin diseases and method for preventing or treating malassezia skin diseases in animals

Abstract

It is an object of the present invention to provide a composition for effectively preventing or treating Malassezia skin diseases.SOLUTION: The above problem can be solved by a composition for preventing or treating Malassezia dermatosis comprising citral of the present invention as an active ingredient, or a method for preventing or treating Malassezia dermatosis of an animal comprising a step of bringing an effective amount of citral into contact with the skin of an animal (excluding human).SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a composition for preventing or treating Malassezia skin diseases and a method for preventing or treating Malassezia skin diseases in dogs or cats. According to the present invention, Malassezia skin diseases can be effectively prevented or treated. [Background technology]

[0002] Otitis externa or Malassezia dermatitis in dogs and cats is thought to be caused by yeast fungi belonging to the genus Malassezia. A therapeutic agent containing urea and chlorhexidine has been proposed for treating otitis externa (Patent Document 1). [Prior art documents] [Patent documents]

[0003] [Patent Document 1] Japanese Patent Application Laid-Open No. 2006-143618 [Non-patent literature]

[0004] [Non-Patent Document 1] Journal of Veterinary Medical Science (Japan) 2014, Vol. 4, pp. 579-81 [Non-patent document 2] "Medical Mycology Journal" (Japan) 2022, Vol. 2, pp. 53-56 [Non-patent document 3] Journal of Veterinary Medical Science (Japan) 2023, Vol. 3, pp. 383-385 Summary of the Invention [Problem to be solved by the invention]

[0005] In addition, for otitis externa or Malassezia dermatitis, washing with a shampoo containing miconazole (2%) and chlorhexidine (2%) is recommended. However, the increase in resistance to antifungal agents has become a problem. Therefore, an object of the present invention is to provide an effective composition for preventing or treating Malassezia skin diseases. [Means for solving the problem]

[0006] The present inventors have conducted extensive research into compositions for preventing or treating Malassezia skin diseases and have surprisingly found that citral is effective in preventing or treating Malassezia skin diseases. The present invention is based on this finding. Therefore, the present invention provides [1] A composition for preventing or treating Malassezia skin diseases, comprising citral as an active ingredient; [2] The composition according to [1], wherein the Malassezia skin disease is Malassezia dermatitis, seborrheic dermatitis, atopic dermatitis, or otitis externa in an animal. [3] The composition according to [1] or [2], wherein the Malassezia is azole antifungal drug-resistant Malassezia. [4] The composition according to [1] or [2], wherein the composition is a shampoo composition, an ear drop composition, an ear canal cleansing composition, a skin moisturizing composition, a soap composition, a skin care composition, a facial cleanser composition, or a body soap composition. [5] A method for preventing or treating Malassezia skin diseases in animals, comprising the step of contacting an effective amount of citral with the skin of an animal (excluding humans); [6] The method for preventing or treating a Malassezia skin disease according to [5], wherein the Malassezia skin disease is Malassezia dermatitis, seborrheic dermatitis, atopic dermatitis, or otitis externa in an animal; and [7] The method for preventing or treating a Malassezia skin disease according to [5] or [6], wherein the contacting step is a step of contacting a shampoo composition, an ear drop composition, an ear canal cleansing composition, a skin moisturizing composition, a soap composition, a skin care composition, a facial cleanser composition, or a body soap composition. Regarding. [Effects of the Invention]

[0007] According to the composition for preventing or treating Malassezia skin diseases of the present invention, Malassezia skin diseases can be effectively prevented or treated. [Brief explanation of the drawings]

[0008] [Figure 1] This is a photograph of Malassezia dermatitis in a dog. [Figure 2] This is a photograph of Malassezia otitis externa in a dog. [Figure 3] Photographs showing the zones of inhibition against strains CBS1879T (A), 22-M2 (B), and 22-M3 (C) using a 10% citral-added shampoo. "+" indicates shampoo with added citral, and "-" indicates shampoo without added citral. [Figure 4] Photographs showing the inhibition zones against strains CBS1879T, 22-M2, 22-M3, 23-M6, and 23-M8 using 10% citral-added ear cleanser. "+" indicates citral-added ear cleanser, and "-" indicates citral-free ear cleanser. DETAILED DESCRIPTION OF THE INVENTION

[0009] [1] Composition for preventing or treating Malassezia skin diseases The composition for preventing or treating Malassezia skin diseases of the present invention contains citral as an active ingredient. The composition of the present invention is not limited, as long as it can be used for preventing or treating Malassezia skin diseases, and examples thereof include pharmaceutical compositions, cosmetic compositions, shampoo compositions, ear drop compositions, ear canal cleansing compositions, skin moisturizing compositions, soap compositions, skin care compositions, facial cleansing compositions, and body soap compositions. The dosage form of the composition of the present invention is not particularly limited, as long as it can be applied, sprayed, immersed, washed, or contacted with the skin of the target animal, and examples thereof include suspensions, emulsions, topical solutions, ointments, topical creams, and eye drops. Compositions that can be applied, sprayed, immersed, washed, or contacted with the skin of the target animal are preferred, but are not limited thereto.

[0010] Malassezia The pathogen that the composition of the present invention prevents or treats is Malassezia. Examples of Malassezia that can be prevented or treated by the composition of the present invention include, but are not limited to, Malassezia caprae, Malassezia cuniculi, Malassezia dermatis, Malassezia equina, Malassezia furfur, Malassezia globosa, Malassezia japonica, Malassezia nana, Malassezia obtusa, Malassezia pachydermatis, Malassezia psittaci, Malassezia restricta, Malassezia slooffiae, Malassezia sympodialis, and Malassezia yamatoensis. Among these Malassezia, Malassezia pachydermatis is a causative agent of skin diseases in dogs and cats. Furthermore, examples of bacteria that cause human skin diseases include Malassezia dermatis, Malassezia furfur, Malassezia globosa, Malassezia japonica, Malassezia obtusa, Malassezia pachydermatis, Malassezia restricta, Malassezia slooffiae, Malassezia sympodialis, and Malassezia yamatoensis.

[0011] The composition of the present invention is particularly useful for preventing or treating skin diseases caused by, but not limited to, azole antifungal drug-resistant Malassezia. Examples of azole antifungal agents include fluconazole, miconazole, clotrimazole, ketoconazole, itraconazole, voriconazole, fosravuconazole, efinaconazole, luliconazole, ravuconazole, posaconazole, and isavuconazole. As used herein, "azole antifungal drug-resistant Malassezia" refers to Malassezia that has acquired resistance to the azole antifungal agent. "Acquiring resistance" means that when the azole antifungal agent is used in a commonly used effective dose, the effectiveness of the azole antifungal agent is weakened due to, for example, genetic changes occurring in Malassezia.

[0012] Malassezia skin disease Malassezia skin diseases are not particularly limited as long as they are skin diseases caused by Malassezia, but examples include Malassezia dermatitis, seborrheic dermatitis, atopic dermatitis, and otitis externa. In particular, examples of skin diseases in dogs and cats include Malassezia dermatitis, seborrheic dermatitis, atopic dermatitis, and otitis externa.

[0013] Citral Citral is a chain monoterpene aldehyde that exists in two isomers: cis-geranial and trans-neral, where geranial is the E-isomer and neral is the Z-isomer. [ka] The lower limit of the citral concentration in the composition is not limited, but in some embodiments it is 0.001% by weight or more, in some embodiments it is 0.01% by weight or more, in some embodiments it is 0.05% by weight, and in some embodiments it is 0.1% by weight. The upper limit is also not limited, as long as it is an amount that can be contained in the composition, but in some embodiments it is 80% by weight or less, in some embodiments it is 50% by weight or less, in some embodiments it is 20% by weight or less, in some embodiments it is 10% by weight or less, in some embodiments it is 50% by weight or less, in some embodiments it is 2% by weight or less, and in some embodiments it is 1% by weight or less. The upper and lower limits can be combined as appropriate.

[0014] "animal" The compositions of the present invention are effective against animals, including humans, but are not limited to humans, dogs, cats, ferrets, hamsters, chinchillas, rabbits, sheep, goats, cattle, water buffalo, yaks, pigs, horses, llamas, alpacas, deer, donkeys, zebu cattle, zebras, elephants, orangutans, chimpanzees, gorillas, lemurs, gibbons, baboons, chickens, turkeys, ducks, emus, geese, ostriches, gerbils, rats, parrots, canaries, Galliformes, Anatidae, or passerines.

[0015] Other ingredients The composition of the present invention may contain ingredients other than citral (other ingredients) as long as the effects of the present invention can be achieved. Examples of other ingredients include excipients such as gelatin, sodium alginate, starch, corn starch, sucrose, lactose, glucose, mannitol, carboxymethylcellulose, dextrin, polyvinylpyrrolidone, crystalline cellulose, soybean lecithin, sucrose, fatty acid esters, talc, magnesium stearate, polyethylene glycol, magnesium silicate, silicic anhydride, and synthetic aluminum silicate, binders, disintegrants, surfactants, lubricants, flow enhancers, diluents, preservatives, colorants, flavorings, flavoring agents, stabilizers, humectants, antiseptics, or antioxidants, water-soluble solvents such as physiological saline or Ringer's solution, water-insoluble solvents such as vegetable oils or fatty acid esters, isotonicity agents such as glucose or sodium chloride, solubilizers, stabilizers, preservatives, suspending agents, or emulsifiers. Further examples of other ingredients include food ingredients and food additives such as edible oils and fats, water, emulsifiers such as edible oils and fats, glycerin fatty acid esters, sucrose fatty acid esters, sorbitan fatty acid esters, propylene glycol fatty acid esters, glycerin organic acid fatty acid esters, polyglycerin fatty acid esters, calcium stearoyl lactylate, sodium stearoyl lactylate, and polyoxyethylene sorbitan fatty acid esters; thickening and stabilizing agents such as locust bean gum, carrageenan, alginic acids, pectin, xanthan gum, crystalline cellulose, carboxymethylcellulose, methylcellulose, agar, glucomannan, gelatin, starch, and modified starch; salting agents such as salt and potassium chloride; acidulants such as acetic acid, lactic acid, and gluconic acid; sugars or sugar alcohols; sweeteners such as stevia or aspartame; coloring agents such as beta-carotene, caramel, and red koji pigment; antioxidants such as tocopherol and tea extract; flavorings; pH adjusters; food preservatives; and shelf-life enhancers. The total content of other components in the composition of the present invention is preferably 80% by mass or less, more preferably 40% by mass or less, and even more preferably 20% by mass or less.

[0016] [2] Method for preventing or treating Malassezia skin diseases The method for preventing or treating Malassezia skin diseases of the present invention includes a step of contacting an effective amount of citral with the skin of an animal (excluding humans). In the method for preventing or treating Malassezia skin diseases of the present invention, the compositions described in the above section "Composition for preventing or treating Malassezia skin diseases" can be used without limitation. In the method for preventing or treating Malassezia skin diseases, "Malassezia," "Malassezia skin diseases," "citral," "animal," etc. are the same as those described in the above section "Composition for preventing or treating Malassezia skin diseases." However, in the method for preventing or treating Malassezia skin diseases, although not limited thereto, the animal is preferably an animal excluding humans.

[0017] The contact of citral with the skin is not particularly limited, and examples thereof include application, spraying, immersion, or washing with the composition of the present invention. The dosage of citral can be determined appropriately depending on, for example, the type or amount of citral isomer used, the type of Malassezia skin disease, the age, sex, and body weight of the animal, the severity of symptoms, or the administration method. For example, the lower limit of the citral concentration when the composition is applied is not limited, but in some embodiments it is 0.001% by weight or more, in some embodiments it is 0.01% by weight or more, in some embodiments it is 0.05% by weight, and in some embodiments it is 0.1% by weight. The upper limit is also not limited, as long as it is an amount that can be contained in the composition, but in some embodiments it is 80% by weight or less, in some embodiments it is 50% by weight or less, in some embodiments it is 20% by weight or less, in some embodiments it is 10% by weight or less, in some embodiments it is 50% by weight or less, in some embodiments it is 2% by weight or less, and in some embodiments it is 1% by weight or less. The upper and lower limits can be combined as appropriate. The administration method, dosage, administration period, administration interval, etc. of citral should preferably be determined through controlled clinical trials. [Example]

[0018] The present invention will be specifically described below with reference to examples, but these examples are not intended to limit the scope of the present invention.

[0019] 《Reference example 1》 In this reference example, the susceptibility of Malassezia pachydermatis isolated from dog skin to itraconazole was examined. The minimum inhibitory concentration (MIC) of the azole antifungal drug itraconazole was measured for Malassezia pachydermatis isolated from domestic pet dogs with healthy skin and dermatitis (including otitis externa) in 2010 and 2020. The 2010 isolates were measured using the disk method (Non-Patent Document 1), and the 2020 isolates were measured using a modified CLSI method (Non-Patent Document 2). The results showed that the MIC of the 2020 isolates from both healthy dogs and dermatitis dogs was significantly higher than that of the 2010 isolates. 50 (50% inhibitory concentration of test strain) and MIC 90 Both values ​​(90% inhibitory concentration of the test strain) were high, and the number of strains with low susceptibility to itraconazole was increasing.

[0020] [Table 1] As shown in Table 1, compared with 2010, there was an increase in itraconazole-resistant strains of Malassezia pachydermati isolated in 2020.

[0021] Malassezia pachydermatis (21 strains, 21 dogs) isolated from canine skin diseases (including otitis externa) between 2020 and 2023 were tested for susceptibility to arylamine and azole antifungal drugs using a modified CLSI method (Non-Patent Document 3). 50 and MIC 90 Both values ​​were high, indicating the emergence of many multidrug-resistant strains (Table 2).

[0022] [Table 2]

[0023] Example 1 In this example, the effect of citral on azole antifungal drug-resistant Malassezia was investigated. The type strain of Malassezia pachydermatis (CBS 1879 T The minimum inhibitory concentrations (expressed as % because it is a liquid) of citral were measured using a modified CLSI method for eight azole antifungal drug-resistant strains isolated from dogs with Malassezia dermatitis (including otitis externa) from 2020 to 2023 (Non-Patent Document 3). The results showed that the inhibitory concentrations for citral were 0.03-0.125%, and growth inhibition was observed even at low concentrations against azole antifungal drug-resistant strains (Table 3).

[0024] [Table 3] As shown in Table 3, citral exhibited a high antibacterial activity against azole antifungal drug-resistant Malassezia.

[0025] Example 2 and Comparative Example 1 In this example, the antibacterial effects of a shampoo containing citral (Example 2) and a shampoo containing no citral (Comparative Example 1) against azole antifungal drug-resistant Malassezia were investigated. CBS1879 T Strains 22-M2, 22-M3, 23-M6, and 23-M8 were cultured on modified Dixon agar medium at 32°C for 4 days. Colonies were collected and adjusted to a McFarland 2.0 turbidity in sterile saline. Each strain was spread onto Sabouraud glucose agar medium supplemented with 1% Twenn 80. Test solutions were prepared by diluting shampoo containing 0.5% citral by weight or shampoo without citral to 10%. After placing discs for susceptibility testing on the agar medium, 10 μL of the test solution was applied dropwise to each disc. After incubation at 32°C for 4 to 7 days, the diameter (cm) of the zone of growth inhibition was measured. The results are shown in Table 4 and Figure 3.

[0026] [Table 4] As shown in Figure 3 and Table 4, the shampoo containing citral had a larger inhibition zone diameter than the shampoo containing no citral.

[0027] Example 3 and Comparative Example 2 Example 2 and Comparative Example 1 In this example, the antibacterial effects of ear cleansing containing citral (Example 3) and ear cleansing containing no citral (Comparative Example 2) against azole antifungal drug-resistant Malassezia were examined. The procedures of Example 2 and Comparative Example 1 were repeated, except that ear cleansing was used instead of shampoo. The results are shown in Table 5 and Figure 4.

[0028] [Table 5] The diameter of the inhibition zone was larger for all strains in the ear cleanser containing citral than in the uncontaining ear cleanser. Although the ear cleanser base alone has antibacterial activity, the antibacterial effect was confirmed to be enhanced by citral. [Industrial Applicability]

[0029] The composition for preventing or treating Malassezia skin diseases and the method for preventing or treating Malassezia skin diseases in animals of the present invention can be used for preventing or treating Malassezia skin diseases.

Claims

1. A composition for preventing or treating Malassezia skin diseases, comprising citral as an active ingredient.

2. The composition of claim 1, wherein the Malassezia skin disease is Malassezia dermatitis, seborrheic dermatitis, atopic dermatitis, or otitis externa in animals.

3. The composition according to claim 1 or 2, wherein the Malassezia is an azole antifungal drug-resistant Malassezia.

4. The composition according to claim 1 or 2, wherein the composition is a shampoo composition, an ear drop composition, an ear canal cleansing composition, a skin moisturizing composition, a soap composition, a skin care composition, a facial cleanser composition, or a body wash composition.

5. A method for preventing or treating Malassezia skin diseases in animals, comprising the step of contacting an effective amount of citral with the skin of an animal (excluding humans).

6. The method for preventing or treating a Malassezia skin disease according to claim 5, wherein the Malassezia skin disease is Malassezia dermatitis, seborrheic dermatitis, atopic dermatitis, or otitis externa in an animal.

7. The method for preventing or treating Malassezia skin diseases according to claim 5 or 6, wherein the contacting step is a step of contacting a shampoo composition, an ear drop composition, an ear canal cleansing composition, a skin moisturizing composition, a soap composition, a skin care composition, a facial cleanser composition, or a body soap composition.

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