Preparation method of soluble florfenicol preparation

Abstract

The invention discloses a preparation method of a soluble florfenicol preparation, which comprises the following steps: (1) mixing starch and an enzyme preparation, putting the mixture into a reaction container, stirring and dispersing to liquefy the starch, with the concentration of the starch being 10-30% and the addition amount of the enzyme preparation being 5-10 U / g of the starch; (2) liquefying starch, cooling to 40-60 DEG C, adding an enzyme preparation and florfenicol in an amount which is 1-3% of the weight of water and in an amount which is 5-10U / g starch, quickly stirring and dispersing, and keeping reaction at set temperature and rotating speed; and (3) carrying out spray drying on the transparent and uniform solution prepared by the reaction to obtain preparation powder. According to the method, in-situ inclusion of florfenicol is achieved through the synergistic effect of enzyme catalysis and florfenicol complexation with the starch raw material as the starting point, the process is efficient and simple, environmental pollution is avoided, cost is low, and economic benefits are high; starting from the starch raw material, the cost is lower, and the by-product syrup contained in the preparation can be directly absorbed and digested by animals.

Description

Technical Field

[0001] The invention belongs to the technical field of antibiotic preparation, and in particular relates to a method for preparing a soluble florfenicol preparation. Background Art

[0002] Florfenicol is a broad-spectrum antibiotic belonging to the fluorobenzamide class, primarily used to treat a variety of bacterial infections. It exerts its antibacterial effects by inhibiting bacterial protein synthesis, exhibiting excellent efficacy and low toxicity. It is widely used in animal husbandry and aquaculture. Due to its effectiveness and safety, florfenicol has gained widespread acceptance in the veterinary field.

[0003] Florfenicol is a time-dependent drug whose antibacterial effect requires only a blood concentration exceeding the minimum inhibitory concentration (MIC) of the bacteria. Formulation and preparation process are important factors influencing the clinical efficacy of florfenicol. Compared with traditional florfenicol preparations, florfenicol preparations that have undergone inclusion treatment can maintain the same effective blood concentration duration as traditional preparations even at a reduced dosage due to their sustained-release properties, thereby significantly reducing the dosage.

[0004] Soluble florfenicol preparations currently on the domestic market, mostly use finished product β-cyclodextrin and its derivatives as inclusion molecules, to increase its solubility and absorption effect. Yang Baoting et al. (Chinese Journal of Animal Husbandry and Veterinary Medicine, 2017, 44 (6): 1854-1860.) use colloid mill and spray drying technology to prepare florfenicol-hydroxypropyl-β-cyclodextrin inclusion compound, so that florfenicol solubility is increased from the original 1.25mg / ml to 40.76mg / ml. However, the price of hydroxypropyl-β-cyclodextrin is high, and the cost of use is too high, which is not suitable for application in florfenicol preparations with stricter cost requirements.

[0005] Invention patent CN119385937A discloses a veterinary florfenicol solution composed of the following components: florfenicol, an inclusion agent, a cosolvent, a solubilizer, a wetting agent, a pH adjuster, an antioxidant, and a flavoring agent. The inclusion agent is selected from hydroxypropyl-β-cyclodextrin, sulfobutyl-β-cyclodextrin, or β-cyclodextrin. The resulting preparation exhibits good solubility and stability.

[0006] Zhou Shengzhi et al. (Jiangxi Journal of Animal Husbandry and Veterinary Medicine, 2019(4):26-28) prepared a florfenicol-β-cyclodextrin inclusion complex with a florfenicol to β-cyclodextrin mass ratio of 1:4. The results showed that the inclusion complex could be completely dissolved at 2000 ppm. Although the solubility of the florfenicol preparation was improved after adding β-cyclodextrin, the improvement capacity was very limited and other cosolvents were still needed for solubilization. In addition, the preparation process of β-cyclodextrin was complicated and produced many by-products. Summary of the Invention

[0007] In order to overcome the shortcomings of the existing technology, the present invention provides a method for preparing a soluble florfenicol preparation. Starch is used as the basic raw material. While cyclodextrin glucosyltransferase catalyzes the starch to produce cyclodextrin, florfenicol is included in the cyclodextrin to promote the dissolution of florfenicol. The prepared florfenicol preparation has a maximum solubility concentration of 20,000 ppm, and the in vitro dissolution rate of the product is significantly improved.

[0008] The technical solution adopted by the present invention to solve the technical problem is: a method for preparing a soluble florfenicol preparation, comprising the following steps:

[0009] (1) Starch and enzyme preparation are mixed and placed in a reaction vessel, and stirred and dispersed to liquefy the starch, wherein the starch concentration is 10-30%, and the amount of enzyme preparation added is 5-10 U / g starch;

[0010] (2) After liquefying the starch, cool it to 40-60°C, add the enzyme preparation and florfenicol, wherein the amount of florfenicol added is 1-3% of the weight of water, and the amount of the enzyme preparation added is 5-10U / g starch, quickly stir and disperse, and maintain the reaction at the set temperature and speed;

[0011] (3) The transparent and uniform solution prepared by the reaction is spray-dried to obtain a preparation powder.

[0012] Furthermore, in step (1), the starch liquefaction temperature is 75-95° C., the rotation speed of the reaction container is 200-500 rpm, and the reaction time is 30-60 minutes.

[0013] Furthermore, in step (1), the starch is one or more of corn starch, tapioca starch, potato starch, and pea starch.

[0014] Furthermore, in the steps (1) and (2), the enzyme preparation is one or more of alpha-cyclodextrin glucosyltransferase, beta-cyclodextrin glucosyltransferase, or gamma-glucosyltransferase.

[0015] Furthermore, in step (2), the stirring speed is 200-500 rpm, the reaction time is 12-30 hours, and the reaction temperature is maintained at 40-60°C.

[0016] Furthermore, the temperature of the spray drying in step (3) is 170-210°C.

[0017] The beneficial effects of the present invention are as follows: 1) using starch as a starting material, in-situ inclusion of florfenicol is achieved through the synergistic effect of enzyme catalysis and florfenicol complexation, and the process is efficient and simple, has no environmental pollution, is low in cost, and has high economic benefits; 2) using starch as a basic raw material, while cyclodextrin glucosyltransferase catalyzes starch to generate cyclodextrin, florfenicol is included in the cyclodextrin, thereby promoting the dissolution of florfenicol. Compared with using finished β-cyclodextrin or β-cyclodextrin derivatives as inclusion agents, starting from starch raw materials, the cost is lower, and the by-product syrup is contained in the preparation and can be directly absorbed and digested by animals; 3) the florfenicol preparation after in-situ inclusion has better solubility, which can reach up to 20,000 ppm. Compared with the physical mixture of pure florfenicol and cyclodextrin, the in vitro dissolution rate of the product is significantly improved. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 This is a photo of the preparation powder obtained after spray drying in Example 1 of the present invention.

[0019] Figure 2 This is a physical picture of the solution state after the preparation powder obtained in Example 1 of the present invention is dissolved.

[0020] Figure 3 The figure is a comparison of the in vitro dissolution test results of the preparation prepared in the present invention, pure florfenicol, and a physical mixture of pure florfenicol and cyclodextrin. DETAILED DESCRIPTION

[0021] In order to enable those skilled in the art to better understand the solutions of the present invention, the following will provide a clear and complete description of the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts should fall within the scope of protection of the present invention.

[0022] Example 1

[0023] (1) Dispersing corn starch in water at a ratio of 15%, adding beta-cyclodextrin glucosyltransferase at a ratio of 5 U / g, heating to 90° C., rotating the reaction vessel at 300 rpm, and maintaining for 1 hour;

[0024] (2) After the starch is liquefied, the temperature is lowered to 50° C., and beta-cyclodextrin glucosyltransferase is added again at a ratio of 5 U / g. Florfenicol powder is added at a ratio of 2.5% of the weight of water in the starch solution. After rapid stirring and dispersion, the mixture is reacted at a speed of 300 rpm and a temperature of 50° C. for 30 hours.

[0025] (3) The solution obtained by the reaction was spray-dried at 200°C to prepare a powder.

[0026] Example 2

[0027] (1) Cassava starch was dispersed in water at a ratio of 30%, and beta-cyclodextrin glucosyltransferase was added at a ratio of 5 U / g. The temperature was raised to 80° C., and the rotation speed of the reaction vessel was set at 400 rpm for 1 hour.

[0028] (2) Cooling the mixture to 50°C, adding 5U / g of beta-cyclodextrin glucosyltransferase, and adding florfenicol powder at a ratio of 1% of the weight of water in the starch solution. After rapid stirring and dispersion, the mixture was reacted at a speed of 300 rpm and a temperature of 50°C for 16 hours.

[0029] (3) The solution obtained by the reaction was spray-dried at 200°C to prepare a powder.

[0030] Example 3

[0031] (1) Corn starch was dispersed in water at a ratio of 20%, and alpha-cyclodextrin glucosyltransferase was added at a ratio of 6 U / g. The temperature was raised to 90° C. and the speed of the reaction vessel was set at 400 rpm for 1 hour.

[0032] (2) Cooling to 45°C, adding alpha-cyclodextrin glucosyltransferase again at a ratio of 6 U / g, adding florfenicol powder at a ratio of 3% by weight of water, rapidly stirring and dispersing, rotating at 300 rpm, at 45°C, and reacting for 16 hours;

[0033] (3) The solution obtained by the reaction was spray-dried at 200°C to prepare a powder.

[0034] Example 4

[0035] (1) Dispersing corn starch in water at a ratio of 20%, adding gamma-cyclodextrin glucosyltransferase at a ratio of 5 U / g, heating to 95° C., rotating the reaction vessel at 500 rpm, and maintaining the temperature for 1 hour;

[0036] (2) Cooling the mixture to 60°C, adding gamma-cyclodextrin glucosyltransferase again at a ratio of 5 U / g, adding florfenicol powder at a ratio of 3% of the weight of water in the starch solution, rapidly stirring and dispersing, rotating at 300 rpm, at 60°C, and reacting for 16 hours;

[0037] (3) The solution obtained by the reaction was spray-dried at 200°C to prepare a powder.

[0038] Example 5

[0039] (1) Potato starch was dispersed in water at a ratio of 20%, and gamma-cyclodextrin glucosyltransferase was added at a ratio of 5 U / g. The temperature was raised to 90° C. and the speed of the reaction vessel was set at 200 rpm for 1 hour.

[0040] (2) Cooling the mixture to 60°C, adding gamma-cyclodextrin glucosyltransferase again at a ratio of 5 U / g, adding florfenicol powder at a ratio of 3% of the weight of water in the starch solution, rapidly stirring and dispersing, rotating at 300 rpm, at 60°C, and reacting for 24 hours;

[0041] (3) The solution obtained by the reaction was spray-dried at 180°C to prepare a powder.

[0042] The florfenicol preparation powders obtained in Examples 1-5 above were dissolved to obtain the maximum soluble concentration and state results shown in Table 1 below.

[0043] Example Florfenicol concentration after dissolution of the preparation Status (within 24 hours) 1 20000ppm Clarification and stability 2 15000ppm Clarification and stability 3 10000ppm Clarification and stability 4 10000ppm Clarification and stability 5 20000ppm Clarification and stability

[0044] Example 6

[0045] The other steps are the same as those in Example 5, except that gamma-cyclodextrin glycosyltransferase is not added in step (2). The system has high viscosity and cannot be spray-dried.

[0046] Example 7

[0047] The rest of the process was the same as in Example 5, except that stirring was not performed in step (1). Florfenicol was suspended in the reaction solution, and no inclusion complex was formed.

[0048] Example 8

[0049] The rest of the process was the same as in Example 5, except that gamma-cyclodextrin glucosyltransferase was not added in step (2). After spray drying, the mixture was dissolved at 10,000 ppm to form a turbid state.

[0050] The above specific embodiments are used to illustrate the present invention rather than to limit the present invention. Any modifications and changes made to the present invention within the spirit of the present invention and the protection scope of the claims shall fall within the protection scope of the present invention.

Claims

1. A method for preparing a soluble florfenicol preparation, characterized in that: The following steps are involved: (1) Starch and enzyme preparation are mixed and placed in a reaction vessel, and stirred and dispersed to liquefy the starch, wherein the starch concentration is 10-30%, and the amount of enzyme preparation added is 5-10 U / g starch; (2) After liquefying the starch, cool it to 40-60°C, add the enzyme preparation and florfenicol, wherein the amount of florfenicol added is 1-3% of the weight of water, and the amount of the enzyme preparation added is 5-10U / g starch, quickly stir and disperse, and maintain the reaction at the set temperature and speed; (3) The transparent and uniform solution prepared by the reaction is spray-dried to obtain a preparation powder.

2. The preparation method according to claim 1, wherein: In the step (1), the starch liquefaction temperature is 75-95° C., the rotation speed of the reaction container is 200-500 rpm, and the reaction time is 30-60 minutes.

3. The preparation method according to claim 1, wherein: In the step (1), the starch is one or more of corn starch, tapioca starch, potato starch, and pea starch.

4. The preparation method according to claim 1, wherein: In the steps (1) and (2), the enzyme preparations are one or more of alpha-cyclodextrin glucosyltransferase, beta-cyclodextrin glucosyltransferase, or gamma-glucosyltransferase.

5. The preparation method according to claim 1, wherein: In the step (2), the stirring speed is 200-500 rpm, the reaction time is 12-30 hours, and the reaction temperature is maintained at 40-60°C.

6. The preparation method according to claim 1, wherein: The temperature of the spray drying in step (3) is 170-210°C.

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