Preparation process of veterinary phloretin solution
A phloretin micelle solution using polyethylene glycol-poly-L-phenylalanine as a carrier addresses solubility and stability issues, ensuring uniformity and intestinal absorption, enhancing therapeutic efficacy.
Patent Information
- Application Number
- CN202411635772.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-15
- Publication Date
- 2025-01-03
AI Technical Summary
Phloretin solutions prepared with organic solvents precipitate in water, leading to uneven dispersion, low intestinal mucosal capture, poor absorption, and oxidation, necessitating a stable, uniform, and easily absorbable veterinary formulation.
A preparation process using polyethylene glycol-poly-L-phenylalanine as a polymer carrier to form a phloretin micelle solution, miscible with water, involving heating, high shear stirring, and controlled cooling to create a stable and uniform micelle solution.
The process results in a stable, uniform phloretin solution that maintains solubility in water, reduces oxidative degradation, and enhances intestinal mucosal absorption, ensuring effective therapeutic action.
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of phloretin preparation, in particular to a preparation process of a phloretin solution for animals. Background Art
[0002] Phloretin is easily soluble in organic solvents such as methanol, ethanol, acetone, and ethyl acetate, and is almost insoluble in water. The solubility of phloretin in water is 0.02 mg / ml. The existing phloretin solution prepared with organic solvents will precipitate out twice during the use of drinking water, resulting in uneven dispersion in drinking water, low intestinal mucosal capture rate, and poor absorption and utilization. Phloretin itself is also easily oxidized and inhibits the absorption of glucose by the intestinal mucosa of animals. When used as a veterinary agent, it needs to be evenly dispersed in water and easily absorbed by the animal intestine, and the carrier must not cause damage to the animal body. The prepared solution needs to be of stable quality during long-term storage, not easy to oxidize and degrade, and uniform and stable. Summary of the invention
[0003] The purpose of the present invention is to provide a preparation process of veterinary phloretin solution. By screening a polymer carrier with a high amount of phloretin and forming a phloretin micelle solution with a high polymer inclusion rate through a certain process, a phloretin solution that is miscible with water in any ratio is obtained. At the same time, the product quality is stable and easy to be absorbed by the intestinal mucosa, so that the prepared drug can exert its due therapeutic effect, thereby solving the problems raised in the above-mentioned background technology.
[0004] To achieve the above object, the present invention provides the following technical solutions: A preparation process of veterinary phloretin solution comprises the following steps: S1: Weigh phloretin and polyethylene glycol-poly-L-phenylalanine at a mass ratio of 1:3; S2: Heat the weighed polyethylene glycol-poly-L-phenylalanine to 80°C to melt into a transparent liquid, then add the weighed phloretin and stir until it is completely dissolved and keep warm at 80°C; S3: Add 16 times the mass of purified water of phloretin into the liquid preparation tank with high shear equipment, heat to 80°C, then add the solution obtained in S2, turn on high shear stirring, set the power to 45HZ, and stir for 30 minutes; S4: After the high shear stops, turn on the cooling water to stir and cool to 50℃ to pass through a 0.45um water film, then fill it.
[0005] Furthermore, the veterinary phloretin solution obtained by filling in S4 can be diluted with water in any proportion.
[0006] Furthermore, the solution after stirring in S3 is a stable and uniform polymer micelle solution.
[0007] Furthermore, the 80° C. insulation in S2 is used to reduce the process of dissolution and recovery of the intermediate solvent, improve the inclusion efficiency and micelle drug loading, and reduce the amount of polyethylene glycol-poly-L-phenylalanine.
[0008] Furthermore, the cooling method in S4 can also be cooling by adding 1.5 times the total volume of purified water.
[0009] Compared with the prior art, the present invention has the following beneficial effects: The present invention provides a preparation process of a veterinary phloretin solution, which selects a polymer carrier with a self-forming micelle function, and selects polyethylene glycol-poly L-phenylalanine with the highest phloretin drug loading concentration, dissolves phloretin in a molten state, reduces the use of organic solvents, and forms a uniform dual-affinity micelle solution in 80°C water by high shear, thereby solving the problem of low solubility of phloretin in water. At the same time, rapid cooling keeps the micelle inclusion rate stable, reducing the oxidative degradation of phloretin in the solution. Due to the dual affinity of the micelles, the intestinal mucosa of the animal is easy to capture and absorb, phloretin is not exposed during the absorption process, and the absorption and utilization of glucose by the intestinal mucosa is not inhibited, so that the drug can better play its due therapeutic effect. DETAILED DESCRIPTION
[0010] The embodiments of the present invention will be described in detail below, however, the embodiments of the present invention are not limited thereto. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.
[0011] The embodiment of the present invention provides a preparation process of a veterinary phloretin solution, comprising the following steps: S1: Weigh phloretin and polyethylene glycol-poly-L-phenylalanine at a mass ratio of 1:3; S2: The weighed polyethylene glycol-poly-L-phenylalanine is heated to 80°C to melt to obtain a transparent liquid, and then the weighed phloretin is added and stirred to completely dissolve and kept at 80°C; this step reduces the process of dissolving and recovering the intermediate solvent, reduces the operation steps, reduces the process loss, improves the inclusion efficiency and micelle drug loading, and reduces the amount of polyethylene glycol-poly-L-phenylalanine used; S3: Add 16 times the mass of phloretin purified water to a liquid preparation tank with a high shear device, heat to 80°C, then add the solution obtained in S2, turn on high shear stirring, set the power to 45HZ, and stir for 30 minutes; in this step, water is heated to 80°C and then the drug-loaded polymer is added, and the high shear setting power is 45HZ and stirred for 30 minutes to obtain a stable and uniform polymer micelle solution; S4: After the high shear stops, turn on the cooling water and stir to cool to 50℃ (or add 1.5 times the total volume of purified water) and pass through a 0.45um water film. Fill the solution to obtain veterinary phloretin solution, which can be diluted with water in any proportion, has high drug concentration, good stability, and high oral blood drug concentration.
[0012] In order to further better explain the present invention, the present invention is further described below in conjunction with specific embodiments: Example 1
[0013] Weigh 5kg of phloretin and 15kg of polyethylene glycol-poly L-phenylalanine. Heat 15kg of polyethylene glycol-poly L-phenylalanine to the melting temperature of 80℃, add 5kg of phloretin, stir to dissolve completely, and keep warm at 80℃. Add 80kg of purified water to the liquid preparation tank equipped with high shear, heat to 80℃, and add the phloretin polyethylene glycol-poly L-phenylalanine solution to the liquid preparation tank. Turn on high shear stirring, power 45HZ, and stir for 30 minutes. After the high shear ends, turn on the cooling water, stir and cool to 50℃, pass through a 0.45um water film, and fill it. Example 2
[0014] Weigh 5kg of phloretin and 15kg of polyethylene glycol-poly L-phenylalanine. Heat 15kg of polyethylene glycol-poly L-phenylalanine to the melting temperature of 80℃, add 5kg of phloretin, stir to dissolve completely, and keep warm at 80℃. Add 80kg of purified water to the liquid preparation tank equipped with high shear, heat to 80℃, and add the phloretin polyethylene glycol-poly L-phenylalanine solution to the liquid preparation tank. Turn on high shear stirring, power 45HZ, and stir for 30 minutes. After the high shear ends, turn on the cooling water, stir and cool to 50℃, add 150kg of purified water, stir evenly, pass through a 0.45um water film, and fill.
[0015] Comparative Example 1: Weigh 2 kg of phloretin and add 98 kg of ethanol, stir to completely dissolve, pass through a 0.45 um organic membrane, and fill.
[0016] Comparative Example 2: Weigh 5 kg of phloretin, add 95 kg of polyethylene glycol 400, heat and stir to completely dissolve, pass through a 0.45 um organic membrane, and fill.
[0017] Comparison of solubility in water: Test groups 1:1 with water With water 1:5 With water 1:10 With water 1:15 Example 1 clear solution clear solution clear solution clear solution Example 2 clear solution clear solution clear solution clear solution Comparative Example 1 Milky white liquid with precipitation Milky white liquid Milky white liquid Light milky white liquid Comparative Example 2 Milky white liquid with crystal precipitation Milky white liquid with precipitation Milky white liquid Light milky white liquid Comparison of long-term stability observation: Test groups 1 month 3 months 6 months 9 months 12 months 18 months 24 months Example 1 clear solution clear solution clear solution clear solution clear solution clear solution clear solution Example 2 clear solution clear solution clear solution clear solution clear solution clear solution clear solution Comparative Example 1 clear solution clear solution A small amount of crystals precipitated Increased crystallization Crystallization remains unchanged Crystallization remains unchanged Crystallization remains unchanged Comparative Example 2 clear solution clear solution clear solution clear solution A small amount of crystals precipitated Increased crystallization Crystallization remains unchanged Clinical trial comparison: 20 mice weighing 20 g were randomly divided into 4 groups. The solution of the test group was diluted with water to a solution containing 2 mg of phloretin per 1 ml. Each mouse was given 0.2 ml of the above diluted solution by gastric tube infusion. 1 ml of blood was collected by decapitation 2 hours later. Serum was separated by centrifugation at 3000 rpm. The phloretin content in serum was determined by high performance liquid chromatography. The liquid phase conditions were UV detector, detection wavelength of 285 nm, chromatographic column C18, 4.6*150 mm*4 µm, column temperature of 30 ° C, mobile phase A purified water, mobile phase B methanol: acetonitrile 4:1, the reference solution was diluted to 25 µg / ml with 70% ethanol solution, gradient elution, and the test results were as follows: Test groups Phloretin content in serum (mg / L) Example 1 26.5±2.5 Example 2 26.4±2.3 Comparative Example 1 12.4±3.6 Comparative Example 2 13.3±3.9 From the above, it can be seen that the preparation process of a veterinary phloretin solution provided by the present invention is not easy to crystallize and the product quality is more stable. And the solution prepared by this process is easier to disperse evenly during the oral use of the product, and the drug use safety is higher. After oral administration to animals, the solution prepared by this process has a higher blood drug concentration than the solution prepared by organic solvents, which solves the problem of low solubility of phloretin in water. The obtained solution can be miscible with water in any ratio, which solves the problem of easy oxidation and degradation of phloretin solution during storage, and at the same time solves the problem of low absorption and utilization rate of phloretin in the animal intestine and easy inhibition of glucose absorption.
[0018] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.
Claims
1. A preparation process of veterinary phloretin solution, characterized in that: The following steps are involved: S1: Weigh phloretin and polyethylene glycol-poly-L-phenylalanine at a mass ratio of 1:3; S2: Heat the weighed polyethylene glycol-poly-L-phenylalanine to 80°C to melt into a transparent liquid, then add the weighed phloretin and stir until it is completely dissolved and keep warm at 80°C; S3: Add 16 times the mass of purified water of phloretin into the liquid preparation tank with high shear equipment, heat to 80°C, then add the solution obtained in S2, turn on high shear stirring, set the power to 45HZ, and stir for 30 minutes; S4: After the high shear stops, turn on the cooling water to stir and cool to 50℃ to pass through a 0.45um water film, then fill it.
2. The preparation process of a veterinary phloretin solution according to claim 1, characterized in that: The veterinary phloretin solution obtained by filling in S4 can be diluted with water in any proportion.
3. The preparation process of a veterinary phloretin solution according to claim 1, characterized in that: The solution after stirring in S3 is a stable and uniform polymer micelle solution.
4. The preparation process of a veterinary phloretin solution according to claim 1, characterized in that: The 80° C. insulation in S2 is used to reduce the process of dissolution and recovery of the intermediate solvent, improve the inclusion efficiency and micelle drug loading, and reduce the amount of polyethylene glycol-poly-L-phenylalanine used.
5. The preparation process of a veterinary phloretin solution according to claim 1, characterized in that: The cooling method in S4 can also be cooling by adding 1.5 times the total volume of purified water.