Florfenicol soluble powder with double-phase release characteristic as well as preparation method and application of florfenicol soluble powder

Abstract

The invention discloses florfenicol soluble powder with a two-phase release characteristic as well as a preparation method and application thereof, and belongs to the technical field of veterinary drug preparations. The florfenicol soluble powder is prepared from the following ingredients in percentage by mass: 10 to 40 percent of florfenicol nanocrystals, 30 to 50 percent of sulfobutyl ether-beta-cyclodextrin, 5 to 15 percent of natural colloid sustained-release materials, 5 to 15 percent of copovidone and 1 to 10 percent of glucose. The florfenicol soluble powder disclosed by the invention has high dissolution dispersity and'quick release-slow release 'double-phase release characteristics, can be quickly and uniformly dispersed when encountering water, and has a double-release mode of quick effect taking and long-acting maintenance in vivo, so that the oral bioavailability is remarkably improved, residues of medicines in edible tissues of animals are reduced, and the curative effect of the florfenicol soluble powder is improved. Therefore, the preparation method has good application prospect and value in the technical field of veterinary drug preparations.

Description

Technical Field

[0001] This invention belongs to the field of veterinary drug formulation technology, specifically relating to a florfenicol soluble powder with biphasic release characteristics, its preparation method and application. Background Technology

[0002] Florfenicol is a key drug for the prevention and treatment of bacterial diseases in livestock, poultry, and aquaculture. However, its poor water solubility severely limits its bioavailability when administered via drinking water. Commercially available soluble powders often rely on large amounts of solubilizers (such as organic acid salts and surfactants) or organic solvents (such as N-methylpyrrolidone) for solubilization, generally resulting in incomplete dissolution, lack of sustained-release function, large fluctuations in blood drug concentration, and a high risk of tissue residue. Furthermore, current technologies struggle to achieve both rapid dissolution and long-term efficacy in a single formulation. Therefore, developing a novel florfenicol formulation that dissolves rapidly and achieves a balance between immediate and sustained release in vivo is crucial for improving efficacy, reducing dosing frequency, and ensuring food safety. Summary of the Invention

[0003] This invention provides a florfenicol soluble powder with biphasic release characteristics, comprising the following components by mass fraction: Florfenicol nanocrystals 10-40%, sulfobutyl ether-β-cyclodextrin 30-50%, natural colloidal sustained-release material 5-15%, copovidone 5-15%, glucose 1-10%.

[0004] In one specific embodiment, the florfenicol soluble powder with biphasic release properties comprises the following components by mass fraction: Florfenicol nanocrystals 30%, sulfobutyl ether-β-cyclodextrin 45%, natural colloidal sustained-release material 10%, copovidone 10%, glucose 5%.

[0005] In the above-mentioned florfenicol soluble powder with biphasic release characteristics, the natural colloidal slow-release material is at least one of carboxymethyl chitosan, sodium alginate, and pectin.

[0006] The preparation method of the above-mentioned florfenicol soluble powder includes the following steps: Florfenicol nanocrystal suspension was added to a coating solution and subjected to high-speed shearing to form a composite nano suspension; the composite nano suspension was spray-dried to obtain a white composite powder; the white composite powder was mixed evenly with copovidone and glucose to obtain florfenicol soluble powder.

[0007] In the above method for preparing florfenicol soluble powder, the florfenicol nanocrystal suspension is prepared by the following method: florfenicol raw material is added to a polyvinylpyrrolidone K30 aqueous solution, initially dispersed, and then homogenized under high pressure to obtain the florfenicol nanocrystal suspension.

[0008] In the above method for preparing florfenicol nanocrystal suspension, the high-pressure homogenization conditions are: cyclic homogenization 15 times at a pressure of 1500 bar.

[0009] In the above method for preparing florfenicol nanocrystal suspension, the mass concentration of the polyvinylpyrrolidone K30 aqueous solution is 0.5~2%; and the solid content of the florfenicol nanocrystal suspension is 5~20%.

[0010] In the above method for preparing florfenicol soluble powder, the coating solution is prepared by the following method: dissolving sulfobutyl ether-β-cyclodextrin and natural colloidal slow-release material in water to obtain the coating solution; the mass concentration of the coating solution is 10~30%.

[0011] In the above method for preparing florfenicol soluble powder, the high-speed shearing conditions are: shearing at 5000~10000 rpm for 10~120 min.

[0012] This invention provides the application of the above-mentioned florfenicol soluble powder in the preparation of veterinary drinking water formulations for the treatment of bacterial diseases.

[0013] This invention provides a veterinary drinking water administration formulation containing the above-mentioned florfenicol soluble powder; it may also contain a pharmaceutically acceptable carrier or excipient.

[0014] The beneficial effects of this invention are as follows: The florfenicol soluble powder of this invention is prepared by high-speed shear compounding and spray drying of florfenicol nanocrystals, sulfobutyl ether-β-cyclodextrin, and natural colloidal sustained-release materials. This product disperses rapidly in water and exhibits a unique dual-phase behavior of immediate and sustained release in vitro. This characteristic results in higher bioavailability and lower drug residues in animals, and the production process does not use harmful organic solvents. The process of this invention is stable and suitable for industrial production.

[0015] The florfenicol soluble powder of the present invention has high solubility and dispersibility and "rapid-release" dual-phase release characteristics. It can be rapidly and uniformly dispersed in water and has a dual release mode of rapid onset and long-term maintenance in vivo, thereby significantly improving oral bioavailability and reducing drug residues in edible animal tissues. Therefore, it has good application prospects and value in the field of veterinary drug formulation technology.

[0016] The florfenicol soluble powder of the present invention can spontaneously disintegrate and disperse within 60 seconds to form a uniform opalescent or clear solution; its in vitro release behavior in pH 6.8 phosphate buffer exhibits a biphasic characteristic, with a cumulative release rate of ≥70% at 30 minutes and ≥95% at 12 hours. Attached Figure Description

[0017] Figure 1 Comparative photographs showing the initial dispersion state (30 seconds) of various florfenicol soluble powders in pure water at 25°C; from left to right: Example 1, Comparative Example 1, Comparative Example 2, and commercially available product.

[0018] Figure 2 Comparative photographs of the states of various florfenicol soluble powder solutions after standing at room temperature for 24 hours; from left to right: Example 1, Comparative Example 1, Comparative Example 2, and commercially available product.

[0019] Figure 3 A comparison chart of the cumulative release curves of various florfenicol soluble powders in vitro.

[0020] Figure 4 The average blood concentration-time curves of various florfenicol products in chickens are shown. Detailed Implementation

[0021] In this invention, florfenicol raw material was purchased from Zhejiang Guobang Pharmaceutical Co., Ltd., with a purity ≥98.5%; sulfobutyl ether-β-cyclodextrin (SBE-β-CD, degree of substitution approximately 6.5) was purchased from Shandong Xinda Biotechnology Co., Ltd., model SBE-β-CD-SD6.5; carboxymethyl chitosan (viscosity specification: 100-200 mPa.s) was purchased from Qingdao Haipu Biotechnology Co., Ltd.; copovidone (PVP VA64) was purchased from BASF Germany as a dispersant to improve the flowability of spray-dried powder and the solubility and dispersibility of the final product; and glucose (anhydrous) was a pharmaceutical excipient purchased from Shandong Tianli Pharmaceutical Co., Ltd., as a filler and flavoring agent.

[0022] In this invention, florfenicol nanocrystals are obtained from the active pharmaceutical ingredient (API) through high-pressure homogenization. The key difference between the nanocrystals and the API lies in their particle size: the API is a micron-sized crystalline powder with low solubility; the nanocrystals, on the other hand, have their particle size reduced to 100-250 nm through high-pressure homogenization, thereby significantly increasing the specific surface area and enabling rapid dissolution. The florfenicol nanocrystal suspension is prepared as follows: 10g of florfenicol API is added to 100mL of an aqueous solution containing 1% (w / v) polyvinylpyrrolidone K30 (PVP K30). After initial dispersion, the suspension is homogenized 15 times at 1500 bar using a high-pressure homogenizer to obtain a florfenicol nanocrystal suspension with a solid content of approximately 10%. The average particle size, determined by dynamic light scattering, is 180±20 nm.

[0023] Other materials used in this invention, unless otherwise stated, are commercially available. Other terms used in this invention, unless otherwise specified, generally have the meanings commonly understood by those skilled in the art. The invention is further described in detail below with reference to specific embodiments and data. The following embodiments are merely illustrative and not intended to limit the scope of the invention in any way.

[0024] Example 1 The formulation of florfenicol soluble powder includes the following components by mass fraction: Florfenicol nanocrystals 30%, sulfobutyl ether-β-cyclodextrin 45%, carboxymethyl chitosan 10%, copolyvinyl ketone 10%, glucose 5%.

[0025] The steps for preparing florfenicol soluble powder are as follows: Florfenicol raw material was prepared into a florfenicol nanocrystalline suspension (10% solid content) according to the above method. Sulfobutyl ether-β-cyclodextrin and carboxymethyl chitosan were dissolved in purified water to prepare a coating solution (20% mass concentration). The florfenicol nanocrystalline suspension was added to the coating solution under a high-speed shear mill at 8000 rpm and sheared continuously for 40 min to form a composite nano-suspension. The composite nano-suspension was spray-dried (inlet air 140℃, outlet air 65℃, feed rate 10 mL / min) to obtain a white composite powder. Finally, the white composite powder was mixed with copovidone and glucose in a three-dimensional mixer for 30 minutes and passed through an 80-mesh sieve to obtain florfenicol soluble powder.

[0026] Comparative Example 1 The formulation of florfenicol soluble powder includes the following components by mass fraction: The formula consists of 30% florfenicol active pharmaceutical ingredient, 45% sulfobutyl ether-β-cyclodextrin, 10% carboxymethyl chitosan, 10% copovidone, and 5% glucose.

[0027] The steps for preparing florfenicol soluble powder are as follows: 10g of florfenicol active pharmaceutical ingredient (API) was added to 100mL of an aqueous solution containing 1% (w / v) polyvinylpyrrolidone K30 (PVP K30), and stirred to disperse, obtaining a florfenicol API suspension (non-nanoscale, 10% solids content). Sulfobutyl ether-β-cyclodextrin and carboxymethyl chitosan were dissolved in purified water to prepare a coating solution (20% mass concentration). The florfenicol API suspension was added to the coating solution under a high-speed shear machine at 8000rpm, and sheared continuously for 40min to form a composite nano-suspension. The composite nano-suspension was spray-dried (inlet air 140℃, outlet air 65℃, feed rate 10 mL / min) to obtain a white composite powder. Finally, the white composite powder was mixed with copovidone and glucose in a three-dimensional mixer for 30 minutes, and then passed through an 80-mesh sieve to obtain florfenicol soluble powder.

[0028] Comparative Example 2 The formulation of florfenicol soluble powder includes the following components by mass fraction: Florfenicol nanocrystals 30%, sulfobutyl ether-β-cyclodextrin 45%, carboxymethyl chitosan 10%, copolyvinyl ketone 10%, glucose 5%.

[0029] The steps for preparing florfenicol soluble powder are as follows: Place the above materials in a three-dimensional mixer and mix them physically for 60 minutes, then pass them through an 80-mesh sieve to obtain florfenicol soluble powder.

[0030] I. Performance Comparison Test 1. Dispersion Take 1.7g each of Example 1, Comparative Example 1, Comparative Example 2 and a commercially available brand of florfenicol soluble powder (each equivalent to 500mg of florfenicol), and slowly pour them into beakers containing 100mL of pure water (25℃), and let them stand for observation.

[0031] Test results are as follows Figure 1 As shown: The sample in Example 1 completely disintegrated within 30 seconds, dispersing into a homogeneous opalescent solution. The sample in Comparative Example 1 had a large amount of undissolved white active pharmaceutical ingredient floating on the surface. The sample in Comparative Example 2 sank, but dispersed slowly, forming many clumps that were difficult to dissipate. The commercially available sample had a large amount of sediment at the bottom, and the solution was turbid and uneven.

[0032] 2. Static stability Let the prepared solution stand for 24 hours. The results are as follows: Figure 2 As shown, the solution in Example 1 remained homogeneous and opalescent, with no visible precipitate at the bottom. Comparative Examples 1 and 2, along with the commercially available sample solutions, all exhibited clear stratification, with a large amount of flocculent or granular precipitate at the bottom.

[0033] 3. In vitro release rate According to the general rules of the Chinese Veterinary Pharmacopoeia, the release medium was 900 mL of phosphate buffer (pH 6.8), the rotation speed was 50 rpm, and the temperature was 37±0.5℃. Each sample (containing approximately 50 mg of florfenicol) was added to the medium, and 5 mL samples were taken at specified time points (5, 15, 30, 60, 120, 240, 480, and 720 min) (with simultaneous addition of isothermal and equal-volume medium). After filtration, the drug concentration was determined by high-performance liquid chromatography (HPLC), and the cumulative release rate was calculated.

[0034] Test results are as follows Figure 3 As shown in Table 1: Table 1. Cumulative in vitro release rates of various florfenicol soluble powders The results showed that only the product of Example 1 exhibited ideal biphasic release characteristics (>70% release at 30 minutes, followed by gradual release to complete release). Comparative Example 1 (using the active pharmaceutical ingredient) showed extremely slow and incomplete release. Comparative Example 2 (physically mixed nanocrystals) showed a release rate and extent far lower than Example 1, indicating that simple physical mixing cannot achieve effective compounding and sustained release. Commercially available products exhibited a single rapid-release mode, lacking sustained-release properties.

[0035] II. Bioavailability and Residue Testing Eighty healthy AA broiler chickens of similar weight were randomly divided into four groups of 20 each: Example 1 group, Comparative Example 1 group, Comparative Example 2 group, and the commercially available product group. After fasting for 12 hours, all chickens were given a single dose of 20 mg / kg BW (calculated as florfenicol) via drinking water.

[0036] Pharmacokinetic studies: Blood samples were collected from the forewing veins before administration and at 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after administration. Plasma was separated, and plasma concentrations were determined by HPLC. The area under the curve (AUC0-24h) and peak concentration (C) were calculated. max ) and other parameters.

[0037] Tissue residue detection: Chickens from each of the above groups (n=6 per group) were administered the same dose via drinking water for 5 consecutive days. On the 5th day after the last administration (the 5th day after drug withdrawal), the chickens were slaughtered, and pectoral muscle and liver tissues were collected, homogenized, and extracted. Florfenicol residues were detected using liquid chromatography-tandem mass spectrometry (LC-MS / MS), with a detection limit of 0.1 μg / kg.

[0038] The test results are as follows Figure 4 As shown in Table 2: Table 2. Major pharmacokinetic parameters of chickens after oral administration of different florfenicol formulations (mean ± SD, n=6) *Calculated with the AUC0-24h mean of Example 1 group as 100%.

[0039] The results of tissue residue analysis are as follows: On the 5th day after drug withdrawal, the florfenicol residue in the pectoral muscle and liver samples of all chickens in Example 1 group was below the detection limit (0.1 μg / kg). Residues were detected in some samples from Comparative Example 1, Comparative Example 2, and the commercially available product group, ranging from 0.2 to 0.5 μg / kg.

[0040] The core parameter of bioavailability is the area under the curve (AUC), which represents the total amount of drug absorbed. The immediate-release phase of the florfenicol soluble powder described in this invention ensures rapid and high-proportion dissolution of the drug in the critical initial absorption stage, overcoming the "difficulty in initiating" absorption problem caused by poor solubility, and laying a decisive foundation for maximizing the total amount absorbed.

[0041] At the same dosage, the level of residual drug is closely related to the efficiency and completeness of its metabolic clearance in the body. This invention systematically optimizes this process through a unique composite structure: Promoting complete absorption and reducing "ineffective passage": Traditional formulations, due to slow or incomplete dissolution, result in a significant proportion of active ingredients passing through the gastrointestinal tract as undissolved solid particles, failing to be effectively absorbed. While this portion of the drug does not enter the systemic circulation to produce therapeutic effects, it may cause local residues in the intestines or disrupt the gut microbiota. This invention fundamentally reduces this non-target exposure through near-complete drug dissolution and absorption.

[0042] Optimizing drug form and distribution: The complex formed by nanocrystal technology and cyclodextrin inclusion alters the initial distribution of drug molecules in the body. This more fluid-soluble form helps reduce the tendency for drugs to bind strongly and nonspecifically to certain deep tissues (such as fat or connective tissue of specific organs), allowing more drugs to exist in circulation in a free form, thus making them easier for the liver's metabolic enzyme system to access and clear.

[0043] Providing sustained substrate clearance: The stable and continuous drug delivery provided by the sustained-release phase is equivalent to providing a stable and moderate metabolic substrate for the liver's metabolic enzyme system. This helps maintain the homeostasis of enzyme metabolic activity and avoids the metabolic "saturation" or fluctuations that may occur with traditional immediate-release formulations due to the influx of high drug concentrations in a short period of time. This promotes more efficient and linear continuous drug clearance throughout the dosing period. This "steady-state clearance" mode helps result in a lower total amount of drug remaining in the body at discontinuation and a more rapid and thorough clearance process.

[0044] Although the soluble powder used in the above implementation cases has the same active ingredient, florfenicol, the "fate" of different formulations in the body depends on their physicochemical state after administration.

[0045] In Comparative Example 1, the hydrophilic colloidal material formed a gel network upon contact with water, which physically confined the un-nanosized hydrophobic drug particles, severely hindering drug dissolution (e.g., Figure 3 As shown in the release curve, most of the drug cannot be released within the absorption window, resulting in extremely low total absorption (AUC).

[0046] Comparative Example 2 used the exact same florfenicol nanocrystals and other components as Example 1, but was prepared solely through physical mixing. Its in vitro release curve ( Figure 3 The results show that although its release rate and extent are better than Comparative Example 1 (API + compounding process), they are still significantly lower than Example 1, and it cannot form a clearly distinguishable biphasic characteristic of immediate and sustained release. This indicates that simple nanocrystals and simple physical mixing cannot achieve the functional synergy and structural integration formed between the components (nanocrystals, cyclodextrin, colloidal materials) through a specific compounding process as in Example 1. This comparative example, in turn, confirms that the "high-speed shear compounding-spray drying" process described in this invention is an indispensable key step for constructing a delivery system with ideal biphasic release behavior.

[0047] Commercially available soluble powders rely on solubilizers (such as certain organic acid salts or surfactants), whose solubilizing effect is highly dependent on external environments (such as pH and ionic strength). While they may be maintained in simple aqueous solutions in vitro, the solubilizing system is easily disrupted in the complex, pH-variable environment of the gastrointestinal tract, leading to drug precipitation or the formation of poorly absorbed colloidal aggregates. Therefore, absorption is incomplete and unstable, resulting in limited overall bioavailability.

[0048] This invention constructs a "delivery system" with synergistic effects of its components: nanocrystals provide an area advantage for dissolution kinetics; sulfobutyl ether-β-cyclodextrin, as a "dissolution enhancer" and "molecular carrier," acts dynamically on the surface of the nanocrystals, continuously maintaining an extremely high local concentration gradient, which is the core driving force for the rapid and complete dissolution of the drug; and the outer colloidal material (such as carboxymethyl chitosan) acts as a "release regulator," transforming the aforementioned high-intensity dissolution process into a controlled and sustained release.

[0049] The synergistic effect of the above-mentioned components through the specific process of this invention ensures that the drug can continue to exist in a more easily absorbed state (molecular or nanoscale) and a more ideal kinetic rate during the absorption period, thereby maximizing the total amount absorbed.

[0050] In summary, this invention transforms a known drug component into a synergistic structural whole through a specific process. This structure not only solves the absorption initiation problem through "rapid release" but also regulates the entire drug delivery process in vivo through "slow release," ultimately resulting in a synergistic effect of "high AUC (more complete absorption)" and "low residue (smoother clearance)," fully demonstrating the creative advancement of this invention compared to simple physical mixing or traditional solubilization techniques.

[0051] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention in any other way. Any person skilled in the art may make changes or modifications to the above-disclosed technical content to create equivalent embodiments. 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 scope of the present invention shall still fall within the protection scope of the present invention.

Claims

1. A florfenicol soluble powder with biphasic release characteristics, characterized in that, It contains the following components by mass fraction: Florfenicol nanocrystals 10-40%, sulfobutyl ether-β-cyclodextrin 30-50%, natural colloidal sustained-release material 5-15%, copovidone 5-15%, glucose 1-10%.

2. The florfenicol soluble powder with biphasic release characteristics according to claim 1, characterized in that, It contains the following components by mass fraction: Florfenicol nanocrystals 30%, sulfobutyl ether-β-cyclodextrin 45%, natural colloidal sustained-release material 10%, copovidone 10%, glucose 5%.

3. The florfenicol soluble powder with biphasic release characteristics according to claim 1, characterized in that, The natural colloidal slow-release material is at least one of carboxymethyl chitosan, sodium alginate, and pectin.

4. The method for preparing florfenicol soluble powder according to any one of claims 1 to 3, characterized in that, The steps are as follows: Florfenicol nanocrystal suspension was added to a coating solution and subjected to high-speed shearing to form a composite nano suspension; the composite nano suspension was spray-dried to obtain a white composite powder; the white composite powder was mixed evenly with copovidone and glucose to obtain florfenicol soluble powder.

5. The method for preparing florfenicol soluble powder according to claim 4, characterized in that, The florfenicol nanocrystal suspension is prepared by the following method: florfenicol raw material is added to a polyvinylpyrrolidone K30 aqueous solution, initially dispersed, and then homogenized under high pressure to obtain the florfenicol nanocrystal suspension.

6. The method for preparing florfenicol soluble powder according to claim 5, characterized in that, The conditions for high-pressure homogenization are: cyclic homogenization 15 times at a pressure of 1500 bar; the mass concentration of the polyvinylpyrrolidone K30 aqueous solution is 0.5~2%; and the solid content of the florfenicol nanocrystal suspension is 5~20%.

7. The method for preparing florfenicol soluble powder according to claim 4, characterized in that, The coating solution is prepared by dissolving sulfobutyl ether-β-cyclodextrin and a natural colloidal sustained-release material in water to obtain the coating solution; the mass concentration of the coating solution is 10~30%.

8. The method for preparing florfenicol soluble powder according to claim 4, characterized in that, The conditions for high-speed shearing are: shearing at 5000~10000 rpm for 10~120 min.

9. The use of the florfenicol soluble powder of claim 1 in the preparation of a veterinary drinking water formulation for the treatment of bacterial diseases.

10. A veterinary drinking water medication, characterized in that, The veterinary drinking water preparation contains the florfenicol soluble powder as described in claim 1.

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