A method for preparing a soluble florfenicol powder

Abstract

The application discloses a preparation method of soluble florfenicol powder and belongs to the field of medicines. The florfenicol powder is subjected to inclusion with a first packaging material to obtain an inclusion compound; and the inclusion compound is subjected to inclusion with a second packaging material to obtain the soluble florfenicol powder. The first packaging material is cyclodextrin and derivatives, and the second packaging material is maltodextrin. The maltodextrin is used to perform first inclusion on beta-cyclodextrin. The maltodextrin and the beta-cyclodextrin have similar molecular structures. After the beta-cyclodextrin is subjected to inclusion, the two form the structure of inclusion micelles, the solubility and the saturation concentration of the beta-cyclodextrin itself are improved, the number of the florfenicol included by the cyclodextrin is increased, and the solubility of the florfenicol in water is improved.

Description

Technical Field

[0001] This invention relates to the field of pharmaceuticals, and more specifically to a method for preparing soluble florfenicol powder. Background Technology

[0002] Florfenicol (FF), as a third-generation thiamphenicol, has advantages such as good absorption, wide distribution in the body, long half-life, no or low residue in the body, and no potential for causing aplastic anemia. It also lacks disadvantages such as teratogenicity, carcinogenicity, and mutagenicity. However, at room temperature, the solubility of FF in pure water is approximately 1.25 mg / mL, which is relatively low and significantly limits its use. Therefore, the development of soluble florfenicol powder with high solubility, high biocompatibility, good animal absorption, and cost-effectiveness has become a market focus.

[0003] There are four main traditional methods for preparing soluble florfenicol powder: 1. Solubilizing florfenicol with β-cyclodextrin and organic solvents in a saturated solution method; 2. Solubilizing florfenicol by compounding β-cyclodextrin with co-solvents (such as PVP); 3. Solubilizing florfenicol by compounding hydroxypropyl β-cyclodextrin and similar substances with co-solvents; 4. Solubilizing florfenicol directly by compounding with other co-solvents. Various dextrins or glucose are also used as filler components. The organic solvents used in traditional methods can leave lethal residues in livestock and aquatic animals, potentially inducing various diseases with prolonged use; the degradation of excipient co-solvents takes time. Hydroxypropyl β-cyclodextrin can improve the solubility of florfenicol, but its price is dozens of times higher than that of β-cyclodextrin, making it not economically viable in practical use.

[0004] Maltodextrin is a starch derivative that does not contain free starch, produced by enzymatic low-degree hydrolysis, refining, and spray drying of starch or starchy substances. Maltodextrin is often used as a filler for florfenicol, but it is only a simple filler and cannot encapsulate the florfenicol. Therefore, the binding with florfenicol is uneven, and the improvement of florfenicol solubility is limited.

[0005] Publication No. CN106177983A discloses a florfenicol-β-cyclodextrin inclusion complex and its preparation method, which discloses the inclusion of florfenicol with β-cyclodextrin. Publication No. CN107693801A discloses a method for preparing florfenicol-β-cyclodextrin inclusion complex by ultrasonic-centrifugal drying, wherein the ratio of florfenicol to β-cyclodextrin is 1:(2-9). Both of these methods use β-cyclodextrin for inclusion, which can effectively increase the solubility of florfenicol. However, β-cyclodextrin has low solubility in water, resulting in a relatively small amount of florfenicol dissolved.

[0006] Publication No. CN111374949A discloses a process for preparing florfenicol soluble powder or solution, which involves encapsulating florfenicol with β-cyclodextrin, and then uniformly mixing the encapsulated compound with sucrose. However, the sucrose is only used as an additive to adjust the product's flavor and does not address the issues of β-cyclodextrin dissolution and the low amount of florfenicol encapsulated.

[0007] Publication No. MX267253B discloses a continuously manufactured particulate pharmaceutical composition for immediate release. The pharmaceutical ingredient includes florfenicol, comprising 0.5% to 20% of the composition and excipients by weight. The excipients (packaging materials) are dextrin compounds, comprising 40% to 85% of the composition. The dextrin is selected from maltodextrin and cyclodextrin and their derivatives, with hydroxypropyl-β-cyclodextrin being preferred. The excipients include maltodextrin as a first excipient and polyethylene glycol as a second excipient. In this patent, polyethylene glycol primarily functions as a filler, binder, and solubilizer, exhibiting conventional surface activity. While suitable for tablet formation, it is unsuitable for molding as a solution or in spray-drying preparations due to poor solubility. Summary of the Invention

[0008] To address the aforementioned problems, this invention proposes a method for preparing soluble florfenicol powder, which can effectively improve the solubility of florfenicol in water.

[0009] To achieve the above objectives, the present invention is implemented through the following technical solution:

[0010] A method for preparing soluble florfenicol powder involves encapsulating florfenicol powder with a first packaging material to obtain an inclusion complex; and then encapsulating the inclusion complex with a second packaging material to obtain soluble florfenicol powder.

[0011] Furthermore, the first packaging material is cyclodextrin and its derivatives.

[0012] Furthermore, the first packaging material is β-cyclodextrin.

[0013] Furthermore, the second packaging material is maltodextrin. Preferably, the maltodextrin is mainly dextrin with a degree of polymerization of 10 or higher and a small amount of oligosaccharides with a degree of polymerization of 10 or lower, wherein the proportion of dextrin with a degree of polymerization of 10 or higher is 80%-90% and the proportion of oligosaccharides with a degree of polymerization of 10 or lower is 10%-20%.

[0014] Furthermore, the mass ratio of florfenicol to cyclodextrin is 1:(1-15). Preferably, the mass ratio of florfenicol to cyclodextrin is 1:(2-5).

[0015] Furthermore, the mass ratio of cyclodextrin to maltodextrin is 1:2-3:1.

[0016] A method for preparing soluble florfenicol powder specifically includes the following steps:

[0017] (1) Mix the first packaging material and the second packaging material, add water at 40℃-120℃ and stir for 1-4 hours to allow the second packaging material to encapsulate the first packaging material for the first time, and obtain the encapsulated material.

[0018] (2) Add florfenicol powder to the inclusion material obtained in step (1), add water at 40℃-120℃ and stir for 2-8 hours for a second inclusion. After the inclusion is completed, spray dry to obtain soluble florfenicol powder.

[0019] Furthermore, the solid-liquid ratio of the solid formed by the florfenicol powder and the packaging material to water is 1-20:100.

[0020] Furthermore, in step (2), the water added during the second inclusion process is added twice. After the first addition of water, the mixture is stirred for 1-4 hours. Then, water is added a second time, and the mixture is stirred and reacted for 1-4 hours before spray drying.

[0021] Furthermore, in step (2), excipients and cosolvents permitted by the pharmaceutical preparation are added. Preferably, the excipients are mainly fillers, such as glucose, sucrose, etc., and the cosolvent may be ethanol.

[0022] This invention involves a secondary inclusion complex of florfenicol powder, in which maltodextrin exhibits better solubility than β-cyclodextrin. Maltodextrin is a linear long chain containing some branches, while β-cyclodextrin has a cyclic molecular structure. Therefore, during the mixing process in step (1), the linear maltodextrin molecules entangle and bind on the surface of the cyclic β-cyclodextrin, and since maltodextrin has a higher solubility, this increases the solubility of β-cyclodextrin. Thus, after adding florfenicol powder in step (2), the florfenicol powder is again included by the maltodextrin-β-cyclodextrin inclusion complex. During this process, the increased solubility of maltodextrin leads to an increased solubility of β-cyclodextrin in water, resulting in an increased content of β-cyclodextrin in the solution. The inclusion of florfenicol increases the number of inclusions, thereby increasing the loading of florfenicol and simultaneously improving the solubility of florfenicol powder in water.

[0023] The beneficial effects of the preparation method of soluble florfenicol powder of the present invention are as follows:

[0024] (1) In this invention, maltodextrin is first used to encapsulate β-cyclodextrin. Maltodextrin and β-cyclodextrin have similar molecular structures. After they combine, they form a complex. After encapsulating β-cyclodextrin, they form an encapsulated micelle structure, which increases the solubility and saturation concentration of β-cyclodextrin itself. This increases the number of cyclodextrins encapsulating florfenicol, thereby increasing the solubility of florfenicol in water.

[0025] (2) In this invention, maltodextrin and β-cyclodextrin are mixed in a specific ratio, and at the same time, they are mixed in a specific ratio with the core material florfenicol powder, which increases the loading of florfenicol and ensures the inclusion quantity.

[0026] (3) Compared with traditional pharmaceutical excipients such as PVP and PEG, maltodextrin is not only more conducive to biological absorption, but also derived from starch, and its source and degradation are safer and more reliable.

[0027] (4) Compared with existing modified β-cyclodextrin (hydroxypropyl β-cyclodextrin), the maltodextrin and β-cyclodextrin used in this invention are cheaper, the raw materials are readily available, and the cost is lower.

[0028] (5) The preparation method of the present invention uses water as a solvent and spray drying, which can effectively ensure that maltodextrin and β-cyclodextrin in the aqueous solution directly encapsulate florfenicol powder, improve the encapsulation yield and encapsulation quantity, and the process is simple, more convenient to operate, and easy to mass production. Attached Figure Description

[0029] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0030] Figure 1 This is the liquid chromatography spectrum of a florfenicol standard.

[0031] Figure 2 The liquid phase spectrum of the soluble florfenicol powder prepared according to this invention. Detailed Implementation

[0032] To enable those skilled in the art to better understand the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0033] Example 1

[0034] A method for preparing soluble florfenicol powder involves weighing 3 parts β-cyclodextrin and 3 parts maltodextrin, adding 30 parts water, reacting at 60℃ for 2 hours. After the reaction, 0.6 parts florfenicol powder are added, and a secondary inclusion of florfenicol is performed using a saturated solution method; specifically, approximately 30 parts water are added again, the temperature is controlled at 50℃, and the reaction is stirred for 2 hours. After the reaction, 40 parts water are added, stirred for 2 hours, and then spray-dried to prepare the finished product. The finished product is a 10% soluble florfenicol powder.

[0035] Example 2

[0036] A method for preparing soluble florfenicol powder involves weighing 0.7 parts β-cyclodextrin and 0.117 parts maltodextrin, adding 20 parts water, reacting at 60℃ for 3 hours. After the reaction, 0.35 parts florfenicol powder are added, and a secondary inclusion of florfenicol is performed using a saturated solution method; specifically, approximately 20 parts water are added again, the temperature is controlled at 100℃, and the reaction is stirred for 2 hours. After the reaction, 60 parts water are added, stirred for 1 hour, and then spray-dried to prepare the finished product. The finished product is a 30% soluble florfenicol powder.

[0037] Example 3

[0038] A method for preparing soluble florfenicol powder involves weighing 1.5 parts β-cyclodextrin and 1 part maltodextrin, adding 40 parts water, reacting at 80℃ for 1 hour. After the reaction, 0.5 parts florfenicol powder are added, and a secondary inclusion of florfenicol is performed using a saturated solution method; specifically, approximately 40 parts water are added again, the temperature is controlled at 50℃, and the reaction is stirred for 3 hours. After the reaction, 30 parts water are added, and the mixture is stirred for 2 hours. The final product is obtained by spray drying. The finished product is a 20% soluble florfenicol powder.

[0039] Example 4

[0040] A method for preparing soluble florfenicol powder involves weighing 0.6 parts β-cyclodextrin and 0.2 parts maltodextrin, adding 20 parts water, reacting at 50°C for 1 hour. After the reaction, 0.4 parts florfenicol powder are added, and a secondary inclusion of florfenicol is performed using a saturated solution method; specifically, approximately 20 parts water are added again, the temperature is controlled at 60°C, and the reaction is stirred for 3 hours. After the reaction, 30 parts water are added, and the mixture is stirred for 2 hours. The final product is then prepared by spray drying. The finished product is approximately 30% soluble florfenicol powder.

[0041] Example 5

[0042] A method for preparing soluble florfenicol powder involves weighing 0.5 parts β-cyclodextrin and 5 parts maltodextrin, adding 30 parts water, reacting at 50℃ for 1 hour. After the reaction, 0.5 parts florfenicol powder are added, and a secondary inclusion of florfenicol is performed using a saturated solution method; specifically, approximately 30 parts water are added again, the temperature is controlled at 60℃, and the reaction is stirred for 3 hours. After the reaction is complete, 40 parts water are added, and the mixture is stirred for 2 hours. The final product is then prepared by spray drying.

[0043] Example 6

[0044] A method for preparing soluble florfenicol powder involves weighing 0.4 parts β-cyclodextrin and 8 parts maltodextrin, adding 40 parts water, reacting at 50℃ for 1 hour. After the reaction, 0.5 parts florfenicol powder are added, and a secondary inclusion of florfenicol is performed using a saturated solution method; specifically, approximately 30 parts water are added, the temperature is controlled at 60℃, and the reaction is stirred for 3 hours. After the reaction is complete, another 30 parts water are added, and the mixture is stirred for 2 hours. The final product is then prepared by spray drying.

[0045] Example 7

[0046] A method for preparing soluble florfenicol powder involves weighing 0.5 parts β-cyclodextrin and 2 parts maltodextrin, adding 40 parts water, reacting at 50℃ for 1 hour. After the reaction, 0.5 parts florfenicol powder are added, and a secondary inclusion of florfenicol is performed using a saturated solution method; specifically, approximately 30 parts water are added, the temperature is controlled at 60℃, and the reaction is stirred for 3 hours. After the reaction is complete, another 30 parts water are added, and the mixture is stirred for 2 hours. The final product is then prepared by spray drying.

[0047] Example 8

[0048] A method for preparing soluble florfenicol powder involves weighing 5 parts β-cyclodextrin and 10 parts maltodextrin, adding 60 parts water, reacting at 50℃ for 1 hour. After the reaction, 0.6 parts florfenicol powder are added, and a secondary inclusion of florfenicol is performed using a saturated solution method; specifically, approximately 20 parts water are added, the temperature is controlled at 60℃, and the reaction is stirred for 3 hours. After the reaction is complete, another 20 parts water are added, and the mixture is stirred for 2 hours. The final product is then prepared by spray drying.

[0049] Comparative Example 1: 10% soluble florfenicol powder sold on the market.

[0050] Comparative Example 2: Following the method of Example 1, the maltodextrin in the example was replaced with 10% soluble florfenicol powder prepared by PVP.

[0051] Comparative Example 3: Following the method of Example 1, the cyclodextrin was replaced with PVP, and the maltodextrin was replaced with 10% soluble florfenicol powder prepared with PEG8000.

[0052] Comparative Example 4: Following the formulation of Example 1, 10% soluble florfenicol powder was prepared by direct mixing and filling with only maltodextrin and spray drying.

[0053] Comparative Example 5: Following the formulation of Example 1, 10% soluble florfenicol powder was prepared by spray drying using only β-cyclodextrin for inclusion.

[0054] Performance testing

[0055] 1. Content determination

[0056] The content in Example 1 was determined using liquid chromatography and standards. The determination method conformed to the requirements of the Veterinary Drug Pharmacopoeia. Please refer to the liquid chromatography chromatogram. Figure 1 and Figure 2 .

[0057] from Figure 1 and Figure 2 It can be seen that the characteristic peaks of the product after secondary inclusion with maltodextrin are the same as those of the florfenicol standard sample, which means that the florfenicol powder with secondary inclusion using maltodextrin meets the pharmacopoeia requirements.

[0058] 2. Solubility test

[0059] The initial solubility of Examples 1-3 and the comparative examples was determined respectively;

[0060] Test method:

[0061] Maximum solubility: At room temperature, take 100 ml of water, add the powder to be tested, stir well until it becomes clear, and multiply the mass of the powder by the effective content of florfenicol (calculated by liquid chromatography) to obtain its maximum solubility. See Table 1 for details.

[0062] Table 1 Solubility of each group

[0063]

[0064]

[0065] Examples 1 and Comparative Examples 1-5 all contained 10% florfenicol powder. Table 1 shows that the maximum solubility obtained after secondary encapsulation with maltodextrin (Example 1) is significantly higher, reaching 5.78 mg / ml. In contrast, the solubility obtained by primary encapsulation with conventional materials such as polyvinylpyrrolidone (PVP) (Comparative Example 2) and commonly used β-cyclodextrin (Example 5) is considerably lower than that obtained by secondary encapsulation with maltodextrin. This invention significantly improves the solubility of florfenicol using secondary encapsulation with maltodextrin, and its performance is superior to that of soluble florfenicol powder prepared by traditional methods.

[0066] Examples 2 and 3 contain 30% and 20% florfenicol powder, respectively. Solubility decreases with increasing content, which is the normal solubility characteristic of florfenicol powder.

[0067] 3. Stability Test

[0068] The solubility of the examples and comparative examples was measured after 3 months, 6 months, and 12 months. Details are shown in Table 2.

[0069] Table 2

[0070]

[0071]

[0072] As can be seen from Table 2, the solubility difference of Example 1 within 12 months is <0.15 over time. The solubility difference of existing mature florfenicol powders obtained by Comparative Example 2 (PVP single inclusion) and Comparative Example 5 (β-cyclodextrin single inclusion) within 12 months is also <0.15. That is, the stability of the florfenicol powder obtained by the secondary inclusion of the present invention is not affected, but the solubility of the present invention is greater.

[0073] In this document, the term "embodiment" means that a particular feature, structure, or characteristic described in connection with an embodiment may be included in at least one embodiment of the invention. The appearance of this phrase in various places throughout the specification does not necessarily refer to the same embodiment, nor is it a separate or alternative embodiment mutually exclusive with other embodiments. It will be explicitly and implicitly understood by those skilled in the art that the embodiments described herein can be combined with other embodiments.

[0074] Finally, it should be noted that the embodiments disclosed in this invention are merely preferred embodiments of this invention and are only used to illustrate the technical solutions of this invention, not to limit it. Although this invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of this invention.

Claims

1. A method for preparing soluble florfenicol powder, characterized in that: Specifically, the following steps are included: (1) Mix the first packaging material and the second packaging material, add water at 40℃-120℃ and stir for 1-4 hours to allow the second packaging material to encapsulate the first packaging material for the first time, and obtain the encapsulated material. (2) Add florfenicol powder to the inclusion material obtained in step (1), add water at 40℃-120℃ and stir for 2-8 hours for the second inclusion. After the inclusion is completed, spray dry to obtain soluble florfenicol powder. The first packaging material is β-cyclodextrin, and the second packaging material is maltodextrin; the amounts of the β-cyclodextrin, the maltodextrin, and the florfenicol powder, in parts by weight, satisfy the following: 3 parts β-cyclodextrin, 3 parts maltodextrin, and 0.6 parts florfenicol powder; Alternatively, 0.7 parts β-cyclodextrin, 0.117 parts maltodextrin, and 0.35 parts florfenicol powder; Alternatively, 1.5 parts β-cyclodextrin, 1 part maltodextrin, and 0.5 parts florfenicol powder; Alternatively, 0.6 parts β-cyclodextrin, 0.2 parts maltodextrin, and 0.4 parts florfenicol powder; Alternatively, 0.5 parts β-cyclodextrin, 5 parts maltodextrin, and 0.5 parts florfenicol powder; Alternatively, 0.4 parts β-cyclodextrin, 8 parts maltodextrin, and 0.5 parts florfenicol powder; Alternatively, 0.5 parts β-cyclodextrin, 2 parts maltodextrin, and 0.5 parts florfenicol powder; Alternatively, 5 parts β-cyclodextrin, 10 parts maltodextrin, and 0.6 parts florfenicol powder.

2. The method for preparing soluble florfenicol powder according to claim 1, characterized in that: The solid-liquid ratio of the solid formed by the florfenicol powder and packaging material to water is 1-20:

100.

3. The method for preparing soluble florfenicol powder according to claim 2, characterized in that: In step (2), the water added during the second encapsulation is added twice. After the first addition of water, the mixture is stirred for 1-4 hours. Then, water is added a second time, and the mixture is stirred and reacted for 1-4 hours before spray drying.

4. The method for preparing soluble florfenicol powder according to claim 1, characterized in that: In step (2), add pharmaceutically permissible excipients and cosolvents.

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