Low-irritation nystatin ointment for pets and preparation method of low-irritation nystatin ointment

Abstract

The invention belongs to the technical field of medicine preparation, and particularly relates to low-irritation nystatin ointment for pets and a preparation method of the low-irritation nystatin ointment. The low-irritation nystatin ointment for pets provided by the invention is prepared from the following raw materials in percentage by mass: 0.1 to 0.5 percent of neomycin sulfate, 5 to 25 percent of sustained-release nystatin, 0.05 to 0.2 percent of triamcinolone acetonide, 0.1 to 2.5 percent of permethrin nanoparticles and the balance of paraffin. According to the low-irritation nystatin ointment for pets provided by the invention, the nystatin ointment with good bactericidal activity, stable components and low irritation is obtained by modifying and optimizing the raw material components in the nystatin ointment, and the nystatin ointment is beneficial to treating fungal infection diseases of pets.

Description

Technical Field

[0001] The invention belongs to the technical field of drug preparation, and particularly relates to a low-irritation nystatin ointment for pets and a preparation method thereof. Background Art

[0002] Compound nystatin ointment uses nystatin as the main antifungal ingredient. Among them, nystatin belongs to the polyene antifungal antibiotics, which can bind to the sterols on the fungal cell membrane, change the permeability of the cell membrane, and cause the leakage of important substances in the cell, thereby exerting an antifungal effect, and has a good inhibitory and killing effect on a variety of fungi such as Candida. In addition to nystatin, other ingredients are added to enhance the efficacy or improve the performance of the drug. For example, an appropriate amount of glucocorticoids such as triamcinolone acetonide may be added, which has anti-inflammatory and antipruritic effects, can reduce the inflammatory response and itching symptoms caused by fungal infections, and also helps to relieve allergic reactions such as local skin redness and swelling. It may also contain antibiotics such as neomycin for the prevention and treatment of possible accompanying bacterial infections, because after skin fungal infections, the skin barrier is damaged and secondary bacterial infections are prone to occur.

[0003] CN103933545A discloses a drug for treating fungal infection and a preparation method thereof. The drug is prepared according to the following mass percentages: 5.86-13.4% of active components, 10-24% of mineral oil, 12-30% of propylene glycol, 10-24% of glycerol, 3-12% of DC-345, 0.5-2% of sodium chloride, 0.5-6% of EM-90, 12-10% of R933, and the balance is made up of water. The active components include 1.2-2.0% of nystatin, 0.4-0.8% of neomycin sulfate, 0.2-0.5% of polymyxin B sulfate, 0.06-0.1% of triamcinolone acetonide, and 4-10% of lidocaine sulfate. The drug is mainly used for various common skin diseases caused by fungal infections in pet dogs and cats, as well as wound infections, ulcers, or long-term non-healing caused by trauma. However, ordinary compound nystatin ointment is highly irritating, and pets have sensitive skin. When using ordinary compound nystatin ointment, skin irritation symptoms may occur. Because some ingredients in the ointment have a direct irritating effect on the skin, such as burning and stinging, it is not only not conducive to the treatment of pet skin diseases, but may also complicate the original skin condition. And when using compound nystatin ointment to treat pet skin diseases, the drugs in it are affected by environmental factors and there is a problem of short drug residence time. Under direct sunlight, nystatin, permethrin, etc. in the ointment applied to the skin surface may undergo photodegradation reactions, and its chemical structure is destroyed, resulting in reduced antifungal activity, which greatly reduces the therapeutic effect of nystatin ointment.

[0004] Therefore, it is of great significance to develop a nystatin ointment that can exert its efficacy for a long time and has low irritation. Summary of the invention

[0005] In view of the deficiencies in the prior art, the present invention provides a low-irritation nystatin ointment for pets. By modifying and optimizing the raw material components therein, a nystatin ointment with good bactericidal properties, stable ingredients and low irritation is obtained, which is beneficial for treating fungal infections of pets.

[0006] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0007] The first aspect of the present invention provides a low-irritation nystatin ointment for pets, which comprises the following raw materials, calculated by 100% by mass:

[0008] Neomycin sulfate 0.1-0.5%, sustained-release nystatin 5-25%, triamcinolone acetonide 0.05-0.2%, permethrin nanoparticles 0.1-2.5%, and the rest is paraffin.

[0009] In some embodiments, the preparation method of the sustained-release nystatin is:

[0010] The dispersion of nystatin is added to the gelatin solution, mixed evenly, and then the solution of polyglycolic acid is added dropwise thereto, stirred sufficiently, and dried to obtain sustained-release nystatin.

[0011] In some embodiments, the mass ratio of gelatin, nystatin, and polyglycolic acid is (2.5-3.5):(0.8-1.3):1.

[0012] Preferably, the mass ratio of gelatin, nystatin and polyglycolic acid is 3:1:1.

[0013] In some embodiments, the number average molecular weight of the polyglycolic acid is 5,000-20,000.

[0014] In some embodiments, the preparation steps of the permethrin nanoparticles are:

[0015] Permethrin is put into a surfactant solution and stirred evenly, then chitosan is added and stirred evenly, high pressure homogenization is performed, and then the mixture is cooled and dried to obtain permethrin nanoparticles.

[0016] In some embodiments, the surfactant is a quaternary ammonium salt surfactant.

[0017] In some embodiments, the mass ratio of permethrin, surfactant, and chitosan in the permethrin nanoparticles is (0.8-1.2):(0.8-1.2):0.1.

[0018] Preferably, the mass ratio of permethrin, surfactant and chitosan in the permethrin nanoparticles is 1:1:0.1.

[0019] In some embodiments, the number average molecular weight of the chitosan is 50,000-150,000.

[0020] In some embodiments, the paraffin wax comprises liquid paraffin and polyethylene paraffin.

[0021] The second aspect of the present invention provides a method for preparing a low-irritation nystatin ointment for pets, comprising the following preparation steps:

[0022] Take liquid paraffin, heat it to 80-90° C., then add polyethylene paraffin, stir until the polyethylene paraffin is completely dissolved into a transparent and clear state, cool it to 40-50° C., add triamcinolone acetonide, neomycin sulfate, sustained-release nystatin, and permethrin nanoparticles in sequence under stirring, and homogenize after each raw material is added, stir to cool, and fill to obtain the nystatin ointment.

[0023] The compound nystatin ointment currently on the market may reduce its efficacy during storage due to environmental factors, and after being applied to the pet's skin, the nystatin and other functional substances therein may be quickly metabolized or lost due to factors such as skin absorption and sweat washing, resulting in a shorter effective action time at the infected site. The present invention processes nystatin to obtain a sustained-release nystatin, so that nystatin can be slowly released, maintained within the effective concentration range for a long time, continuously inhibiting fungal growth, reducing the number of ointment applications, and improving the convenience of treatment; at the same time, the stability of nystatin is also improved to a certain extent. In the preparation process of the present invention, the nystatin dispersion is first added to the gelatin solution, gelatin is a natural high molecular polymer, rich in functional groups such as carboxyl and amino groups, and nystatin molecules can be combined with gelatin molecules in the gelatin solution through physical adsorption, hydrogen bonds and other interactions, and then the polyglycolic acid solution is added dropwise, and the active groups such as carboxyl groups on its molecular chain further interact with the gelatin molecules and nystatin molecules. Moreover, the solubility of polyglycolic acid in water and other properties are different from those of gelatin. This difference leads to the gradual formation of a coacervate phase among the three during the stirring process, which wraps the nystatin inside. After drying, gelatin and polyglycolic acid form a solid carrier with a certain pore structure. The nystatin molecules are dispersed and fixed in this carrier structure, which can act as a physical barrier for nystatin, prevent its release too quickly, and improve stability.

[0024] In addition, the permethrin in the raw material of compound nystatin ointment may cause certain irritation to the skin and mucous membrane of pets, especially in the case of high concentration or frequent use; permethrin may reduce its actual antiparasitic effect on the skin surface because it is difficult to penetrate the stratum corneum, and permethrin may be affected by environmental factors during storage and use to reduce the efficacy. In view of these problems, the present invention uses permethrin, quaternary ammonium salt surfactant and chitosan as raw materials, and through high-pressure homogenization, the amino and other functional groups on the chitosan molecules interact with the molecules of the surfactant and the permethrin molecules, and the chitosan can interact with the surfactant and permethrin through electrostatic attraction and other methods. During the high-pressure homogenization process, the system is subjected to high shear force and high pressure, so that permethrin, surfactant and chitosan are further mixed evenly, and the formed aggregates are broken and refined to prepare nano-scale particles that can exist stably. The form of nanoparticles can increase the stability of permethrin and prevent it from being rapidly degraded or volatilized in the ointment. At the same time, nanoparticles can slowly release permethrin, reduce irritation, prolong its action time on the skin surface, continuously exert antiparasitic effects, and improve the effect of nystatin ointment. In addition, quaternary ammonium salt surfactants and chitosan both have antibacterial effects and can synergistically exert antibacterial and bactericidal effects with permethrin.

[0025] Compared with the prior art, the present invention has the following beneficial effects:

[0026] 1. The present invention provides a low-irritation nystatin ointment for pets. By modifying and optimizing the raw material components therein, a nystatin ointment with good bactericidal properties, stable ingredients and low irritation is obtained, which is beneficial for treating fungal infections of pets.

[0027] 2. The present invention processes nystatin to obtain a sustained-release nystatin, so that nystatin can be slowly released and maintained within an effective concentration range for a long time, thereby continuously inhibiting fungal growth, reducing the number of times the ointment is applied, improving the convenience of treatment, and also improving the stability of nystatin to a certain extent.

[0028] 3. The present invention uses permethrin, quaternary ammonium salt surfactant and chitosan as raw materials, and forms nano-scale particles that can exist stably through high-pressure homogenization, thereby increasing the stability of permethrin, slowly releasing permethrin, reducing irritation, prolonging its action time on the skin surface, continuously exerting antiparasitic effects, and improving the effect of nystatin ointment. DETAILED DESCRIPTION

[0029] Now describe in detail various exemplary embodiments of the present invention, this detailed description should not be considered as limitation of the present invention, but should be understood as a more detailed description of certain aspects, characteristics and embodiments of the present invention. It should be understood that the terms described in the present invention are only for describing a particular embodiment, and are not used to limit the present invention. In addition, for the numerical range in the present invention, it should be understood that each intermediate value between the upper limit and the lower limit of the range is also specifically disclosed. Each smaller range between the intermediate value in any stated value or stated range and any other stated value or intermediate value in the range is also included in the present invention. The upper and lower limits of these smaller ranges can be independently included or excluded in the range.

[0030] Unless otherwise indicated, all technical and scientific terms used herein have the same meanings as commonly understood by those skilled in the art. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein may also be used in the practice or testing of the present invention. Various modifications and variations may be made to the specific embodiments of the present invention specification without departing from the scope or spirit of the present invention, which will be apparent to those skilled in the art. Other embodiments obtained from the present invention specification will be apparent to the technician. The present application specification and examples are exemplary only.

[0031] The words “include,” “including,” “have,” or “contain,” etc. used in this document are open-ended terms, meaning including but not limited to.

[0032] It should be noted that the operations such as “grinding”, “centrifuging” and “stirring” described in the present invention are routine operations for those skilled in the art and can be selected according to actual operations.

[0033] The number average molecular weight of the polyglycolic acid used in the present invention is 10,000; the number average molecular weight of the chitosan used is 100,000; and the polyethylene paraffin used is PE-WAX 100.

[0034] Preparation Example 1

[0035] The preparation method of sustained-release nystatin is as follows:

[0036] Add 100 mL of 5 wt % nystatin dispersion to 100 mL of 15 wt % gelatin aqueous solution, stir at 300 r / min for 10 min to mix evenly, then add 50 mL of 10 wt % polyglycolic acid aqueous solution dropwise thereto, stir at 500 r / min for 20 min, and spray dry to obtain sustained-release nystatin.

[0037] Preparation Example 2

[0038] The preparation method of sustained-release nystatin is the same as that of Preparation Example 1, except that 50 mL of 15 wt % gelatin aqueous solution is used.

[0039] Preparation Example 3

[0040] The preparation method of sustained-release nystatin is the same as that of Preparation Example 1, except that 25 mL of 10 wt % polyglycolic acid aqueous solution is used.

[0041] Preparation Example 4

[0042] The preparation method of sustained-release nystatin is as follows:

[0043] Add 100 mL of 5 wt % nystatin dispersion to 100 mL of 15 wt % gelatin aqueous solution, stir at 300 r / min for 10 min to mix evenly, and spray dry to obtain sustained-release nystatin.

[0044] Preparation Example 5

[0045] The preparation method of sustained-release nystatin is as follows:

[0046] 50 mL of 10 wt % polyglycolic acid aqueous solution was added dropwise to 100 mL of 5 wt % nystatin dispersion, stirred at 500 r / min for 20 min, and spray-dried to obtain sustained-release nystatin.

[0047] Preparation Example 6

[0048] The preparation steps of permethrin nanoparticles are as follows:

[0049] 5 g of permethrin was placed in 100 mL of a 5 wt% aqueous solution of hexadecyltrimethylammonium bromide, stirred at 100 r / min for 10 min, and then 0.5 g of chitosan was added, stirred at 500 r / min for 30 min, homogenized at 50°C and 250 MPa for 5 min, cycled 4 times, cooled to room temperature, and spray-dried to obtain permethrin nanoparticles.

[0050] Preparation Example 7

[0051] The preparation steps of permethrin nanoparticles are the same as those in Preparation Example 6, except that 4 g of permethrin is used.

[0052] Preparation Example 8

[0053] The preparation steps of permethrin nanoparticles are the same as those of Preparation Example 6, except that the concentration of the aqueous solution of hexadecyltrimethylammonium bromide used in 100 mL is 2.5 wt %.

[0054] Preparation Example 9

[0055] The preparation steps of permethrin nanoparticles are the same as those in Preparation Example 6, except that the number average molecular weight of the chitosan used is 30,000.

[0056] Example 1

[0057] A method for preparing a low-irritation nystatin ointment for pets, comprising the following preparation steps:

[0058] Take 65g of liquid paraffin, heat it to 80°C, add 29.75g of polyethylene paraffin, stir until the polyethylene paraffin is completely dissolved into a transparent and clear state, then cool to 50°C, add 0.05g of triamcinolone acetonide in sequence under stirring at 100r / min, homogenize at 50MPa for 5min; add 0.1g of neomycin sulfate, homogenize at 50MPa for 5min; add 5g of sustained-release nystatin, homogenize at 50MPa for 5min; finally, add 0.1g of permethrin nanoparticles, homogenize at 50MPa for 5min, stir to cool to room temperature, and fill to obtain the nystatin ointment.

[0059] The sustained-release nystatin used in this example is obtained from Preparation Example 1; the permethrin nanoparticles used are obtained from Preparation Example 6.

[0060] Example 2

[0061] A method for preparing a low-irritation nystatin ointment for pets, comprising the following preparation steps:

[0062] Take 50g of liquid paraffin, heat it to 90°C, add 21.8g of polyethylene paraffin, stir until the polyethylene paraffin is completely dissolved into a transparent and clear state, then cool to 40°C, add 0.2g of triamcinolone acetonide in sequence under stirring at 100r / min, homogenize at 80MPa for 3min; add 0.5g of neomycin sulfate, homogenize at 80MPa for 3min; add 25g of sustained-release nystatin, homogenize at 80MPa for 3min; finally, add 2.5g of permethrin nanoparticles, homogenize at 80MPa for 3min, stir to cool to room temperature, and fill to obtain the nystatin ointment.

[0063] The sustained-release nystatin used in this example is obtained from Preparation Example 1; the permethrin nanoparticles used are obtained from Preparation Example 6.

[0064] Example 3

[0065] A method for preparing a low-irritation nystatin ointment for pets, comprising the following preparation steps:

[0066] Take 60g of liquid paraffin, heat it to 85°C, add 23.1g of polyethylene paraffin, stir until the polyethylene paraffin is completely dissolved into a transparent and clear state, then cool to 45°C, add 0.1g of triamcinolone acetonide in sequence under stirring conditions of 100r / min, homogenize at 65MPa for 4min; add 0.3g of neomycin sulfate, homogenize at 65MPa for 4min; add 15g of sustained-release nystatin, homogenize at 65MPa for 4min; finally, add 1.5g of permethrin nanoparticles, homogenize at 65MPa for 4min, stir to cool to room temperature, and fill to obtain the nystatin ointment.

[0067] The sustained-release nystatin used in this example is obtained from Preparation Example 1; the permethrin nanoparticles used are obtained from Preparation Example 6.

[0068] Performance Testing

[0069] 1. Antibacterial activity experiment of sustained-release nystatin

[0070] Thirty New Zealand white rabbits of similar age and no significant difference in weight were randomly divided into 6 groups. The skin of each New Zealand white rabbit was infected with Escherichia coli, Proteus, Enterobacter, Staphylococcus, Candida albicans, Aspergillus niger, Trichophyton rubrum and Epidermophyton floccosum (all of the above strains can be obtained from commercial channels), and the infection area of ​​each strain was 2cm×2cm. The sustained-release nystatin and nystatin prepared in Preparation Examples 1-5 were prepared with pure water to form a 1wt% test solution, and the in vitro antibacterial activity comparison test was carried out after being placed at 25°C for 0h and at 45°C for 48h, respectively, with a dosage of 25μL / cm 2 The experiment lasted for one week, and the product was applied once a day. The complete disappearance of the infected area on the skin of the New Zealand white rabbit was considered effective and recorded as *, otherwise it was considered ineffective and recorded as ×. The specific results after application are shown in Table 1.

[0071] Table 1

[0072]

[0073] As shown in Table 1, compared with the nystatin group, the sustained-release nystatin obtained in the preparation example has better stability. The sustained-release nystatin obtained in Preparation Example 1 has good bactericidal properties and stability, and still has excellent bactericidal properties after being placed at 45°C for 48 hours. Compared with Preparation Example 1, the stability of the sustained-release nystatin in Preparation Examples 2-5 was reduced to varying degrees due to the change in preparation conditions.

[0074] 2. Photostability experiment of permethrin nanoparticles

[0075] Each of the preparation examples 6-9 and permethrin (control group) were dissolved in 65 wt % ethanol aqueous solution to obtain dispersions (with a concentration of 100 μg / mL), and each dispersion was evenly divided into 6 portions, 3 portions in each group, and marked as the 0h and 4h experimental groups respectively; the marked samples were placed in a light stability test box and tested at 500 W / m 2 , 30℃, and full wavelength range; after the set light exposure time is reached, the corresponding sample group is quickly taken out from the light stability test box, 6mL of sample is drawn with a syringe, transferred to a centrifuge tube, centrifuged, the supernatant is taken, filtered, and a clear test solution is obtained; the permethrin content in the test solution is detected by HPLC. The specific test results are shown in Table 2.

[0076] Table 2

[0077]

[0078] As can be seen from Table 2, compared with the control group, the permethrin nanoparticles obtained in each preparation example have excellent photostability, especially in Preparation Example 6, the degradation rate of permethrin under light conditions is very low. Compared with Preparation Example 6, the photostability of the permethrin nanoparticles prepared in Preparation Examples 7-9 is reduced to varying degrees due to changes in the preparation process.

[0079] 3. Animal clinical trials

[0080] A total of 30 New Zealand rabbits with parasitic skin diseases were selected and randomly divided into 3 groups. The nystatin ointment in Examples 1-3 was applied to the affected areas once a day for 7 consecutive days, with an application amount of 0.05 g / cm each time. 2 .

[0081] Experimental methods:

[0082] (1) Clinical examination: A full-body clinical examination is performed, including routine indicators such as body temperature, respiration, and heart rate; local examination is performed to check the degree of itching on the body surface, the degree of skin damage, the number of rashes or pustules, and the location and distribution of skin lesions.

[0083] (2) Examination of external parasites: Take the skin of the affected area and observe and count the number of external parasites in the local lesions under a microscope. For flea infestation: count and count the number of fleas, the distribution and number of flea feces; for tick bite dermatitis: count and count the number of ticks and the condition of skin lesions.

[0084] Efficacy evaluation indicators:

[0085] Effective: During and after the treatment, the number of external parasites on the skin decreased by an average of ≥90%, and there was no itching, rash, dandruff or self-biting damage on the affected area;

[0086] Ineffective: During and after the treatment, the average reduction rate of the number of external parasites on the skin was <90%, and the affected area still had itching, rashes, dandruff, etc., and animal self-gnaw injuries were obvious.

[0087] The specific test results are shown in Table 3.

[0088] Table 3

[0089] serial number Effective quantity (only) Invalid quantity (pieces) Example 1 10 0 Example 2 10 0 Example 3 10 0

[0090] As shown in Table 3, the nystatin ointment prepared in Examples 1-3 has excellent therapeutic effects.

[0091] The above is only a preferred embodiment of the present invention and does not constitute any form of limitation to the present application. Although the present application is disclosed as above in the preferred embodiment, it is not intended to limit the present application. Any technician familiar with the profession, without departing from the scope of the technical solution of the present application, using the technical content disclosed above to make slight changes or modifications are equivalent to equivalent implementation cases. However, any simple modifications, equivalent changes and modifications made to the above embodiments based on the technical essence of the present invention without departing from the content of the technical solution of the present invention are still within the scope of the technical solution.

Claims

1. A low-irritation nystatin ointment for pets, characterized in that: Based on 100% by mass, it includes the following raw materials: Neomycin sulfate 0.1-0.5%, sustained-release nystatin 5-25%, triamcinolone acetonide 0.05-0.2%, permethrin nanoparticles 0.1-2.5%, and the rest is paraffin.

2. The nystatin ointment according to claim 1, characterized in that The preparation method of the sustained-release nystatin is as follows: The dispersion of nystatin is added to the gelatin solution, mixed evenly, and then the solution of polyglycolic acid is added dropwise thereto, stirred sufficiently, and dried to obtain sustained-release nystatin.

3. The nystatin ointment according to claim 2, characterized in that The mass ratio of gelatin, nystatin and polyglycolic acid is (2.5-3.5):(0.8-1.3):

1.

4. The nystatin ointment according to claim 2, characterized in that The number average molecular weight of the polyglycolic acid is 5000-20000.

5. The nystatin ointment according to claim 1, characterized in that The preparation steps of the permethrin nanoparticles are: Permethrin is put into a surfactant solution and stirred evenly, then chitosan is added and stirred evenly, high pressure homogenization is performed, and then the mixture is cooled and dried to obtain permethrin nanoparticles.

6. The nystatin ointment according to claim 5, characterized in that The surfactant is a quaternary ammonium salt surfactant.

7. The nystatin ointment according to claim 5, characterized in that The mass ratio of permethrin, surfactant and chitosan in the permethrin nanoparticles is (0.8-1.2):(0.8-1.2):0.

1.

8. The nystatin ointment according to claim 5, characterized in that The number average molecular weight of the chitosan is 50,000-150,000.

9. The nystatin ointment according to claim 1, characterized in that The paraffin wax includes liquid paraffin and polyethylene paraffin.

10. A method for preparing the nystatin ointment according to any one of claims 1 to 9, characterized in that: The method comprises the following preparation steps: Take liquid paraffin, heat it to 80-90° C., then add polyethylene paraffin, stir until the polyethylene paraffin is completely dissolved into a transparent and clear state, cool it to 40-50° C., add triamcinolone acetonide, neomycin sulfate, sustained-release nystatin, and permethrin nanoparticles in sequence under stirring, and homogenize after each raw material is added, stir to cool, and fill to obtain the nystatin ointment.

Images