Process for the preparation of florfenicol complex

Abstract

The application discloses a preparation method of florfenicol composite medicine and belongs to the technical field of pharmaceutical preparations. First, florfenicol is added into a chitosan solution, and the florfenicol is attached to the chitosan to form a precursor composite. Then, a Spirulina platensis sulfated polysaccharide extract is added into the precursor composite. Due to the binding force between the Spirulina platensis sulfated polysaccharide extract and the chitosan, the composite particles coated with the florfenicol are formed. The Spirulina platensis sulfated polysaccharide extract is located at the periphery of the composite particles, so that the composite particles are hydrophilic and have negative charges. The composite particles coated with the florfenicol are the florfenicol composite medicine. The method reduces the types of medicines used, integrates multiple treatment functions in one medicine, reduces the types of medicines that need to be taken by patients at the same time, and simplifies the treatment scheme. The method has the characteristics of biocompatibility and degradability, improves the water solubility of the florfenicol, and has a very simple reaction process and is suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparations, in particular to a preparation method of florfenicol compound drugs. BACKGROUND

[0002] Florfenicol, also known as flumeftum, is a 3-fluorine derivative of thiamphenicol, belonging to a new type of amide alcohol antibiotic. It has a wide antibacterial spectrum and excellent pharmacological properties, and has a wide application prospect in veterinary clinics. Florfenicol mainly exerts antibacterial effect by inhibiting bacterial protein synthesis. It binds to the 50S subunit of the 70S ribosome of bacteria, prevents the activity of peptidyl transferase, and thus inhibits the extension of peptide chains and prevents the synthesis of proteins. Florfenicol is active against many gram-positive and gram-negative bacteria, including antibiotic-resistant strains. This makes it have a wide application prospect in the treatment of animal diseases caused by sensitive bacteria.

[0003] Florfenicol has the following disadvantages:

[0004] 1. Florfenicol has low solubility in pharmacokinetics, which affects its bioavailability. Florfenicol is a time-dependent drug, and its efficacy depends on the time when the blood drug concentration exceeds the minimum inhibitory concentration, rather than the peak concentration. In the biological classification of pharmaceuticals, it belongs to Class II drugs, i.e. drugs with low solubility but high permeability. The extremely low solubility in water limits the release and absorption of the drug in the gastrointestinal tract, thereby affecting the bioavailability.

[0005] Currently, there are two main ways to improve the water solubility of florfenicol: the first is to develop new types of florfenicol clathrates from the perspective of pharmacy. However, common wrapping materials such as hydroxypropyl-β-cyclodextrin cannot increase the efficacy and are difficult to be widely used; the second is to modify and transform the structure of florfenicol, such as preparing florfenicol phosphate and florfenicol diacid monoester precursor drugs, which can significantly improve its solubility in water. However, the preparation conditions of these precursor drugs are usually harsh, requiring special reaction conditions and equipment, which increases the difficulty and cost of production, and also cannot increase the efficacy, making it difficult to be industrialized. At present, florfenicol in its original form (i.e. florfenicol without structural modification or transformation) is still the main treatment drug.

[0006] 2. The disease cycle is often accompanied by complex symptoms, immune deficiency, complications after treatment, and side effects, especially in the case of mixed bacterial and viral infections, treatment becomes more complex. The use of a single drug, such as florfenicol, may be effective against some bacterial infections, but may not fully cover all pathogens and may not alleviate symptoms caused by viruses or other factors.

[0007] In this case, the composite drug with antibacterial and antiviral functions shows its unique advantages. This kind of drug can act on bacteria and viruses at the same time by combining multiple active ingredients, thereby alleviating symptoms and improving treatment effect. SUMMARY

[0008] In view of the deficiencies of the prior art, the application provides a preparation method of florfenicol composite drug.

[0009] The preparation method of the florfenicol composite drug comprises the following steps:

[0010] The preparation method of the florfenicol composite drug comprises the following steps:

[0011] Step S1, preparation of spirulina sulfate polysaccharide extract solution:

[0012] At room temperature, the spirulina sulfate polysaccharide extract is dissolved in deionized water at a concentration of 0.8-1.2 mg / mL, and stirred uniformly to prepare the spirulina sulfate polysaccharide extract solution for standby use;

[0013] Step S2, preparation of chitosan solution:

[0014] At room temperature, the chitosan is dissolved in 1wt% acetic acid with a concentration of 8-12 mg / mL, and then the high-concentration chitosan solution is diluted to a target concentration of 1 mg / mL using phosphate buffered saline, and the pH value is kept at 5.5-6.5, and stirred uniformly to prepare the chitosan solution for standby use;

[0015] Step S3, preparation of first solution:

[0016] The florfenicol is added to the chitosan solution and stirred uniformly, so that the weight concentration ratio of the chitosan and the florfenicol is 1:1, and the first solution is prepared for standby use;

[0017] In the first solution, the florfenicol and the chitosan both have weak hydrophobicity, and the two are combined first to form a precursor composite;

[0018] Step S4, preparation of second solution:

[0019] The Arthrospira sulphated polysaccharide extract solution is continuously stirred, and the first solution is added dropwise into the Arthrospira sulphated polysaccharide extract solution at a slow speed, at this time, the florfenicol concentration is 500 ppm; then, the second solution is prepared by uniformly mixing, and is ready for use;

[0020] At this time, the weight concentration ratio of chitosan to Arthrospira sulphated polysaccharide extract is less than 1.5:1;

[0021] In the second solution, the chitosan and Arthrospira sulphated polysaccharide extract in the precursor complex self-assemble into nanoparticles and achieve florfenicol loading to form composite particles.

[0022] The preparation method of the florfenicol composite drug further includes the following steps:

[0023] In step S5, the second solution is centrifuged:

[0024] After centrifugation of the second solution, the first precipitate is obtained.

[0025] In step S6, the precipitate is added into deionized water again to form a suspension, and the suspension is left to stand for 1 hour, and the supernatant is taken, centrifuged to obtain the second precipitate, and at this time, the second precipitate is the florfenicol composite particles, i.e., the florfenicol composite drug.

[0026] In step S4, the weight concentration ratio of chitosan, florfenicol and Arthrospira sulphated polysaccharide extract is 0.75:0.75:1.

[0027] The Arthrospira sulphated polysaccharide extract has negatively charged sulphate groups and carboxyl groups, and the weight average molecular weight is about 272 kDa; the chitosan has positively charged amine groups, and the number average molecular weight is 1.4*10 5 Da; and the weight concentration ratio of chitosan to Arthrospira sulphated polysaccharide extract is 0.5-1.5:1.

[0028] The present application provides a preparation method of a florfenicol composite drug, and has the following effects:

[0029] 1. Reducing the types of drugs used: the composite drug integrates multiple treatment functions in one drug, reduces the types of drugs that the patient needs to take at the same time, and simplifies the treatment plan.

[0030] 2. Reducing the risk of drug overdose: when using a single drug, in order to achieve the treatment effect, the dose may need to be increased, which increases the risk of drug overdose. The composite drug can reduce the risk of drug overdose while ensuring efficacy by reasonably matching various components.

[0031] 3. Avoid drug interactions: Different drugs may interact, leading to weakened or enhanced efficacy, or even adverse reactions. Combination drugs are developed with these factors in mind, thus avoiding or reducing drug interactions.

[0032] 4. Ensure the compatibility and stability between various components. Attached Figure Description

[0033] Figure 1 A schematic diagram showing the structural changes of composite particles at different pH levels;

[0034] Figure 2 TEM image of composite particles;

[0035] Figure 3 This is a graph showing the trend of cell survival rate for different concentrations of florfenicol compound drugs. Detailed Implementation

[0036] The technical solutions of 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 some embodiments of the present invention, and not all embodiments. 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.

[0037] Spirulina macrophylla sulfated polysaccharide extract is a high-purity bio-derived polymer with a broad molecular weight distribution and variable monosaccharide arrangement. The molecular weight distribution was confirmed by high-performance size exclusion chromatography (HPSEC-RI) with refractive index detection: it exhibits a unimodal distribution with a weight-average molecular weight of approximately 272 kDa, indicating high polysaccharide homogeneity. The Spirulina macrophylla sulfated polysaccharide extract used in this application is a purified sulfated polysaccharide (polysaccharide content approximately 99%, weight-average molecular weight Mw = 272 kDa) extracted from Spirulina macrophylla using pressurized hot water extraction, provided by Far Eastern Biotechnology Co., Ltd., Taiwan.

[0038] Spirulina sulfated polysaccharide extract, possessing negatively charged sulfate and carboxylic acid groups, is a hydrophilic and negatively charged material. This study did not investigate other types of sulfated polysaccharide extracts, such as those from Spirulina, because the structural determination of polysaccharides is quite complex, and it cannot be simply determined that other types of sulfated polysaccharide extracts have the same physicochemical and biological properties as Spirulina sulfated polysaccharide extract. Each sulfated polysaccharide extract may possess its own unique biological activity, physical properties, and chemical stability, which require specific experimental determination and verification.

[0039] Arthrospira and Spirulina are two different genera in biological classification. Arthrospira is multicellular algal filament, loose and regular curling, usually having relatively large diameter and large spiral; its typical feature is that its filament is regular spiral or undulating. Spirulina is single algal filament, often gathered in thin sheet, algal filament bending, most of which are regular spiral winding.

[0040] Chitosan is a product of removing part of acetyl group from natural polysaccharide chitin, which is not soluble in water by itself, and must be modified or combined with other materials to improve its hydrophilicity, so as to overcome the limitation of its water insolubility. The chitosan used in the present scheme has a number average molecular weight Mn = 1.4 × 10 5 Da, purchased from Polybead International Co., Ltd.

[0041] In the present scheme, first, fluorophenical is added to the chitosan solution, and the fluorophenical adheres to the chitosan to form a precursor complex. Then, the Arthrospira sulfated polysaccharide extract is added to the precursor complex, and due to the binding force between the Arthrospira sulfated polysaccharide extract and the chitosan, a composite particle coated with fluorophenical is formed, and the Arthrospira sulfated polysaccharide extract is located at the periphery of the composite particle, so that the composite particle is hydrophilic and has a negative charge.

[0042] A preparation method of a fluorophenical composite drug, comprising the following steps:

[0043] Step S1, preparing an Arthrospira sulfated polysaccharide extract solution:

[0044] At room temperature, the Arthrospira sulfated polysaccharide extract is dissolved in deionized water at a concentration of 0.8-1.2 mg / mL, and stirred uniformly to prepare an Arthrospira sulfated polysaccharide extract solution for standby use;

[0045] Step S2, preparing a chitosan solution:

[0046] At room temperature, the chitosan is dissolved in 1wt% acetic acid with a concentration of 8-12 mg / mL, and then the high-concentration chitosan solution is diluted to a target concentration of 1 mg / mL using phosphate buffered saline, and the pH value is kept at 5.5-6.5 (preferably at 6.0), and stirred uniformly to prepare a chitosan solution for standby use;

[0047] Step S3, preparing a first solution:

[0048] The fluorophenical is added to the chitosan solution and stirred uniformly, so that the weight concentration ratio of chitosan and fluorophenical is 1:1, to prepare a first solution for standby use.

[0049] In the first solution, both fluorophenical and chitosan have weak hydrophobicity, and the two are combined first to form a precursor complex.

[0050] Step S4, preparing a second solution:

[0051] The Arthrospira sulphated polysaccharide extract solution is continuously stirred, and the first solution is added dropwise into the Arthrospira sulphated polysaccharide extract solution at a slow speed, at which time the florfenicol concentration is 400-600 ppm (optimum 500 ppm); then, mixing is performed at a speed of 800 rpm to prepare a second solution, which is ready for use;

[0052] At this time, the weight concentration ratio of chitosan to Arthrospira sulphated polysaccharide extract is less than 1.5:1; as a preferred, the weight concentration ratio of chitosan, florfenicol and Arthrospira sulphated polysaccharide extract is 0.75:0.75:1.

[0053] In the second solution, the chitosan and Arthrospira sulphated polysaccharide extract in the precursor complex self-assemble into nanoparticles and achieve loading of florfenicol, forming a composite particle.

[0054] Step S5, centrifuging the second solution:

[0055] The second solution is centrifuged at 2500 rpm for 15 minutes to obtain a first precipitate.

[0056] Step S6, the precipitate is re-dispersed in deionized water to form a suspension, and the suspension is allowed to stand for 1 hour, and the supernatant is taken and centrifuged at 2500 rpm for 15 minutes to obtain a second precipitate, which is the florfenicol composite particle, i.e. florfenicol composite drug.

[0057] Steps S5 and S6 are steps for purifying the florfenicol composite drug. In step S5, most of the florfenicol composite drug is centrifuged out in the form of a first precipitate. In step S6, most of the florfenicol composite drug is suspended in the supernatant, which is water-soluble, and the drug is separated out after centrifugation of the supernatant, thereby filtering out most of the unreacted raw material.

[0058] As Figure 1The release behavior of the composite particles in different pH media was investigated for different drugs, and the pH-sensitive release characteristics of the composite particles were evaluated. The drug under review exhibited the best release efficiency under acidic conditions. The Arthrospira sulphated polysaccharide extract exhibited stronger negative electrical properties under acidic conditions, which led to the displacement of the binding sites of the drug, thereby accelerating the release rate of florfenicol. In addition, the conformational changes of chitosan made the composite particles have sufficient responsiveness because the swelling of chitosan in an acidic environment, the loosely structured composite particles accelerated the release of florfenicol. The lower release rate in a neutral environment can be attributed to the high stability of the composite, which makes it difficult for structural changes to occur, thereby hindering the release of florfenicol. In addition, under alkaline conditions, the hydrophobic florfenicol and the precursor complex of chitosan in the composite particles will shrink due to the repulsion reaction with the surrounding alkaline aqueous environment. At the same time, the physical properties of the Arthrospira sulphated polysaccharide extract make it more inclined to approach the environment, which reduces the probability of competing for florfenicol with the binding sites of chitosan, thus being unfavorable for the diffusion of the drug.

[0059] As shown in Figure 2 , Figure 2 In the drawings, Figure A is a TEM image of the composite particles on day 0; Figure B is a TEM image of the composite particles soaked in an environment with pH = 4 for 7 days; Figure C is a TEM image of the composite particles soaked in an environment with pH = 7 for 7 days; and Figure D is a TEM image of the composite particles soaked in an environment with pH = 10 for 7 days.

[0060] The method for evaluating the antiviral effect of florfenicol composite drug is mainly based on neutralization test to measure the inhibition ability of the material on the lesion effect of Vero cells induced by Herpes Simplex Virus-2 (HSV-2).

[0061] The purpose of the experiment is to evaluate the antiviral effect: through neutralization test, measure the inhibition ability of successive concentrations of Arthrospira sulphated polysaccharide extract solution, chitosan, and florfenicol composite drug on the lesion effect of Vero cells induced by HSV-2 virus.

[0062] The experimental materials are as follows: cells: Vero cells, containing 1 x 10 4 cells per well. Virus: HSV-2 virus, plaque-forming unit is 0.15. Culture medium: Dulbecco's modified Eagle's medium with 2 wt% fetal bovine serum.

[0063] Experimental steps:

[0064] The density of the cells was 1 x 10 4Vero cells in 96-well plates were infected with HSV-2 virus. And treated with serial concentrations of the Spirulina sulfated polysaccharide extract solution, chitosan, florfenicol combination drug.

[0065] The cells were incubated at 37°C for 96 hours.

[0066] 0.5 wt% formaldehyde was added to fix the plates and incubated at room temperature for 4 hours.

[0067] The formaldehyde-fixed plates were removed and the wells of the 96-well plates were stained with 0.1 wt% crystal violet for 10 minutes.

[0068] The 96-well plates were washed and air-dried.

[0069] The cell density of each well was measured at 570 nm using a microplate spectrophotometer.

[0070] Data analysis:

[0071] The concentration of the Spirulina sulfated polysaccharide extract solution, chitosan, florfenicol combination drug required to reduce the virus-induced cytopathic effect by 50% was calculated and expressed as EC 50 .

[0072] In this protocol, EC 50 = 6.596 μg / mL, at a lower concentration, has good antiviral properties, showing the effective inhibition of the virus by the combination drug, while protecting cell viability.

[0073] Figure 3 is a graph of the cell survival rate trend of the florfenicol combination drug at different pH concentrations. As shown in Figure 3 , under the conditions of 37°C, PBST (PBS buffer containing 5% polysorbate-20) was used, and the pH values were set to 4.0, 7.4 and 10.0, respectively. The florfenicol combination drug was added to 75 mL of PBST. The absorbance was measured by microplate spectrophotometer, and the same calculation method was used to determine the weight of florfenicol released into the environment solution at the predetermined time point. Figure 3 is the release curve under three different pH conditions, showing similar trends within the first 12 hours. Under the pH 7.4 environment, the drug release rate is the fastest within the next 24 hours. However, after 48 hours, the release efficiency in the acidic environment exceeds that in the neutral environment. After 168 hours, the release efficiency in the acidic environment reaches 27%, which is 5% higher than in the neutral environment and 10% higher than in the alkaline environment.

[0074] The release rate of florfenicol = (W a / W0) x 100%;

[0075] wherein W a represents the mass of florfenicol released from the composite particles into the environment solution at a predetermined time point, and W0 represents the total mass of florfenicol in the composite drug.

[0076] The present application has the following features:

[0077] 1. In the present application, the Arthrospira sulphated polysaccharide extract has negatively charged sulphate groups and carboxyl groups, while chitosan has positively charged amine groups. Therefore, the composite particles formed by self-assembly of the Arthrospira sulphated polysaccharide extract and chitosan have a binding force from electrostatic force rather than chemical bonds, and do not change the chemical material of florfenicol, thus preserving the original properties of florfenicol.

[0078] 2. The present application found that the ratio of Arthrospira sulphated polysaccharide extract to chitosan affects the stability of the composite drug, and this ratio was further explored. During the self-assembly process, the hydrophilic and negatively charged Arthrospira sulphated polysaccharide extract wraps most of the relatively hydrophobic chitosan, forming nanoscale composite particles. However, when the amount of chitosan is excessive, it will lead to an excess of hydrophobic chitosan, which in turn destroys the structural stability of the nanoparticles.

[0079] The present application found that when the weight concentration ratio of chitosan to Arthrospira sulphated polysaccharide extract reaches 1.5:1, a significant precipitation phenomenon occurs. This phenomenon is attributed to the hydrophobic nature of chitosan; when the concentration of chitosan exceeds a certain threshold, even in the presence of hydrophilic Arthrospira sulphated polysaccharide extract, the suspension stability of the composite particles is weakened. In addition, as the proportion of chitosan increases, the size of the composite nanoparticles gradually increases, and when the size reaches the micron level, it will trigger the aggregation and precipitation of the composite particles.

[0080] 3. The present application studied the size change characteristics of the composite particles under different pH conditions. In particular, in the physiological neutral environment (pH = 7.4), the morphology and size of the composite particles remained highly stable during the seven-day observation period. This finding is in sharp contrast to previous studies, which showed that composite nanoparticles composed of sulfated polysaccharides (such as heparin) and chitosan often cannot maintain stable structures when the pH value exceeds 6.5, and are prone to decomposition and collapse. Previous literature indicates that chitosan will undergo deprotonation when the pH value is greater than 6.5, causing the positively charged amino groups on its surface to gradually lose their positive charge. This reduction in the number of positively charged groups weakens the ability of chitosan to bind to other materials through electrostatic interactions. However, the composite particles in the present application exhibit excellent size and morphology stability when the pH value is higher than 6.5, which is likely due to the unique preparation method and special properties of the materials used in the present application.

[0081] During the preparation process, chitosan is first fully ionized in an environment with a pH of about 6.0, and then tightly combined with the also ionized Spirulina polysaccharide extract under suitable conditions. This preparation strategy forms stable electrostatic interactions between the Spirulina polysaccharide extract and chitosan, effectively stabilizing the structure of the composite particles. Only under extremely alkaline conditions can the deprotonation of chitosan lead to changes in the structure of the stripped changes.

[0082] In addition, the Spirulina polysaccharide extract itself also has certain swelling properties. Although chitosan can be deprotonated above a pH of about 6.5, the structure of the composite particle nanoparticles is supported by both polymers, so it can remain stable in size in a neutral environment. In an acidic environment, the main size change of the composite particles is due to the swelling behavior of chitosan under acidic conditions. Conversely, in an alkaline environment, the size change can be due to further aggregation caused by the disintegration of the chitosan structure after deprotonation.

[0083] 4. The florfenicol composite drug prepared by the present scheme has antiviral efficacy in addition to the original antibacterial efficacy.

[0084] Chitosan does not have effective virus inhibition properties. The Spirulina polysaccharide extract exhibits significant antiviral properties due to its abundant negative charges, especially from the sulfate groups. The Spirulina polysaccharide extract can interact with virus particles, inhibit the adsorption process, hinder the binding of viruses to cell receptors, and prevent the invasion of host cells, thereby interfering with the life cycle of viruses.

[0085] In addition, the combination of chitosan and the Spirulina polysaccharide extract occupies the sulfate groups of the Spirulina polysaccharide extract, indirectly affecting the virus inhibition of the composite drug. However, the composite drug still has antiviral properties, which may be related to the nucleocapsid structure: since the Spirulina polysaccharide extract is located on the outer layer of the composite particle shell, and the zeta potential of the composite particle is negative, this means that part of the negative groups of the Spirulina polysaccharide extract are not neutralized and are exposed, making it easier to bind to viruses.

[0086] 5. It has biocompatibility and degradability. The present scheme improves the water solubility of florfenicol, and the reaction process is very simple and suitable for industrial production.

[0087] In addition, it should be understood that although the present specification is described in terms of embodiments, not every embodiment contains only one independent technical solution, and the specification is described in this way only for clarity, and those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that those skilled in the art can understand.

Claims

1. A process for the preparation of florfenicol complex pharmaceuticals, characterized by: The fluorophenical is added to the chitosan solution, and the fluorophenical is attached to the chitosan to form a precursor complex; then the arthrospira sulphated polysaccharide extract is added to the precursor complex, and due to the binding force between the arthrospira sulphated polysaccharide extract and the chitosan, the composite particles coated with the fluorophenical are formed, the arthrospira sulphated polysaccharide extract is at the periphery of the composite particles, so that the composite particles are hydrophilic and have negative charges; the composite particles coated with the fluorophenical are the fluorophenical composite drug; The arthrospira sulphated polysaccharide extract has negative charges of sulphate groups and carboxylic acid groups, and a weight average molecular weight of 272 kDa; Chitosan, amine groups with positive charges, number average molecular weight of 1.4 x 10 5 Da; The method comprises the following steps: Step S1, preparing an arthrospira sulphated polysaccharide extract solution; Step S2, preparing a chitosan solution; Step S3, preparing a first solution: The fluorophenical is added to the chitosan solution, and stirred uniformly to prepare the first solution for standby; In the first solution, the fluorophenical and the chitosan both have weak hydrophobicity, and the two are combined first to form a precursor complex; Step S4, preparing a second solution: The arthrospira sulphated polysaccharide extract solution is continuously stirred, and at the same time, the first solution is slowly dropped into the arthrospira sulphated polysaccharide extract solution, at this time, the concentration of the fluorophenical is 500 ppm; then, the mixture is uniformly mixed to prepare the second solution for standby; At this time, the weight concentration ratio of the chitosan to the arthrospira sulphated polysaccharide extract is 0.5-1.5:1; In the second solution, the chitosan and the arthrospira sulphated polysaccharide extract in the precursor complex are self-assembled into nanoparticle morphology, and the fluorophenical is loaded to form the composite particles; The composite particles formed by the self-assembly of the arthrospira sulphated polysaccharide extract and the chitosan have electrostatic force.

2. The method for preparing a florfenicol compound drug according to claim 1, characterized in that, In step S4, the weight concentration ratio of the chitosan, the fluorophenical and the arthrospira sulphated polysaccharide extract is 0.75:0.75:

1.

3. The method according to claim 1, wherein In step S1, the arthrospira sulphated polysaccharide extract is dissolved in deionized water at a concentration of 0.8-1.2 mg / mL at room temperature, and stirred uniformly to prepare the arthrospira sulphated polysaccharide extract solution for standby; In step S2, the chitosan is dissolved in 1wt% acetic acid with a concentration of 8-12 mg / mL at room temperature, and then the high-concentration chitosan solution is diluted to a target concentration of 1 mg / mL using a phosphate buffered saline, and the pH value is kept at 5.5-6.5, and the mixture is stirred uniformly to prepare the chitosan solution for standby; In step S3, the weight concentration ratio of the chitosan to the fluorophenical is 1:1; The method further comprises: Step S5, centrifuging the second solution: The first precipitate is obtained after centrifuging the second solution; Step S6, the precipitate is added into deionized water again to form a suspension, and the suspension is left to stand for 1 hour, and the supernatant is taken, and the second precipitate is obtained after centrifugation, at this time, the second precipitate is the fluorophenical composite particles, i.e. the fluorophenical composite drug; the fluorophenical composite drug is an oral drug.

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