Application of luliconazole in preparation of medicine for treating mycotic tinea disease of pets

Abstract

The invention belongs to the technical field of veterinary chemical preparations, and particularly relates to application of luliconazole in preparation of a medicine for treating pet fungal tinea. The invention further provides a luliconazole spray for treating the pet fungal tinea disease. The luliconazole spray is prepared from luliconazole, a solvent, a bacteriostatic agent, a transdermal enhancer, a tackifier, a pH regulator and an aromatic. The luliconazole spray prepared by the invention is simple in preparation process, has a remarkable effect on treating mycotic tinea diseases, such as claw tinea, tinea corporis, tinea cruris and the like, of pets caused by microsporum canis infection, and has a wide clinical prospect.

Description

Technical Field

[0001] The invention belongs to the technical field of veterinary chemical preparations, and in particular relates to the application of luliconazole in preparing a medicine for treating fungal tinea of ​​pets. Background Art

[0002] Microsporum canis was first discovered by Gruby in 1843 and has been considered a common pathogenic fungus. It is often the pathogen of tinea capitis, tinea corporis, a few onychomycosis and other rare fungal diseases. As an animal-loving fungus and a keratinophilic dermatophyte, Microsporum canis is particularly prone to parasitizing the stratum corneum of the skin of dogs and cats. It can exist on animals for a long time without causing disease (especially in dogs and cats), but when the animal's resistance is reduced, fungal skin diseases will occur. When the disease occurs, irregular scaly protrusions will appear on the affected area, and symptoms such as hair loss, broken hair, papules, itching, and pustules will appear. Once infected, not only is the course of the disease long, but it is also difficult to cure, and it is easy to relapse after recovery, causing great harm to the health of pets. According to surveys, 70% of canine fungal skin diseases are caused by Microsporum canis, and in cats, it is as high as 98%. And Microsporum canis is a zoonotic bacteria. Once it infects humans, it will cause skin damage and endanger human health. It is understood that about 50% of infected people are infected through animals. Therefore, it is very important to treat pet fungal diseases caused by Microsporum canis and cut off the source of infection.

[0003] According to the data published in the "2021 Pet Industry White Paper", the number of dogs and cats in urban areas across the country reached 110 million in 2021, an increase of 11.4% over 2020. More and more people are raising dogs and cats, which greatly increases the chance of infection with Microsporum canis. If the disease is not treated in time or the local treatment is improper, such as the application of highly irritating drugs or the use of adrenocortical hormones and antibiotics, it can often cause additional skin damage, which can easily lead to accidental injuries and missed treatment. The disease continues to develop and worsen, and it is also easy to stimulate the body's response to Microsporum canis, resulting in systemic itching, redness, swelling, and abscesses, and even the development of kerion or secondary bacterial infection, such as preparations containing ethanol, glucocorticoids, etc.

[0004] Luliconazole is a new type of imidazole topical antifungal drug. It was approved by the US FDA in November 2013 for the treatment of interdigital tinea pedis, tinea cruris and tinea corporis. It became the first drug in the United States that only needs to be taken once a day for one week for the treatment of tinea cruris and tinea corporis (other drugs require two weeks of treatment). Later, other dosage forms were launched, including creams and topical solutions. Currently, it is only used for humans, and no drugs have been approved for pets. Other antifungal drugs approved for pets include lanoconazole, fluconazole, enilconazole, terbinafine, itraconazole, etc., but in comparison, luliconazole has the lowest MIC value for Microsporum canis (0.001-0.004μg / ml) and is more sensitive. In addition, terbinafine is widely used in humans, but is frequently abused in pets, and has durability, while itraconazole has certain restrictions on dog breeds (such as it cannot be used in Collies), etc. Therefore, it is more advantageous to develop preparations with luliconazole as the active ingredient.

[0005] Compared with the dosage forms of luliconazole drug preparations for human use, such as creams and topical solutions, creams have the disadvantages of slow absorption, inconvenient administration to pets, and easy licking by pets. Topical solutions also have the disadvantages of inconvenient administration, so the development of luliconazole spray is a good choice. Currently, the existing patented technologies for luliconazole spray mostly use a large amount of anhydrous ethanol as a solvent, which is highly irritating. People and pets have different sensitivities and control. When containing irritating solvents, pets may resist administration, severely cause animals to scratch and aggravate skin damage, and low viscosity may easily cause drug loss and waste. Drug sprays are easy to lose and have poor transdermal absorption effects. Therefore, preparing a luliconazole spray with low irritation, long drug residence time, good transdermal absorption effect, and high bioavailability is a major problem that needs to be solved in this field. Summary of the invention

[0006] In order to solve the problems in the prior art, the present invention provides the use of luliconazole in the preparation of a drug for treating fungal ringworm in pets. The specific technical scheme is as follows:

[0007] In a first aspect, the present invention provides the use of luliconazole in the preparation of a medicament for treating fungal tinea in pets.

[0008] Furthermore, the pet fungal tinea is tinea cruris, tinea corporis, and tinea cruris.

[0009] Furthermore, the pet fungal ringworm is caused by infection with Microsporum canis.

[0010] In a second aspect, the present invention provides a luliconazole spray for treating fungal ringworm in pets, characterized in that the luliconazole spray is composed of the following components: luliconazole, a solvent, an antibacterial agent, a transdermal enhancer, a viscosity enhancer, a pH regulator, and a fragrance.

[0011] Furthermore, the components in the luliconazole spray and their mass volume ratios are: luliconazole 0.2-10%, antibacterial agent 0.1-4%, transdermal enhancer 0.2-10%, viscosity enhancer 0.2-10%, pH adjuster 0.5-5%, fragrance 0.5-10%, and the balance is solvent.

[0012] Preferably, the components in the spray and their mass volume ratios are: luliconazole 1-5%, antibacterial agent 0.1-1%, transdermal enhancer 2-8%, viscosity enhancer 3-10%, pH adjuster 0.5-2%, fragrance 1-5%, and the balance is solvent.

[0013] More preferably, the components in the spray and their mass volume ratios are: luliconazole 1%, antibacterial agent 0.1%, transdermal enhancer 5%, viscosity enhancer 10%, pH adjuster 0.5%, fragrance 1%, and the balance is solvent.

[0014] Furthermore, the solvent is selected from one or a combination of anhydrous ethanol, propylene glycol, isopropanol, and polyethylene glycol.

[0015] Furthermore, the antibacterial agent is selected from one or a combination of sodium benzoate, benzyl alcohol, and phenoxyethanol.

[0016] Furthermore, the transdermal enhancer is selected from one or a combination of laurocapram, N-methyl-2-pyrrolidone, and sodium dodecyl sulfate.

[0017] Furthermore, the viscosity enhancer is selected from one or a combination of cetyl alcohol, stearyl alcohol, cetostearyl alcohol, and povidone.

[0018] Furthermore, the pH adjuster is selected from one or a combination of phosphoric acid, hydrochloric acid, and sodium hydroxide, preferably sodium hydroxide.

[0019] Furthermore, the fragrance is selected from one or a combination of lavender essential oil, peppermint essence, and aloe essence.

[0020] Furthermore, a preferred implementation scheme is: the components in the spray and their mass volume ratios are: 1% luliconazole, 0.1% benzyl alcohol, 5% N-methyl-2-pyrrolidone, 10% povidone, 0.5% pH adjuster, 1% lavender essential oil, and 82.4% isopropyl alcohol.

[0021] In a third aspect, the present invention provides a method for preparing a luliconazole spray for treating fungal ringworm in pets, the steps of which are as follows:

[0022] (1) Add 80% of the prescribed amount of solvent into a liquid preparation tank, start stirring, and add a transdermal enhancer, a viscosity enhancer, an antibacterial agent, and a fragrance in sequence to completely dissolve and mix to obtain a solution for use;

[0023] (2) adding a prescribed amount of luliconazole to the solution of step (1), stirring to dissolve the solution, and setting aside;

[0024] (3) diluting the solution obtained in step (2) to the required volume with the remaining solvent;

[0025] (4) adjusting the pH of the solution to 7.5-8.0 with a pH adjuster;

[0026] (5) The solution is filtered and bottled to obtain the finished product.

[0027] The technical solution of the present invention is based on the fact that luliconazole is a new type of imidazole antifungal drug, which has a lower MIC value and is more sensitive to Microsporum canis than several commercially available antifungal drugs.

[0028] Beneficial effects:

[0029] 1. The luliconazole spray prepared by the present invention has a relatively simple preparation process and uses isopropyl alcohol or the like as a solvent, thereby reducing the irritation of the solvents used in the prior art to the pet's skin, making it easier for the pet to accept, reducing pain and scratching.

[0030] 2. The luliconazole spray prepared by the present invention adds povidone or the like as a viscosity enhancer, which prolongs the retention time of the drug solution in the skin, thereby prolonging the drug efficacy and achieving a long-lasting effect.

[0031] 3. The luliconazole spray prepared by the present invention is added with aromatics such as lavender essential oil. It has a fragrant smell and is easy for pets to accept. It can also promote cell regeneration, remove scars, and relieve irritability.

[0032] 4. The luliconazole spray prepared by the present invention has a simple preparation process and is effective in treating fungal tinea (such as tinea cruris, tinea corporis, and tinea cruris) caused by Microsporum canis infection in dogs and cats. DETAILED DESCRIPTION

[0033] Example 1

[0034] A luliconazole spray for treating fungal ringworm in pets, the ingredients and dosage of which are as follows:

[0035] Element Single dose (100ml / bottle) Luliconazole 1g Phenoxyethanol (antibacterial agent) 0.1g Sodium lauryl sulfate (skin penetration enhancer) 5g Povidone (thickening agent) 10g Sodium hydroxide (pH adjuster) 0.5g Lavender essential oil (fragrance) 1g Propylene glycol (solvent) Make up to 100ml

[0036] Example 2

[0037] A luliconazole spray for treating fungal ringworm in pets, the ingredients and dosage of which are as follows:

[0038] Element Single dose (100ml / bottle) Luliconazole 1g Benzyl alcohol (antibacterial agent) 0.1g N-Methyl-2-pyrrolidone (skin penetration enhancer) 5g Cetostearyl Alcohol (Thickener) 10g Sodium hydroxide (pH adjuster) 0.5g Mint flavor (fragrance) 1g Polyethylene glycol (solvent) Make up to 100ml

[0039] Example 3

[0040] A luliconazole spray for treating fungal ringworm in pets, the ingredients and dosage of which are as follows:

[0041]

[0042]

[0043] Example 4

[0044] A luliconazole spray for treating fungal ringworm in pets, the ingredients and dosage of which are as follows:

[0045] Element Single dose (100ml / bottle) Luliconazole 1g Benzyl alcohol (antibacterial agent) 0.1g N-Methyl-2-pyrrolidone (skin penetration enhancer) 5g Povidone (thickening agent) 10g Sodium hydroxide (pH adjuster) 0.5g Lavender essential oil (fragrance) 1g Isopropyl alcohol (solvent) Make up to 100ml

[0046] Comparative Example 1

[0047] A luliconazole spray for treating fungal ringworm in pets, the ingredients and dosage of which are as follows:

[0048] Element Single dose (100ml / bottle) Luliconazole 1g Benzyl alcohol (antibacterial agent) 0.1g N-Methyl-2-pyrrolidone (skin penetration enhancer) 5g Povidone (thickening agent) 10g Sodium hydroxide (pH adjuster) 0.5g Aloe Vera Fragrance (Fragrance) 1g Isopropyl alcohol (solvent) Make up to 100ml

[0049] Comparative Example 2

[0050] A luliconazole spray for treating fungal ringworm in pets, the ingredients and dosage of which are as follows:

[0051]

[0052]

[0053] The preparation methods of Examples 1-4 and Comparative Examples 1-2 are as follows: Weigh 80% of the prescribed amount of solvent, add it to the liquid preparation tank, start stirring, add the transdermal enhancer, viscosity enhancer, antibacterial agent, and fragrance in sequence, and make them completely dissolved and mixed evenly to obtain a solution. Add the prescribed amount of luliconazole to the solution, stir and dissolve, dilute to 100 ml with the remaining solvent, and adjust the pH to 7.5-8.0 with a pH adjuster. The solution is filtered and filled to obtain luliconazole spray.

[0054] Example 5 Skin irritation study

[0055] Test method: 15 rabbits were collected and divided into 5 groups (3 rabbits / group). Before administration, the hair on both sides of the spine of the rabbits were shaved, and the shaved area on the left and right sides was the same. The hair-free and disinfected skin was scratched with a sterilized needle tip until bleeding occurred to simulate the affected area. Each group of rabbits had a total of 6 hair-free areas, and were administered with Examples 1-4, Comparative Example 2, and normal saline, respectively. After 48 hours, the skin was observed with the naked eye and the skin changes were recorded.

[0056] Table 1 Scoring criteria and stimulus intensity judgment criteria

[0057]

[0058] Skin irritation intensity standard (the sum of redness and edema scores): no irritation: 0 points, mild irritation: 1-2 points, moderate irritation: 3-5 points, severe irritation: 6-8 points.

[0059] Test results:

[0060] Table 2 Skin irritation test results

[0061]

[0062] The skin irritation test results of Examples 1-4, Comparative Example 2 and the saline control group show that Comparative Example 2 and Example 1 are moderately or severely irritating, indicating that when anhydrous ethanol and propylene glycol are used as solvents in luliconazole spray, the solution is irritating to the skin, causing different degrees of redness, swelling and edema; while when polyethylene glycol and isopropanol are used as solvents, mild irritation is caused, which is not much different from the saline control group.

[0063] Example 6 Investigation of skin repair at the affected area

[0064] The repair situation of the skin affected part of 15 rabbits after medication was statistically analyzed in Examples 1-4 and Comparative Examples 1-2. According to the observation, the wound of the rabbit affected part of Example 4 began to heal about 5 days after administration, and the wound of the rabbit affected part of Comparative Example 1, Comparative Example 2, Examples 1, 2, and 3 began to heal at 7 days, 9 days, 10 days, 10 days, and 10 days, respectively. Therefore, it can be preliminarily concluded that lavender essential oil has the effect of accelerating cell regeneration and promoting cell growth. In addition, the reason why the affected part skin repaired slowly by using anhydrous ethanol as a solvent in Comparative Example 2 may be that ethanol causes irritation, causing secondary skin infection.

[0065] Example 7 Release Amount Investigation

[0066] Take pig abdominal skin (including stratum corneum and dermis) to simulate pet skin, soak in saline for half an hour to thaw before use, and use within 24 hours. The Franz diffusion cell method was used for the test, and the pig skin was fixed in the middle of the diffusion cell. The pig skin area was 0.785cm 2(i.e., effective penetration area), the stratum corneum of pig skin faces the supply pool, the dermis faces the receiving pool, the receiving solution is 5% Tween pH7.4 phosphate buffer, the receiving solution temperature is 37±0.5°C, and the rotor stirring speed in the diffusion pool is 300rpm. Take the luliconazole spray prepared in Examples 1-4 and Comparative Example 2, 6 diffusion pools for each example, the diffusion pool volume is 3ml, the dosage is 1ml, take 1ml of the receiving solution from the receiving pool at 0.5, 1, 2, 4, 6, and 12 hours, filter through a 0.22μm microporous membrane, and perform liquid chromatography detection. After taking out the receiving solution, replenish the receiving solution immediately. Calculate the cumulative penetration, the results are as follows:

[0067] Table 3 Product transdermal effect investigation

[0068]

[0069] From the above results, it can be seen that Examples 1-4 and Comparative Example 2 all show a trend of release rate being fast at first and then slow. After 12 hours of release, the cumulative release amounts of Comparative Example 2 and Examples 2 and 4 are higher than those of Examples 1 and 3, indicating that the transdermal promotion effect of N-methyl-2-pyrrolidone in this formula is stronger than that of sodium dodecyl sulfate and laurocapron.

[0070] Example 8 Evaluation of the effect of treating dog and cat claw ringworm

[0071] Comparative Example 2, Examples 2 and 4 were selected to evaluate the effect of luliconazole spray in treating nail tinea. A total of 20 dogs (5 dogs in each of Comparative Example 2, Examples 2 and 4 as experimental groups, and 5 dogs in blank control groups) and 20 cats (5 dogs in each of Comparative Example 2, Examples 2 and 4 as experimental groups, and 5 dogs in blank control groups) suffering from nail tinea were collected, wherein the experimental group was given luliconazole spray once a day for 7 consecutive days. The control group was not given any treatment, and the effect was observed after 7 days. The pruritus level was used as the criterion for judgment.

[0072] Table 4 Itch grade scoring criteria

[0073]

[0074] The test results of dogs using comparative example 2, embodiments 2, 4 and a blank control group are as follows:

[0075] Table 5 Evaluation results of the effect on canine nail ringworm

[0076]

[0077] The test results of cat using comparative example 2, embodiments 2, 4 and blank control group are as follows:

[0078] Table 6 Evaluation results of cat's claw ringworm effect

[0079]

[0080] The test results show that after 7 days of treatment with luliconazole spray, the scores of dogs and cats were reduced compared with the blank control group. However, it was found during the test that when comparative example 2 used ethanol as the solvent, it was highly irritating and secondary skin diseases may occur after the drug is sprayed on the affected area. The scores of Examples 2 and 4 were greatly reduced after administration, indicating that luliconazole spray has a significant effect on the treatment of ringworm in dogs and cats.

[0081] The affected area size of Examples 2 and 4 was evaluated 7 days after administration, and the evaluation basis was as follows:

[0082] Table 7 Basis for evaluating the therapeutic effect of dog and cat claw ringworm

[0083] Rating (points) symptom 0 The affected area has not changed much 1 The affected area is reduced by 10% 2 Reduced the affected area by 50% 3 The affected area is reduced by 70% 4 The affected area has basically healed

[0084] The test results are as follows:

[0085] Table 8 Evaluation results of the treatment effect of dog and cat tinea

[0086]

[0087] The test results show that the addition of lavender essential oil to luliconazole spray is beneficial to the rapid healing of wounds on the affected area. In addition, during the test, it was found that after the administration of Example 4, due to the low boiling point of isopropyl alcohol, it quickly evaporated and quickly formed a film attached to the affected area due to the presence of the thickener povidone, and the affected area disappeared faster.

[0088] In summary, the luliconazole spray provided by the present invention can be effectively used to treat pet fungal skin diseases caused by Microsporum canis.

[0089] The present invention is described above by way of example. It should be noted that, without departing from the core of the present invention, any simple deformation, modification or other equivalent replacement that can be made by those skilled in the art without inventive effort falls within the protection scope of the present invention.

Claims

1. The use of luliconazole in the preparation of a drug for treating fungal tinea in pets, characterized in that: The fungal tinea of ​​pets are tinea pedis, tinea corporis and tinea cruris.

2. The use according to claim 1, characterized in that The pet fungal tinea is caused by infection with Microsporum canis.

3. A luliconazole spray for treating fungal tinea in pets, characterized in that: The spray is composed of the following components: luliconazole, solvent, antibacterial agent, skin penetration accelerator, viscosity enhancer, pH regulator and fragrance.

4. The luliconazole spray according to claim 3, characterized in that The components in the spray and their mass volume ratios are: 0.2-10% luliconazole, 0.1-4% antibacterial agent, 0.2-10% transdermal enhancer, 0.2-10% viscosity enhancer, 0.5-5% pH regulator, 0.5-10% fragrance, and the balance is solvent.

5. The luliconazole spray according to claim 4, characterized in that: The components in the spray and their mass volume ratios are: 1-5% of luliconazole, 0.1-1% of antibacterial agent, 2-8% of transdermal enhancer, 3-10% of viscosity enhancer, The pH adjuster is 0.5-2%, the fragrance is 1-5%, and the balance is solvent.

6. The luliconazole spray according to any one of claims 3 to 5, characterized in that The solvent is selected from one or a combination of anhydrous ethanol, propylene glycol, isopropanol, and polyethylene glycol.

7. The luliconazole spray according to any one of claims 3 to 5, characterized in that The transdermal enhancer is selected from one or a combination of laurocapram, N-methyl-2-pyrrolidone and sodium dodecyl sulfate.

8. The luliconazole spray according to any one of claims 3 to 5, characterized in that The viscosity enhancer is selected from one or a combination of cetyl alcohol, stearyl alcohol, cetostearyl alcohol, and povidone.

9. The luliconazole spray according to any one of claims 3 to 5, characterized in that The antibacterial agent is selected from one or a combination of sodium benzoate, benzyl alcohol, and phenoxyethanol; the pH regulator is selected from one or a combination of phosphoric acid, hydrochloric acid, and sodium hydroxide.

10. The luliconazole spray according to any one of claims 3 to 5, characterized in that The aromatic agent is selected from a combination of lavender essential oil, mint essence, and aloe essence.

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