Moxidectin pouring solution and preparation method thereof

Abstract

The invention discloses a moxidectin pouring solution and a preparation method thereof, and belongs to the technical field of veterinary drug preparations. Every 500 ml of the moxidectin pouring solution comprises 0.1%-10% of moxidectin, an antioxidant, a penetrating agent, a tackifier, a cosolvent, a coloring agent and the balance of a fat solvent, and preferably, soybean oil is used as the fat solvent. The preparation method comprises the following steps: mixing and dissolving the components according to a specific sequence, filtering and sub-packaging. The moxidectin pouring solution disclosed by the invention has the advantages of low cost, convenience in preparation, good quality stability, no influence on impurity detection and the like, effectively solves a plurality of problems of the moxidectin pouring solution in the prior art, and has a good application prospect.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of veterinary preparations, in particular to a moxidectin pour-on solution and a preparation method thereof. BACKGROUND

[0002] Moxidectin is a new type of antiparasitic drug, which is produced by fermentation of Streptomyces and belongs to single-component macrolide antibiotics. It has a broad spectrum of activity against helminths and is effective in killing and expelling various internal and external parasites in animals. For example, it has a high expelling rate for the larvae and adult worms of gastrointestinal nematodes and pulmonary nematodes in cattle, and a long-lasting effect of 5-6 weeks. It can also be used to treat external parasites in dogs and rabbits, and has been approved for the treatment of scabies in dogs. Compared with other macrolide antiparasitic drugs, moxidectin has the characteristics of single component, higher safety, long-acting and high efficiency, and higher expelling activity, and has strong activity against nematodes and arthropods at a very low dose.

[0003] However, the moxidectin pour-on solution in the prior art has many problems. For example, some products on the market are oil solutions, and medium-chain triglycerides are often selected as solvents, which have high cost and increase the medication cost of end users; the dissolution rate of moxidectin in lipid solvents is slow, and the preparation process usually needs to be heated to accelerate dissolution, which is time-consuming and laborious; some products add colorants that have ultraviolet characteristic absorption peaks, which interfere with the detection of impurity C in moxidectin and affect the accuracy of the detection results; the antiparasitic active ingredient moxidectin is easily oxidized, and the existing antioxidants and anti-oxidation enhancers added in the preparation have poor lipid solubility and poor compatibility with the solvent system, which affects the quality stability and preparation convenience of the product. Therefore, it is of great practical significance to develop a moxidectin pour-on solution with low cost, stable quality, non-interference in detection and simple preparation. SUMMARY

[0004] (I) Technical problems solved The purpose of the present application is to provide a moxidectin pour-on solution and a preparation method thereof, to solve the technical problems of high cost, poor quality stability, interference in detection and inconvenience in preparation of the moxidectin pour-on solution in the prior art.

[0005] (II) Technical solutions To achieve the above-mentioned purpose, the present application provides the following technical solutions: A moxidectin pour-on solution, comprising the following components per 500ml of solution: Moxidectin 0.1%-10%; Antioxidant 0.02%-2%; Penetrant 9%-15%; Viscosity enhancer 10%-16%; Co-solvent 10% - 30%; Colorant 0.01% - 2%; The balance is a liposolvent.

[0006] Further, the moxidectin pour-on solution comprises the following preferred components per 500 ml of solution: Moxidectin 0.1% - 5%; Antioxidant 0.02% - 0.8%; Penetrant 11% - 13%; Viscosity enhancer 10% - 16%; Co-solvent 18% - 22%; Colorant 0.01% - 1%; The balance is a liposolvent.

[0007] Specifically, the antioxidant is one or more of dibutylhydroxytoluene, tertiary butylhydroxyanisole, tertiary butylhydroquinone and vitamin E, and the antioxidant includes an antioxidant enhancer, which is vitamin E.

[0008] Specifically, the penetrant is one or more of isopropyl myristate, menthol, oleic acid, diethylene glycol monoethyl ether, polyglyceryl oleate and propylene glycol laurate.

[0009] Specifically, the viscosity enhancer is hydrogenated polyisobutene or propylene carbonate, preferably hydrogenated polyisobutene, and the hydrogenated polyisobutene has a kinematic viscosity at 98.9°C of 270 m 2 / s - 850 m 2 / s, and when the hydrogenated polyisobutene has a kinematic viscosity at 98.9°C of 270 m 2 / s - 400 m 2 / s, it is added in an amount of 12% - 16% (g / ml), and when the hydrogenated polyisobutene has a kinematic viscosity at 98.9°C of 650 m 2 / s - 850 m 2 / s, it is added in an amount of 10% - 14% (g / ml).

[0010] Specifically, the co-solvent is any one of isopropyl alcohol, benzyl alcohol and propylene glycol.

[0011] Specifically, the colorant is one or more of violet, oil-soluble violet, solvent violet and crystal violet.

[0012] Specifically, the liposolvent is one or more of medium-chain triglycerides, soybean oil, corn oil and white oil.

[0013] A preparation method of moxidectin pour-on solution, each component is dissolved, mixed uniformly, filtered, and packaged to obtain the moxidectin pour-on solution; the specific preparation steps are as follows: First, the antioxidant is added to the cosolvent and stirred to dissolve; Then, the moxidectin is added and stirred to dissolve; Then, half of the amount of the liposoluble solvent is added and mixed uniformly; Finally, the tackifier, the penetrant and the colorant are added in sequence and stirred to mix uniformly, the remaining liposoluble solvent is added to the full amount, and then stirred to mix uniformly, filtered, and packaged to obtain the moxidectin pour-on solution.

[0014] (Three) beneficial effects Cost advantage: the soybean oil and other low-cost and safe and non-toxic liposoluble solvents are used to replace the conventional medium-chain triglyceride, which greatly reduces the cost of raw and auxiliary materials and improves the performance-price ratio of the product used by the end user.

[0015] High quality stability: the hydrogenated polyisobutylene with a specific kinematic viscosity range (270m 2 / s - 850m 2 / s at 98.9℃) is selected as the tackifier, which not only can be used as a drug carrier to adhere to the animal body surface to ensure long-term slow release of the drug and achieve long-acting anti-parasitic, but also has certain antioxidant function, further improving the product quality stability. At the same time, the mixed antioxidant is used to replace the commonly used antioxidant enhancer anhydrous citric acid, which solves the problems of poor liposolubility, slow dissolution rate and poor compatibility with the solvent system of anhydrous citric acid, and enhances the antioxidant performance of the product.

[0016] Detection is not disturbed: the violet and other non-ultraviolet absorbing colorants are selected, which do not interfere with the related substance detection of the product, and can better control the quality of the product.

[0017] Preparation is simple: the cosolvent such as benzyl alcohol can quickly dissolve the moxidectin without heating, which greatly shortens the liquid preparation time and reduces the labor intensity of the operator.

[0018] The product has excellent performance: the moxidectin pour-on solution prepared by the present application has a low freezing point (-10℃ to -16℃) and a high flash point (144.1℃), and the product preparation and storage and transportation process are safe and controllable. DETAILED DESCRIPTION

[0019] In order to make the purpose, technical scheme and advantages of the present application clearer and more apparent, the present application will be further described in detail below with specific examples. It should be understood that the specific examples described herein are only used to explain the present application and not to limit the present application.

[0020] It should be noted that all technical and scientific terms used in the present application have the same meaning as commonly understood by one of ordinary skill in the art to which the present application belongs unless otherwise specifically defined.

[0021] Example 1 Formulation of moxidectin pour-on solution (per 500ml solution): Moxidectin: 0.5g (0.1%); Antioxidant (dibutylhydroxytoluene 0.05g, vitamin E 0.05g): 0.1g (0.02%); Penetrant (isopropyl myristate 6g, polyglyceryl oleate 5g): 11g (2.2%); Viscosity enhancer (hydrogenated polyisobutene, kinematic viscosity at 98.9°C 300m 2 / s): 8g (1.6%); Co-solvent (benzyl alcohol): 100g (20%); Colorant (violet): 0.05g (0.01%); Lipid solvent (soybean oil): 380.35g (balance).

[0022] Preparation method: Add dibutylhydroxytoluene and vitamin E into benzyl alcohol, stir until completely dissolved; Add moxidectin, continue to stir until completely dissolved; Add 200g soybean oil, mix well; Add hydrogenated polyisobutene, isopropyl myristate and polyglyceryl oleate, and violet in turn, stir well; Add the remaining 180.35g soybean oil to the full amount, stir well; Filter the solution through a 0.45μm filter, and then dispense to obtain moxidectin pour-on solution.

[0023] Example 2 Formulation of moxidectin pour-on solution (per 500ml solution): Moxidectin: 2.5g (0.5%); Antioxidant (tert-butylhydroxyanisole 0.1g, vitamin E 0.1g): 0.2g (0.04%); Penetrant (menthol 7g, oleic acid 6g): 13g (2.6%); Viscosity enhancer (hydrogenated polyisobutene, kinematic viscosity at 98.9°C 700m 2 / s): 7g (1.4%); Co-solvent (isopropyl alcohol): 110g (22%); Colorant (Oil soluble violet): 0.1 g (0.02%); Fat-soluble solvent (Corn oil): 367.2 g (balance).

[0024] Preparation method: Add tert-butylhydroxyanisole and vitamin E into isopropyl alcohol, stir to dissolve; Add moxidectin, stir to dissolve; Add 200 g corn oil, mix well; Add hydrogenated polyisobutene, menthol and oleic acid, and oil soluble violet in sequence, stir to mix well; Add the remaining 167.2 g corn oil to the full amount, stir to mix well; Filter the solution through a 0.45 μm filter cartridge, and then dispense to obtain moxidectin pour-on solution.

[0025] Example 3 Formulation of moxidectin pour-on solution (per 500 ml solution): Moxidectin: 5 g (1%); Antioxidant (Tert-butylhydroquinone 0.2 g, vitamin E 0.2 g): 0.4 g (0.08%); Penetrant (Diethylene glycol monoethyl ether 8 g, propylene glycol laurate 5 g): 13 g (2.6%); Viscosity enhancer (Hydrogenated polyisobutene, kinematic viscosity 400 m 2 / s at 98.9°C): 8 g (1.6%); Co-solvent (Propylene glycol): 90 g (18%); Colorant (Solvent violet): 0.1 g (0.02%); Fat-soluble solvent (Medium-chain triglyceride and white oil mixed at 1:1): 383.5 g (balance).

[0026] Preparation method: Add tert-butylhydroquinone and vitamin E into propylene glycol, stir to dissolve; Add moxidectin, stir to dissolve; Add 191.75 g mixed fat-soluble solvent (medium-chain triglyceride and white oil), mix well; Add hydrogenated polyisobutene, diethylene glycol monoethyl ether and propylene glycol laurate, and solvent violet in sequence, stir to mix well; Add the remaining 191.75 g mixed fat-soluble solvent to the full amount, stir to mix well; Filter the solution through a 0.45 μm filter cartridge, and then dispense to obtain moxidectin pour-on solution.

[0027] Comparative Example 1 The pouring solution of moxidectin is prepared by using the formulation and preparation method in the prior art, in which medium-chain triglyceride is used as a solvent, anhydrous citric acid is used as an antioxidant enhancer, and the relationship between the kinematic viscosity of the tackifier and the amount of addition is not considered.

[0028] Comparative Example 2 The pouring solution of moxidectin is prepared by using the formulation and preparation method in the prior art, in which the solvent system is not optimized, resulting in slow dissolution of moxidectin, and a coloring agent that interferes with detection is used.

[0029] Performance test Stability test: The pouring solutions of moxidectin prepared in Examples 1-3 and Comparative Examples 1-2 are placed under accelerated test conditions (temperature 40°C±2°C, relative humidity 75%±5%) for 6 months, and the content of moxidectin and related substances in the solution are detected regularly. The results show that the content of moxidectin in the products of Examples 1-3 is basically stable, and the increase of related substances is slow; in Comparative Example 1, the content of moxidectin decreases significantly due to the poor antioxidant system, and the related substances increase more; in Comparative Example 2, the solution is stratified due to the solvent system problem, and the detection is severely interfered, so that the quality change of the product cannot be accurately judged.

[0030] Dissolution rate test: Under the same temperature and stirring conditions, the time required for complete dissolution of moxidectin in Examples 1-3 and Comparative Example 2 is recorded. In Examples 1-3, moxidectin dissolves rapidly in a short time after the addition of the cosolvent, and the average dissolution time is 10-15 minutes; in Comparative Example 2, moxidectin dissolves slowly, and the average dissolution time is as long as 30-40 minutes.

[0031] Interference test for impurity detection: The products of Examples 1-3 and Comparative Example 2 are detected for impurity C by high performance liquid chromatography, and the accuracy of the detection results is compared. In Examples 1-3, the separation degree of impurity C is good due to the use of a coloring agent without ultraviolet absorption, and the detection result is accurate and reliable; in Comparative Example 2, the peak shape of impurity C is severely tailing due to the interference of the coloring agent, and accurate integration cannot be achieved, resulting in a large detection error.

[0032] Through the comparison of the above examples and comparative examples and the performance test, it is fully proved that the pouring solution of moxidectin and the preparation method thereof have significant advantages in cost, quality stability, detection accuracy and preparation convenience, etc.

[0033] The above description is only the preferred embodiment of the present application and is not intended to limit the present application. Any modification, equivalent replacement and improvement made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A moxicritin pourable solution, characterized in that, Each 500ml solution contains the following components: Moxicillin 0.1% - 10%; Antioxidants 0.02% - 2%; Penetrant 9% - 15%; Tackifier 10% - 16%; Cosolvent 10% - 30%; Colorant 0.01% - 2%; The remainder is a lipid solvent.

2. The moxifloxacin pourable solution according to claim 1, characterized in that, Each 500ml solution contains the following components: Moxicillin 0.1% - 5%; Antioxidant content: 0.02% - 0.8%; Penetrant 11% - 13%; Tackifier 10% - 16%; Cosolvent 18% - 22%; Colorant 0.01% - 1%; The remainder is a lipid solvent.

3. The moxifloxacin pourable solution according to claim 1 or 2, characterized in that, The antioxidant is one or more of butylated hydroxytoluene, tert-butylhydroxyanisole, tert-butylhydroquinone, and vitamin E, and the antioxidant includes an antioxidant enhancer, wherein the antioxidant enhancer is vitamin E.

4. The moxifloxacin pourable solution according to claim 1 or 2, characterized in that, The penetrant is one or more of isopropyl myristate, menthol, oleic acid, diethylene glycol monoethyl ether, polyglycerol oleate, and propylene glycol laurate.

5. The moxifloxacin pourable solution according to claim 1 or 2, characterized in that, The tackifier is hydrogenated polyisobutylene or propylene carbonate, preferably hydrogenated polyisobutylene, and the kinematic viscosity of hydrogenated polyisobutylene at 98.9°C is 270 mM. 2 / s - 850m 2 / s, when the kinematic viscosity of hydrogenated polyisobutylene at 98.9℃ is 270m. 2 / s - 400m 2 When the concentration is / s, the addition amount is 12% - 16% (g / ml), and the kinematic viscosity of hydrogenated polyisobutylene at 98.9℃ is 650m. 2 / s -850m 2 When the concentration is 1 / s, the addition amount is 10% - 14% (g / ml).

6. The moxifloxacin pourable solution according to claim 1 or 2, characterized in that, The co-solvent is any one of isopropanol, benzyl alcohol, and propylene glycol.

7. The moxifloxacin pourable solution according to claim 1 or 2, characterized in that, The colorant is one or more of violet, oil-soluble violet, solvent violet, and crystal violet.

8. The moxifloxacin pourable solution according to claim 1 or 2, characterized in that, The lipid solvent is one or more of medium-chain triglycerides, soybean oil, corn oil, and white oil.

9. A method for preparing a moxicritin pourable solution as described in any one of claims 1-8, characterized in that: The components were dissolved and mixed thoroughly according to the addition ratio, filtered, and dispensed to obtain a moxifloxacin pourable solution; the specific preparation steps are as follows: First, add the antioxidant to the co-solvent and stir to dissolve; Add moxifloxacin and stir to dissolve; Then add half of the required amount of lipid solvent and mix well. Finally, add the thickener, penetrant, and colorant in sequence and stir until well mixed. Then add the remaining lipid solvent to the total volume, stir until well mixed, filter, and dispense to obtain the moxicillin pourable solution.