Preparation method and application of oral doxycycline paste

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a preparation method and application of oral doxycycline paste, and the preparation method comprises the following steps: S1, immersing composite carrier powder into a doxycycline solution, carrying out ultrasonic treatment, oscillating and adsorbing, centrifugally collecting precipitate, drying, and sieving with a 100-mesh sieve to obtain a drug carrier; and S2, heating caprylic / capric triglyceride, adding paraffin, stirring and dissolving, cooling, sequentially adding sodium pyrosulfite and disodium ethylene diamine tetraacetate, stirring, adding the drug carrier, stirring and dispersing, adding saccharin sodium and glycerol, continuously stirring, finally adding silicon dioxide, homogenizing, defoaming, and sterilizing to obtain the doxycycline oral paste. Through regulation and control of a carrier structure, chelation loss caused by early release of the medicine in the stomach is avoided, the slow release effect is improved, stable release of the medicine concentration in the intestinal tract is maintained, and fluctuation of the blood concentration is reduced.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and in particular to a method for preparing doxycycline oral paste and its application. Background Technology

[0002] The chemical formula of doxycycline is C 22 H 24 N2O8, a yellow crystalline solid at room temperature, belongs to the second-generation tetracycline class of antibiotics. It is a semi-synthetic derivative of oxytetracycline and is known for its high oral bioavailability, long half-life, and broad antibacterial spectrum. In veterinary clinical practice, doxycycline is mainly used to treat respiratory infections caused by susceptible bacteria and mycoplasma, particularly effective against tracheitis and bronchitis caused by Gram-negative bacteria and mycoplasma. Furthermore, doxycycline has good activity against a variety of Gram-positive and Gram-negative bacteria and can inhibit pathogens such as respiratory mycoplasma and rickettsiae that are resistant or insensitive to other drugs.

[0003] Currently, the main formulations of doxycycline for veterinary use include powder and injection, but these formulations have certain limitations in clinical application. While powder is convenient for storage and transportation, its efficacy may be affected by solubility issues when mixed with feed, and long-term use may lead to the inactivation of beneficial intestinal bacteria in pigs, causing secondary infections. Injections, although fast-acting, may cause stress in animals, and for some animals (such as pets), the injection procedure is difficult and not easily tolerated. Therefore, oral doxycycline paste has broad market prospects. It is expected to play an important role, especially in the pet medication market, the young animal medication market, and the market for animals with chronic diseases requiring long-term treatment. Furthermore, it is easy to administer, has significant efficacy, and minimal gastrointestinal irritation, making it particularly suitable for pets, young animals, and other animals with swallowing difficulties or who are unwilling to accept injections.

[0004] However, pastes often cause strong rejection in animals (such as dogs and cats) due to their bitterness or unpleasant taste, requiring forced administration and easily triggering stress reactions. Furthermore, oral pastes may cause fluctuations in doxycycline absorption due to the gastrointestinal environment, affecting the stability of blood drug concentrations. Doxycycline readily reacts with calcium... 2+ Mg 2+ Al 3+ The presence of divalent / trivalent cation chelates in the paste, especially if the paste contains such excipients or is taken with food, can significantly reduce its absorption rate. Furthermore, oral doxycycline paste may directly irritate the oral or gastric mucosa, causing vomiting, diarrhea, or loss of appetite. Animals may exhibit salivation and refusal to eat after administration. Summary of the Invention

[0005] To address the problems mentioned in the background section, this invention provides a method for preparing doxycycline oral paste and its application.

[0006] To achieve the above objectives, the present invention adopts the following technical solution: A method for preparing an oral doxycycline paste includes the following steps: S1. Take the composite carrier powder, immerse it in doxycycline solution, sonicate to assist drug loading, shake and adsorb for 20-24 hours, centrifuge at 3000-4000 rpm to collect the precipitate, dry at 40℃ for 10-12 hours, and pass through a 100-mesh sieve to obtain the drug-loaded carrier. S2. Heat caprylic / capric triglyceride, add paraffin and stir to dissolve. After cooling, add sodium metabisulfite and disodium EDTA in sequence and stir for 20-30 min. Add the drug carrier and stir at low speed to disperse for 20-30 min. Add sodium saccharin and glycerol and continue stirring for 20-30 min. Finally, add silica and homogenize for 30-40 min. After degassing, sterilize to obtain doxycycline oral paste.

[0007] Furthermore, the raw materials include composite carrier powder, doxycycline, caprylic / capric triglyceride, paraffin, sodium metabisulfite, disodium EDTA, sodium saccharin, glycerol, and silicon dioxide, with a mass ratio of (90-95):(10-12):(825-850):(30-35):(40-43):(0.5-0.8):(0.2-0.4):(1-1.2):(2.8-3). The mass-to-volume ratio of doxycycline to solvent in the doxycycline solution is 10-15 mg / mL, and the solvent is a 0.1M hydrochloric acid solution containing 8% ethanol with a pH of 3.8-4.0.

[0008] Furthermore, the ingredients also include flavorings and colorings, with flavorings including chocolate flavoring and colorings including chocolate brown pigment.

[0009] Further, the composite carrier powder in step S1 is prepared by the following steps: A1. Disperse mesoporous silica in deionized water, sonicate for 15-25 min, centrifuge at 3000-4000 rpm to collect the precipitate, and dry at 40℃ to constant weight for later use to obtain pretreated mesoporous silica. A2. Disperse gellan gum in deionized water and stir in a water bath until completely dissolved. After cooling, add polyaspartic acid and pretreated mesoporous silica, stir for 30-40 minutes, adjust the pH value, and slowly add genipin solution under light-proof and nitrogen protection. Stir at room temperature for 30-40 minutes, filter, dry at 40°C to constant weight, and grind through a 100-mesh sieve to obtain composite carrier powder.

[0010] Furthermore, in step S1, the frequency of ultrasonic treatment is 30-40kHz, the power is 200-300W, the temperature during oscillation adsorption is 25-30℃, and the speed is 100-200rpm.

[0011] Furthermore, in step S2, the heating temperature is 60-65℃, the temperature is cooled to 35-40℃, the stirring speed is 200-300 rpm, and the homogenization speed is 2000-2500 rpm.

[0012] Further, in step A1, the mass ratio of mesoporous silica to deionized water is (1-1.2):(100-110).

[0013] Further, in step A2, the mass ratio of gellan gum, deionized water, polyaspartic acid, pretreated mesoporous silica, and genipin solution is (3-5):(300-400):(2-4):(6-8):(50-80), and the concentration of genipin solution is 0.5-1.0% (w / v).

[0014] Furthermore, in step A1, the frequency of the ultrasonic treatment is 30-40kHz, and the power is 200-300W.

[0015] Furthermore, in step A2, the water bath temperature is 80-85℃, the stirring speed is 100-200rpm, the pH value is adjusted to 8.5-9.0, and the pH value is adjusted back to 6.8-7.2 after the reaction is completed.

[0016] According to another aspect of the present invention, the application of the doxycycline oral paste obtained by the above preparation method in the preparation of a drug for treating bacterial infections in livestock and poultry is provided. It is used to treat digestive or respiratory tract infections caused by Escherichia coli, Pasteurella multocida or Salmonella, with a dosage of 10-15 mg per kilogram of body weight, once daily for 3-5 days.

[0017] The beneficial effects of this invention are: 1. The beneficial effects of this invention are that the composite carrier constructed by mesoporous silica and gellan gum-polyaspartic acid crosslinking network can embed doxycycline molecules within the pores. The rigid framework of mesoporous silica forms a physical barrier, preventing direct contact between the drug and taste buds, while the gel layer formed by gellan gum-polyaspartic acid rapidly swells in the oral environment to form a protective film, effectively masking bitterness. This significantly reduces the amount of drug released when the paste remains in the animal's oral cavity. Combined with the synergistic taste-masking effect of sodium saccharin, it greatly reduces rejection reactions during drug administration in animals and increases their willingness to lick the medication.

[0018] 2. In the acidic environment of gastric juice, the gellan gel network contracts and seals the pores, preventing doxycycline from contacting metal ions in the gastric juice. After entering the intestine, the pH-responsive groups of polyaspartic acid dissociate, and the gel network swells and opens the pores, allowing the drug to be released in the small intestine environment where absorption is more efficient. Through carrier structure regulation, chelation loss caused by premature drug release in the stomach is avoided, improving the sustained-release effect, while maintaining a stable drug concentration in the intestine and reducing fluctuations in blood drug concentration.

[0019] 3. In the technical solution of this invention, the gellan gum-polyaspartic acid composite gel forms an adhesive hydration layer on the gastric mucosa surface, binding to mucosal glycoproteins through hydrogen bonding, thus blocking the direct stimulation of epithelial cells by drug molecules. The hydrophobic matrix formed by caprylic / capric triglyceride and paraffin further slows down the drug dissolution rate, allowing doxycycline to exhibit gradient release characteristics in the gastrointestinal tract, avoiding inflammatory reactions caused by excessively high local drug concentrations, and significantly reducing the incidence of adverse reactions such as vomiting and diarrhea.

[0020] 4. In the technical solution of the present invention, the high specific surface area of ​​mesoporous silica greatly increases the drug dispersion. The polyaspartic acid modified on its surface prevents drug crystallization and aggregation through charge repulsion, maintains the high solubility of the molecular state, and keeps the blood drug concentration within the effective therapeutic window for a long time. This ensures the antibacterial effect and avoids the screening pressure of drug-resistant bacteria caused by concentration fluctuations. It is particularly suitable for the treatment of chronic infections that require long-term administration.

[0021] 5. In the technical solution of this invention, the organic-inorganic hybrid structure of the composite carrier forms a dense coating layer, and the rigid support of the silica framework, combined with the hydrophobic barrier of the paraffin matrix, effectively blocks the penetration of oxygen and moisture. Disodium EDTA blocks the oxidative degradation pathway by chelating trace metal ions, and sodium metabisulfite synergistically scavenge free radicals, improving the chemical stability of doxycycline during storage, allowing the paste to be stored for a long time at room temperature. Detailed Implementation

[0022] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. 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.

[0023] Unless otherwise specified, the raw materials used in this invention are all from commercially available conventional products.

[0024] Preparation Example 1 The composite carrier powder is prepared by the following steps: A1. Disperse 1g of mesoporous silica in 100g of deionized water, sonicate for 15min at a frequency of 30kHz and a power of 200W, centrifuge at 3000rpm to collect the precipitate, and dry at 40℃ to constant weight for later use to obtain pretreated mesoporous silica. A2. Disperse 3g of gellan gum in 300g of deionized water and stir at 100rpm in a water bath at 80℃ until completely dissolved. After cooling, add 2g of polyaspartic acid and 6g of pretreated mesoporous silica, stir at 100rpm for 30min, adjust the pH to 8.5, slowly add 50g of 0.5% (w / v) genipin solution, stir at 100rpm for 30min at room temperature, and adjust the pH to 6.8 after the reaction is complete. Filter, dry at 40℃ to constant weight, grind through a 100-mesh sieve to obtain composite carrier powder.

[0025] Preparation Example 2 The composite carrier powder is prepared by the following steps: A1. Disperse 1.1g of mesoporous silica in 105g of deionized water, sonicate for 20min at a frequency of 35kHz and a power of 250W, centrifuge at 3500rpm to collect the precipitate, and dry at 40℃ to constant weight for later use to obtain pretreated mesoporous silica. A2. Disperse 4g of gellan gum in 350g of deionized water and stir at 150rpm in a water bath at 82℃ until completely dissolved. After cooling, add 3g of polyaspartic acid and 7g of pretreated mesoporous silica, and stir at 150rpm for 35min. Adjust the pH to 8.7, and slowly add 64g of 0.7% (w / v) genipin solution. Stir at 150rpm for 35min at room temperature. After the reaction is complete, adjust the pH to 7.0, filter, dry at 40℃ to constant weight, and grind through a 100-mesh sieve to obtain composite carrier powder.

[0026] Preparation Example 3 The composite carrier powder is prepared by the following steps: A1. Disperse 1.2g of mesoporous silica in 110g of deionized water, sonicate for 25min at a frequency of 40kHz and a power of 300W, centrifuge at 4000rpm to collect the precipitate, and dry at 40℃ to constant weight for later use to obtain pretreated mesoporous silica. A2. Disperse 5g of gellan gum in 400g of deionized water and stir at 200rpm in a water bath at 85℃ until completely dissolved. After cooling, add 4g of polyaspartic acid and 8g of pretreated mesoporous silica, stir at 200rpm for 40min, adjust the pH to 9.0, slowly add 80g of 1.0% (w / v) genipin solution, stir at 200rpm for 40min at room temperature, and adjust the pH to 7.2 after the reaction is complete. Filter, dry at 40℃ to constant weight, grind through a 100-mesh sieve to obtain composite carrier powder.

[0027] Example 1 A method for preparing an oral doxycycline paste includes the following steps: S1. Weigh 10g of doxycycline and dissolve it in 1000mL of 0.1M HCl solution containing 8% ethanol. Immerse 90g of the composite carrier powder prepared in Example 1 in the solution. Use ultrasonic treatment to assist drug loading. The frequency of ultrasonic treatment is 30kHz and the power is 200W. The adsorption is carried out at 25℃ and 100rpm for 20h. The precipitate is collected by centrifugation at 3000rpm and dried at 40℃ for 10h. The precipitate is then passed through a 100-mesh sieve to obtain the drug-loaded carrier. S2. Heat 825g of caprylic / capric triglyceride to 60℃, add 30g of paraffin and stir to dissolve. After cooling to 35℃, add 40g of sodium metabisulfite and 0.5g of disodium EDTA and stir at 200rpm for 20min. Add the drug carrier from step S1 and stir at 200rpm for 20min. Add 0.2g of sodium saccharin and 1g of glycerol and continue stirring at 200rpm for 20min. Finally, add 2.8g of silica and homogenize at 2000rpm for 30min. After degassing, sterilize to obtain doxycycline oral paste.

[0028] Example 2 A method for preparing an oral doxycycline paste includes the following steps: S1. Weigh 11g of doxycycline and dissolve it in 1000mL of 0.1M HCl solution containing 8% ethanol. Immerse 92g of the composite carrier powder prepared in Example 2, and use ultrasonic treatment to assist drug loading. The frequency of ultrasonic treatment is 35kHz and the power is 250W. The adsorption is carried out at 27℃ and 150rpm for 22h. The precipitate is collected by centrifugation at 3500rpm and dried at 40℃ for 11h. The precipitate is then passed through a 100-mesh sieve to obtain the drug-loaded carrier. S2. Heat 840g of caprylic / capric triglyceride to 62℃, add 32g of paraffin and stir to dissolve. After cooling to 37℃, add 41.5g of sodium metabisulfite and 0.7g of disodium EDTA and stir at 250rpm for 25min. Add the drug carrier from step S1 and stir at 250rpm for 25min. Add 0.3g of sodium saccharin and 1.1g of glycerol and continue stirring at 250rpm for 25min. Finally, add 2.9g of silicon dioxide and homogenize at 2200rpm for 35min. After degassing, sterilize to obtain doxycycline oral paste.

[0029] Example 3 A method for preparing an oral doxycycline paste includes the following steps: S1. Weigh 12g of doxycycline and dissolve it in 1000mL of 0.1M HCl solution containing 8% ethanol. Immerse 95g of the composite carrier powder prepared in Example 3, and use ultrasonic treatment to assist drug loading. The frequency of ultrasonic treatment is 40kHz and the power is 300W. The adsorption is carried out at 200rpm at 30℃ for 24h. The precipitate is collected by centrifugation at 4000rpm and dried at 40℃ for 10-12h. The precipitate is then passed through a 100-mesh sieve to obtain the drug-loaded carrier. S2. Heat 850g of caprylic / capric triglyceride to 65℃, add 35g of paraffin and stir to dissolve. After cooling to 40℃, add 43g of sodium metabisulfite and 0.8g of disodium EDTA and stir at 300rpm for 30min. Add the drug carrier from step S1 and stir at 300rpm for 30min. Add 0.4g of sodium saccharin and 1.2g of glycerol and continue stirring at 300rpm for 30min. Finally, add 3g of silicon dioxide and homogenize at 2500rpm for 40min. After degassing, sterilize to obtain doxycycline oral paste.

[0030] Comparative Example 1 The difference between this comparative example and Example 1 is that mesoporous silica is used instead of the composite carrier powder prepared in Example 1, while the remaining steps are the same as in Example 1.

[0031] Comparative Example 2 The difference between this comparative example and Example 2 is that polyaspartic acid is used instead of the composite carrier powder prepared in Example 2, while the other steps are the same as in Example 2.

[0032] Comparative Example 3 The difference between this comparative example and Example 3 is that gellan gum is used instead of the composite carrier powder prepared in Example 3, while the other steps are the same as in Example 3.

[0033] Take 3 batches of the pastes prepared in Examples 1-3 and Comparative Examples 1-3, each batch containing 1g, and uniformly disperse them in 200mL of artificial gastric fluid (0.2% NaCl solution, pH adjusted to 1.2±0.1 with concentrated hydrochloric acid). Pre-equilibrate at 37℃, and start constant temperature shaking at 100rpm.

[0034] Gastric fluid stage (0-2h): 5mL samples were taken at 1h and 2h, respectively. The concentration of doxycycline was determined by HPLC. Chromatographic conditions: mobile phase: acetonitrile-0.01M potassium dihydrogen phosphate (25:75, v / v); flow rate: 1.0mL / min; column temperature: 30℃; detection wavelength: 280nm; injection volume: 20μL. Immediately afterward, 5mL of fresh artificial gastric fluid was added. The sample was filtered through a 0.22μm filter membrane into a brown bottle and stored at 4℃ protected from light until analysis.

[0035] Intestinal fluid stage (2-12h): After 2h, remove all remaining gastric fluid media and quickly add 200mL of pre-warmed artificial intestinal fluid (0.05M phosphate buffer (containing 0.5% SDS), pH 6.8±0.1) at 37℃. Continue shaking, and take 5mL samples at 4h, 8h, and 12h respectively. Measure the doxycycline concentration, add 5mL of fresh artificial intestinal fluid, filter and preserve the sample using the same method. Calculate the cumulative release rate (%), cumulative release rate (%) = C n V represents the drug concentration (μg / mL) measured in the nth sample; V is the total volume of the release medium (200mL); V s The volume of a single sample (5 mL); W drug The total mass (mg) of doxycycline in the paste. The results are shown in Table 1. Table 1. Cumulative release rate results of Examples 1-3 and Comparative Examples 1-3 (unit: %)

[0036] As shown in Table 1, the cumulative release rate of doxycycline was relatively low in the gastric fluid stage (0-2h) of Examples 1-3. The cumulative release rates at 1h and 2h were 14.5% and 18.7% for Example 1, 13.9% and 18.0% for Example 2, and 13.1% and 15.8% for Example 3. This indicates that the composite carrier powder effectively sustained-released doxycycline in the gastric fluid environment, reducing premature drug release in the stomach. After entering the intestinal fluid stage (2-12h), the cumulative release rate of doxycycline increased rapidly, indicating that the composite carrier powder effectively released the drug in the intestinal fluid environment, meeting the absorption requirements of the drug in the intestine and achieving sustained-release and controlled-release effects in the gastrointestinal tract.

[0037] In Comparative Examples 1-3, Comparative Example 1 used mesoporous silica instead of the composite carrier powder. During the gastric fluid stage, the cumulative release rate of doxycycline was significantly higher than in the examples, with cumulative release rates of 38.4% and 55.7% at 1h and 2h, respectively. This may be because mesoporous silica alone has limited adsorption and sustained-release capacity for doxycycline, leading to rapid drug release in gastric fluid. Comparative Example 2 used polyaspartic acid instead of the composite carrier powder. During the gastric fluid stage, the cumulative release rates were as high as 62.7% and 78.9% at 1h and 2h, respectively. Polyaspartic acid may have a weaker adsorption effect on doxycycline, failing to effectively control the drug release rate in the stomach, resulting in a large release of the drug in gastric fluid. Comparative Example 3 used gellan gum instead of the composite carrier powder. During the gastric fluid stage, the cumulative release rates were 10.5% and 12.3% at 1h and 2h, respectively, but during the intestinal fluid stage, the cumulative release rates were only 18.6%, 27.9%, and 32.1% at 4h, 8h, and 12h, respectively. While gellan gum can control drug release in the stomach to some extent, it does not sufficiently promote drug release in the intestinal fluid environment, resulting in incomplete drug release.

[0038] In the preparation example, mesoporous silica possesses a large specific surface area and pore volume, enabling it to adsorb doxycycline. Gellan gum and polyaspartic acid may form a network structure with certain viscosity and stability, synergistically enhancing the drug loading and sustained-release effect in conjunction with mesoporous silica. Genipin may act as a cross-linking agent, promoting the interaction between the components and improving the performance of the composite carrier. Therefore, in gastric juice, the composite carrier powder can effectively protect doxycycline and reduce its release in an acidic environment. Upon entering the intestinal environment, the structure of the composite carrier may change with the pH value, gradually releasing doxycycline, thereby achieving targeted intestinal release of the drug.

[0039] Comparative Example 1 used only mesoporous silica as a carrier. Although mesoporous silica has a certain adsorption capacity, it lacks the synergistic effect of other components, resulting in a higher drug release in gastric juice and a less effective sustained-release effect in intestinal juice compared to the composite carrier powder. Comparative Example 2 used polyaspartic acid instead of the composite carrier powder. When polyaspartic acid was used alone as a carrier, its loading and sustained-release capacity for doxycycline were limited, resulting in a higher drug release in gastric juice and a less effective release in intestinal juice compared to the composite carrier powder. In Comparative Example 3, when gellan gum was used alone as a carrier, its loading and release performance for doxycycline was poor, with a low release rate in gastric juice (10.5-12.3%) and a low cumulative release rate in intestinal juice (27.9-32.1%), indicating that gellan gum alone cannot effectively achieve sustained and controlled release of the drug.

[0040] In summary, the composite carrier powder, through the synergistic effect of mesoporous silica, gellan gum, and polyaspartic acid, achieved sustained release of doxycycline in gastric fluid and effective release in intestinal fluid, significantly outperforming the effects of using mesoporous silica, polyaspartic acid, or gellan gum alone. This demonstrates that the composite carrier powder prepared in Examples 1-3 can effectively control the drug release rate and improve the sustained release effect of doxycycline in Examples 1-3.

[0041] In the description of this specification, the terms "preparation example," "example," "various examples," etc., refer to specific features, structures, materials, or characteristics described in connection with that example or preparation example, which are included in at least one example or preparation example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same example or preparation example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more examples or preparation examples.

[0042] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A method for preparing an oral doxycycline paste, characterized in that, Includes the following steps: S1. Take the composite carrier powder, immerse it in doxycycline solution, sonicate it, shake and adsorb it for 20-24 hours, centrifuge to collect the precipitate, dry it for 10-12 hours, and pass it through a 100-mesh sieve to obtain the drug-loaded carrier. S2. Heat caprylic / capric triglyceride, add paraffin and stir to dissolve. After cooling, add sodium metabisulfite and disodium EDTA in sequence and stir for 20-30 min. Add the drug carrier and stir to disperse for 20-30 min. Add sodium saccharin and glycerol and continue stirring for 20-30 min. Finally, add silica and homogenize for 30-40 min. After degassing, sterilize to obtain doxycycline oral paste.

2. The method for preparing a doxycycline oral paste according to claim 1, characterized in that, The raw materials include composite carrier powder, doxycycline, caprylic / capric triglyceride, paraffin, sodium metabisulfite, disodium EDTA, sodium saccharin, glycerol, and silicon dioxide, in a mass ratio of (90-95):(10-12):(825-850):(30-35):(40-43):(0.5-0.8):(0.2-0.4):(1-1.2):(2.8-3).

3. The method for preparing a doxycycline oral paste according to claim 1, characterized in that, The composite carrier powder in step S1 is prepared by the following steps: A1. Disperse mesoporous silica in deionized water, sonicate for 15-25 min, centrifuge to collect the precipitate, dry for later use, and obtain pretreated mesoporous silica. A2. Disperse gellan gum in deionized water and stir in a water bath until completely dissolved. After cooling, add polyaspartic acid and pretreated mesoporous silica, stir for 30-40 minutes, adjust the pH value, and slowly add genipin solution dropwise under light-proof and nitrogen protection. Stir at room temperature for 30-40 minutes, filter, dry, grind and sieve to obtain composite carrier powder.

4. The method for preparing a doxycycline oral paste according to claim 1, characterized in that, In step S1, the ultrasonic treatment frequency is 30-40kHz, the power is 200-300W, the temperature during oscillation adsorption is 25-30℃, and the speed is 100-200rpm.

5. The method for preparing a doxycycline oral paste according to claim 1, characterized in that, In step S2, the heating temperature is 60-65℃, the temperature is cooled to 35-40℃, the stirring speed is 200-300 rpm, and the homogenization speed is 2000-2500 rpm.

6. The method for preparing a doxycycline oral paste according to claim 3, characterized in that, In step A1, the mass ratio of mesoporous silica to deionized water is (1-1.2):(100-110).

7. The method for preparing a doxycycline oral paste according to claim 3, characterized in that, In step A2, the mass ratio of gellan gum, deionized water, polyaspartic acid, pretreated mesoporous silica, and genipin solution is (3-5):(300-400):(2-4):(6-8):(50-80), and the concentration of genipin solution is 0.5-1.0% (w / v).

8. The method for preparing a doxycycline oral paste according to claim 3, characterized in that, In step A1, the frequency of ultrasonic treatment is 30-40kHz and the power is 200-300W.

9. The method for preparing a doxycycline oral paste according to claim 3, characterized in that, In step A2, the water bath temperature is 80-85℃, the stirring speed is 100-200rpm, the pH value is adjusted to 8.5-9.0, and the pH value is adjusted back to 6.8-7.2 after the reaction is completed.

10. The application of the doxycycline oral paste obtained by the preparation method according to any one of claims 1-9 in the preparation of drugs for treating bacterial infections in livestock and poultry, characterized in that, It is used to treat gastrointestinal or respiratory tract infections caused by Escherichia coli, Pasteurella, or Salmonella. The dosage is 10-15 mg per kilogram of body weight, once daily for 3-5 days.

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