Florfenicol enteric sustained-release gel capsule for veterinary use and preparation method of florfenicol enteric sustained-release gel capsule

Abstract

The invention relates to the technical field of veterinary drug preparations, and discloses a veterinary florfenicol enteric sustained-release gel capsule and a preparation method thereof. The content of the capsule consists of florfenicol serving as a main drug, carbomer 940 serving as a gel framework material, hydroxypropyl methylcellulose and lauryl sodium sulfate serving as a suspending aid. The preparation method comprises the following steps: uniformly mixing the components to prepare gel powder, and filling the gel powder into the enteric hollow hard capsule. According to the invention, the enteric capsule shell is utilized to enable the medicine to pass through the stomach, and after the content absorbs moisture in the intestinal environment, a gel skeleton with a slow-release effect is formed in situ. The preparation ingeniously combines an enteric coating technology and a slow release technology, the stability of the medicine in the intestinal tract is improved, long-time continuous release of florfenicol is achieved, the medicine effect is prolonged, and the administration frequency is reduced. Experimental results show that the preparation is stable in physicochemical property, the in-vitro release behavior conforms to a Weibull model, and the preparation has the slow release characteristic.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of veterinary preparations, in particular to a veterinary florfenicol enteric-soluble sustained-release gel capsule and a preparation method thereof. BACKGROUND

[0002] Florfenicol is a broad-spectrum veterinary antibiotic, which is widely used in the prevention and treatment of bacterial diseases in animal husbandry and aquaculture due to its strong antibacterial activity and effectiveness against a variety of pathogens. Currently, the commercially available florfenicol oral preparations are mostly premixes, soluble powders or ordinary tablets.

[0003] However, florfenicol raw material itself has some inherent physical and chemical properties, which brings challenges to the development and application of its oral preparations. First, florfenicol has low solubility in water and strong bitter taste, which leads to low acceptance of oral administration by animals, affecting the accuracy of actual administration dose and the stability of therapeutic effect.

[0004] Secondly, after conventional oral preparations are swallowed by animals, the drug usually starts to disintegrate and release in the stomach. Florfenicol will be degraded to some extent in the acidic environment of the stomach, which not only reduces the amount of effective drug reaching the main absorption site-intestine, but also increases the variability of drug absorption among different individuals, thereby affecting its bioavailability and clinical efficacy.

[0005] In addition, the existing ordinary preparations are mostly immediate-release dosage forms, and the drug is rapidly absorbed and eliminated in the animal body after administration, with a fast peak of blood drug concentration but a short maintenance time. In order to keep the blood drug concentration above the minimum effective concentration, frequent administration strategy must be adopted. This administration method not only increases the labor cost and operational complexity, but also causes continuous stress reaction to animals. Therefore, it has important practical application value to develop a new type of veterinary florfenicol oral preparation which can improve drug solubility, mask bad taste, and realize targeted release and long-term sustained release of drug in the intestine. SUMMARY

[0006] In view of the technical problems in the prior art that florfenicol has poor water solubility and poor palatability, resulting in low bioavailability, and ordinary preparations cannot achieve sustained-release effect and need frequent administration, the present application provides a veterinary florfenicol enteric-soluble sustained-release gel capsule and a preparation method thereof.

[0007] To achieve the above purpose, the present application is realized by the following technical scheme: The present application provides a veterinary florfenicol enteric-soluble sustained-release gel capsule in the first aspect, comprising an enteric capsule shell and a gel powder filled in the enteric capsule shell. The gel powder is made by mixing carbomer 940, hypromellose, florfenicol and sodium dodecyl sulfate; The weight ratio of the carbomer 940, hypromellose, florfenicol and sodium dodecyl sulfate is (1.8-2.2):(2.7-3.3):(3.6-4.4):(4.5-5.5).

[0008] In some embodiments, the weight ratio of the carbomer 940, hypromellose, florfenicol and sodium dodecyl sulfate is 2:3:4:5.

[0009] In some embodiments, the enteric capsule shell is composed of a capsule shell body made of gelatin or hypromellose and an enteric coating layer coated outside the capsule shell body, which is composed of one or more of acrylic resin or cellulose acetate phthalate. This structure ensures that the capsule shell remains intact in the acidic environment of gastric juice and disintegrates in the alkaline environment of the intestine.

[0010] In some embodiments, the carbomer 940 and the hypromellose together constitute a gel matrix.

[0011] In some embodiments, the weight ratio of the florfenicol and the sodium dodecyl sulfate is 1:(1.02-1.53).

[0012] The second aspect of the present application provides a preparation method of a veterinary florfenicol enteric sustained-release gel capsule, comprising the following steps: S1: providing carbomer 940, hypromellose, florfenicol and sodium dodecyl sulfate, and mixing them to obtain a mixed powder; S2: stirring the mixed powder obtained in step S1 at a speed of 800r / min to 1200r / min for 8min to 15min at room temperature to obtain a gel powder; S3: filling the gel powder obtained in step S2 into an enteric capsule shell to obtain the veterinary florfenicol enteric sustained-release gel capsule.

[0013] In some embodiments, the stirring speed in step S2 is 900r / min to 1100r / min.

[0014] In some embodiments, the stirring time in step S2 is 9min to 12min.

[0015] In some embodiments, the stirring process parameters in step S2 are: the stirring speed is 900r / min to 1100r / min, and the stirring time is 9min to 12min.

[0016] In some embodiments, the stirring in step S2 is continued until the mixed powder forms a gel powder with a uniform appearance as observed visually.

[0017] The present application provides a veterinary florfenicol enteric sustained-release gel capsule and a preparation method thereof. 1、The present application uses sodium dodecyl sulfate as a solubilizing agent to improve the solubility of florfenicol in aqueous environment, and at the same time, the bitter taste of florfenicol is masked by filling the gel powder into the enteric capsule shell in a physical isolation manner, solving the problems of poor water solubility and poor palatability of the raw material drug.

[0018] 2、The present application uses an enteric capsule shell composed of specific materials, which maintains its structure intact in the acidic environment of the stomach and disintegrates to release the contents after entering the alkaline environment of the intestine, preventing the drug from being destroyed in the acidic environment of the stomach, allowing the drug to be released in the intestine, thereby improving the bioavailability of the drug.

[0019] 3、The present application uses carbomer 940 and hydroxypropyl methyl cellulose as the gel matrix, so that the capsule contents form a gel skeleton when they come into contact with water in the intestine, and the drug is encapsulated in the skeleton and gradually released through the dissolution mechanism, allowing the preparation to have a sustained-release effect, which can maintain the blood drug concentration in the animal body above the effective concentration for a long time after a single administration, thereby reducing the frequency of administration. BRIEF DESCRIPTION OF DRAWINGS

[0020] Figure 1 A chromatogram for verifying the specificity of the HPLC analysis method in the embodiments of the present application; Figure 2 A standard curve graph of the linear relationship between the concentration of florfenicol and the peak area in the embodiments of the present application; Figure 3 A column chart of the content change of the preparation under different storage conditions in the embodiments of the present application; Figure 4 A column chart of the content change of the related substances of the preparation under different storage conditions in the embodiments of the present application; Figure 5 A cumulative release rate curve graph of the preparation and the control sample in vitro in the embodiments of the present application; Figure 6 An infrared spectrum graph of florfenicol raw material, blank gel and capsule contents in the embodiments of the present application. DETAILED DESCRIPTION

[0021] Clearly, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative efforts belong to the protection scope of the present application.

[0022] The prepared veterinary florfenicol enteric sustained-release gel capsule is filled with gel powder in an animal-specific enteric capsule shell. Among them, carbomer 940 and hydroxypropyl methyl cellulose together constitute a gel matrix, which plays a role in sustained release and biological adhesion. The animal-specific enteric capsule shell used is composed of a capsule shell body made of gelatin or hydroxypropyl methyl cellulose and an enteric coating layer wrapped outside the capsule shell body, and the enteric coating layer is composed of one or more of acrylic resin or cellulose acetate phthalate.

[0023] Embodiment 1-3: Embodiment 1:

[0024] The embodiment provides a preparation method of a veterinary florfenicol enteric sustained-release gel capsule. The specific steps are as follows: S1, weighing and mixing: weigh 20g of carbomer 940, 30g of hydroxypropyl methyl cellulose, 40g of florfenicol and 50g of sodium dodecyl sulfate. At this time, the weight ratio of the four materials is 2:3:4:5, and the materials weighed are placed in a mixing container for preliminary mixing to obtain a mixed powder.

[0025] S2, stirring: the mixed powder obtained in step S1 is stirred at a speed of 1000r / min for 10 minutes under room temperature conditions. Continue to stir until the powder appearance is uniform by visual observation to obtain a gel powder.

[0026] S3, filling: the gel powder obtained in step S2 is filled into an animal-specific enteric capsule shell according to claim 3 to prepare a veterinary florfenicol enteric sustained-release gel capsule.

[0027] The capsule prepared in this embodiment is used for detection in subsequent test examples 1 to 4.

[0028] Embodiment 2:

[0029] The embodiment provides a preparation method of a veterinary florfenicol enteric sustained-release gel capsule. The specific steps are as follows: S1, weighing and mixing: weigh 20g of carbomer 940, 30g of hydroxypropyl methyl cellulose, 40g of florfenicol and 50g of sodium dodecyl sulfate. At this time, the weight ratio of the four materials is 2:3:4:5, and the materials weighed are placed in a mixing container for preliminary mixing to obtain a mixed powder.

[0030] S2, stirring: the mixed powder obtained in step S1 was stirred at a speed of 800 r / min for 8 minutes at room temperature, and the stirring was continued until the powder appearance was uniform observed visually, to obtain a gel powder.

[0031] S3, filling: the gel powder obtained in step S2 was filled into the enteric capsule shells specially for animals, to prepare the enteric sustained-release gel capsule of florfenicol for veterinary use.

[0032] Example 3:

[0033] The present example provides a preparation method of the enteric sustained-release gel capsule of florfenicol for veterinary use. The specific steps are as follows: S1, weighing and mixing: 22 g of carbomer 940, 33 g of hydroxypropyl methyl cellulose, 44 g of florfenicol, and 55 g of sodium dodecyl sulfate were weighed. At this time, the weight ratio of the four materials was 2.2:3.3:4.4:5.5. The weighed materials were placed in a mixing container for preliminary mixing, to obtain a mixed powder.

[0034] S2, stirring: the mixed powder obtained in step S1 was stirred at a speed of 1200 r / min for 15 minutes at room temperature, and the stirring was continued until the powder appearance was uniform observed visually, to obtain a gel powder.

[0035] S3, filling: the gel powder obtained in step S2 was filled into the enteric capsule shells specially for animals, to prepare the enteric sustained-release gel capsule of florfenicol for veterinary use.

[0036] Comparative example: Compared with Example 1, the difference is that, in the present comparative example, carbomer 940, hydroxypropyl methyl cellulose, and sodium dodecyl sulfate are not used, and the gel capsule is not prepared. The florfenicol raw material is directly prepared into a suspension for use as a control group in the subsequent in vitro release experiment.

[0037] Test examples 1-4: Test example 1: verification of HPLC analysis method for determination of florfenicol content In order to accurately quantify the florfenicol in the preparation of the present application, a high performance liquid chromatography (HPLC) analysis method was first established and verified. The chromatographic conditions used are as follows: the chromatographic column is ACE Generix 5-C18 (4.6 mm x 250 mm, 5 μm); the mobile phase is composed of acetonitrile and water mixed at a volume ratio of 34:66, and isocratic elution is used; the flow rate is set to 1.0 mL·min -1 , the column temperature is maintained at 25℃; the detection wavelength is set to 224 nm, and the injection volume is 20 µL.

[0038] Under these chromatographic conditions, the specificity of the method was investigated. Florfenicol solution, blank gel matrix solution (containing carbomer 940, hydroxypropyl methylcellulose, and sodium dodecyl sulfate), and a mixed solution containing both florfenicol and the gel matrix were prepared. The blank gel matrix solution was subjected to chromatography at 12000 rpm. -1 After centrifugation for 10 minutes, the supernatant was collected. All solutions were filtered through a 0.22µm filter membrane before analysis.

[0039] Reference Figure 1 The results showed that the chromatographic peak of florfenicol appeared at about 5.4 min with good peak shape, while the blank gel matrix and mobile phase had no interfering peaks at the corresponding retention times, indicating that the analytical method is specific for the determination of florfenicol in the formulation of the present invention.

[0040] To investigate the linearity of this analytical method, florfenicol raw material was first accurately weighed, dissolved and diluted to volume with the mobile phase to prepare a solution with a concentration of 499.80 μg·mL. -1 The stock solution was then serially diluted with the mobile phase to prepare concentrations of 0.10 μg·mL⁻¹. -1 24.99 μg·mL -1、 49.98 μg·mL -1 74.97 μg·mL -1 and 99.96 μg·mL -1 A series of working solutions were prepared. Under the chromatographic conditions determined above, the working solutions of each concentration were analyzed, and their corresponding peak areas were recorded. The specific data are shown in Table 1 below.

[0041] Table 1. Linearity data of the florfenicol standard curve

[0042] A standard curve was plotted with florfenicol concentration (C) on the x-axis and peak area (A) on the y-axis. See the results below. Figure 2 As shown in the figure: Coordinate axes: The horizontal axis is " The vertical axis represents the concentration of florfenicol, in micrograms per milliliter (µg / mL), with values ​​ranging from approximately 0 to 100. The vertical axis represents the peak area, with values ​​ranging from approximately 0 to 60,000,000. Curves and data points: The graph shows a linearly increasing red line with several black dots (corresponding to measured peak area data at different concentrations), showing an overall trend of "peak area increasing linearly with increasing concentration." Linear equation and correlation: The linear equation is labeled above the graph. (in" "is the peak area," "(for florfenicol concentration), and correlation coefficient" ".because The results show that the concentration of florfenicol has a good linear correlation with the peak area.

[0043] The results of the analysis methodology validation provide a reliable quantitative basis for subsequent stability and in vitro release performance studies of the preparation. The results of the specificity experiment show that the excipient system composed of carbomer 940, hydroxypropyl methyl cellulose and sodium dodecyl sulfate does not produce interference signals under the established chromatographic conditions, which enables the florfenicol released from the gel matrix to be accurately detected. The establishment of the method is the basis for verifying the function of each component in the technical solution of the application, i.e., it can quantify the effect of sodium dodecyl sulfate on the dissolution of florfenicol and track the release process of the drug from the gel matrix composed of carbomer 940 and hydroxypropyl methyl cellulose over time, thereby objectively evaluating the sustained-release performance of the preparation.

[0044] To investigate the precision of the analysis method, repeatability and inter-day precision experiments were conducted. In the repeatability test, six solutions of florfenicol with a concentration of 49.98 μg·mL -1 were prepared in parallel, and the peak areas of each solution were recorded and the relative standard deviation (RSD) was calculated under the established chromatographic conditions. The specific data are shown in Table 2 below. In the inter-day precision test, six solutions of florfenicol with a concentration of 49.98 μg·mL -1 were also prepared in parallel, and the peak areas were recorded and the RSD was calculated for each day on two consecutive days. The specific data are shown in Table 3 below.

[0045] Table 2. Repeatability test results of florfenicol solution

[0046] Table 3. Inter-day precision test results of florfenicol solution

[0047] The above precision test results show that the RSD values of the repeatability and inter-day precision of the HPLC analysis method are less than 1%. This indicates that the results of repeated measurements of the same sample at different time points by this detection method have high consistency and reproducibility. The precision of the method is the basis for subsequent objective evaluation of the performance of the preparation, as it ensures that the changes in the florfenicol content or release amount measured in the stability test and in vitro release experiment truly reflect the changes in the physical and chemical properties of the preparation itself, rather than being caused by analysis errors, providing a reliable measurement means for accurately evaluating the control effect of the gel matrix composed of carbomer 940 and hydroxypropyl methyl cellulose on the release behavior of the drug.

[0048] To investigate the stability of the sample solution during the analysis process, a solution of florfenicol with a concentration of 74.97 μg·mL-1 The florfenicol solution was placed at room temperature, and was analyzed by injection under the established chromatographic conditions at 0, 2, 4, 6, 8, 10, 12, 24 hours after preparation, respectively. The peak area was recorded and the relative standard deviation (RSD) was calculated. The specific data are shown in Table 4 below. To investigate the accuracy of the analysis method, a spike recovery experiment was performed for verification. A blank gel matrix solution was prepared, and low, medium and high concentrations of florfenicol solution were added to it, respectively. Three samples were prepared in parallel at each concentration level, and were determined under the established chromatographic conditions. The average recovery rate and RSD were calculated, and the specific data are shown in Table 5.

[0049] Table 4. Florfenicol solution stability determination results

[0050] Table 5. Florfenicol spike recovery determination results

[0051] To investigate the robustness of the analysis method, the reliability of the method was tested when the chromatographic conditions were slightly changed. The detection wavelength and the flow rate of the mobile phase were adjusted as variables. The florfenicol solution with a concentration of 49.98 μg / mL was injected three times under each changed condition, the peak area was recorded and the RSD was calculated. The specific data are shown in Table 6.

[0052] Table 6. Florfenicol analysis method robustness determination results

[0053] The above method validation results show that the test solution has good stability within 24 hours, the average recovery rate of the method is between 99.28% and 100.57%, and when the chromatographic conditions are slightly changed, the RSD of the determination results is less than 2%. These results together confirm that the HPLC analysis method has good stability, accuracy and robustness, and can provide a reliable and robust quantitative analysis means for the quality control and performance evaluation of the veterinary florfenicol enteric-sustained-release gel capsules of the present application.

[0054] Test Example 2: Infrared Spectroscopy Structure Characterization To confirm the chemical structure integrity of florfenicol in the preparation, Fourier transform infrared spectroscopy was used to detect the capsule contents prepared in Example 1, florfenicol drug substance, and blank gel matrix without florfenicol (prepared by mixing carbopol 940, hydroxypropyl methyl cellulose and sodium dodecyl sulfate at a weight ratio of 2:3:5). After sample preparation, the obtained spectrograms are shown in Figure 6 , the horizontal axis is the wave number (unit cm -1 ) and the wave number range is approximately 500-3500 cm -1The infrared absorption curves of several samples are plotted in the figure to present the infrared absorption characteristics of different samples.

[0055] The results show that the infrared spectrum of the capsule content presents characteristic absorption peaks at 3447 cm -1 , 3315 cm -1 , 1681 cm -1 , 1533 cm -1 and 1269 cm -1 , which are consistent with the spectrum of florfenicol raw material. These absorption peaks correspond to the secondary hydroxyl stretching vibration, secondary amide stretching vibration, carbonyl stretching vibration and secondary amide bending vibration in the molecular structure of florfenicol, respectively. In the spectrum of the blank gel matrix, the above characteristic absorption peaks do not appear. The spectrum analysis result shows that after florfenicol is mixed with carbomer 940, hydroxypropyl methyl cellulose and sodium dodecyl sulfate and other excipients to prepare a gel powder, the key chemical functional group structure of florfenicol does not change, which confirms that the drug and excipients have physical compatibility, and no chemical reaction or degradation occurs during the preparation process.

[0056] Test Example 3: Preparation stability investigation To investigate the stability of the preparation of the present application, the veterinary florfenicol enteric sustained-release gel capsules prepared in Example 1 were stored at room temperature and 4°C refrigeration. Samples were taken at 0, 5, 10 days, respectively, and the content of florfenicol was determined by the HPLC analysis method established in Test Example 1 and the content change was calculated, and the content of related substances was calculated by area normalization method.

[0057] 3.1 Content and related substance change The content change data of florfenicol in the preparation under different storage conditions are shown in Table 7, and the content change data of related substances are shown in Table 8.

[0058] Table 7. Content change of the preparation under different storage conditions

[0059] Table 8. Change of related substances of the preparation under different storage conditions

[0060] The results of the stability investigation are shown in Tables 7 and 8, and are graphically displayed by Figure 3 and Figure 4 .

[0061] Figure 3is a "content change" column chart, the horizontal axis is divided into "room temperature" and "refrigeration" two groups, the vertical axis is content; the legend blue represents the 0th day (D0), red represents the 5th day (D5), and green represents the 10th day (D10). In the "room temperature" group, the column heights of D0, D5 and D10 are nearly consistent, and the contents are close to 100; in the "refrigeration" group, the column heights of D0, D5 and D10 are also basically consistent, and the contents are also close to 100, indicating that under room temperature and refrigeration conditions, the contents of samples at different time points are stable as a whole, and the change is not obvious.

[0062] Figure 4 is a "impurity change" column chart, the horizontal axis is divided into "room temperature" and "refrigeration" two groups, the vertical axis is the content of impurity; the legend blue, red and green still respectively represent D0, D5 and D10. In the "room temperature" group, the content of impurity of D0 is about 0.15, D5 rises to about 0.22, and D10 further rises to about 0.25, showing a trend of gradually increasing with time; in the "refrigeration" group, the content of impurity of D0 is about 0.15, D5 rises to about 0.18, and D10 rises to about 0.20, although it also increases with time, but the amplitude is smaller than that of the room temperature group, indicating that the growth of impurity under refrigeration condition is slower, and the sample stability is relatively better.

[0063] The data show that, within the 10-day observation period, the maximum content change of flunixin of the sample stored at room temperature is 2.170%, and the highest content of impurity is 0.269%. The maximum content change of flunixin of the sample stored at 4°C under refrigeration condition is 1.066%, and the highest content of impurity is 0.216%. The results show that in the preparation system of the application, the chemical properties of the main drug flunixin remain stable under the set storage conditions, and the degradation and impurity generation are effectively controlled.

[0064] 3.2 Disintegration time change At the same time of content investigation, the appearance and disintegration time of the capsule samples stored at room temperature and 4°C were determined. On the 0th, 5th and 10th day, first of all, whether the capsule shell has leakage or deformation was observed by visual observation, then the capsule was placed in artificial gastric juice, and it was observed that there should be no cracks or disintegration within a specified time; then the capsule was placed in artificial intestinal juice, and the time of complete disintegration was recorded.

[0065] Table 9. Disintegration time of capsules under 4°C storage condition (min)

[0066] Table 10. Disintegration time of capsules under room temperature storage condition (min)

[0067] The results of the disintegration time limit determination are shown in Tables 9 and 10. At each detection time point, visual observation showed that all the capsule shells had no leakage or deformation. In the artificial gastric juice, none of the capsules showed cracking or disintegration. In the artificial intestinal juice, all the capsules disintegrated completely within 1 hour. The results show that the enteric capsule shell of the preparation of the present application maintains stable physical structure and enteric disintegration function under the set storage conditions.

[0068] Test Example 4: In vitro release performance test To evaluate the in vitro release characteristics of the preparation of the present application, a membrane dialysis method was used for the determination. One capsule prepared in Example 1 containing 14 mg of gel powder (corresponding to 4 mg of florfenicol) and 1 mL of the suspension containing 4 mg of florfenicol prepared in Comparative Example 1 were placed in dialysis bags, respectively. After the two ends of the dialysis bag were tightly tied, it was placed in a beaker containing 50 mL of artificial intestinal juice as the release medium. After timing, 1 mL of sample was taken from the release medium at time points of 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, and 5 hours, and immediately supplemented with an equal volume of fresh release medium at the same temperature. The sample was determined for the concentration of florfenicol using the HPLC method established in Test Example 1, and the cumulative release percentage was calculated.

[0069] 4.1 Release results and analysis Table 11. In vitro cumulative release rate (%) of the preparation and the control sample

[0070] The in vitro release results are shown in Table 11, and graphically displayed by Figure 5 . Figure 5 : The horizontal axis is time (hours), and the vertical axis is the cumulative release rate (%). The gray dotted line (representing the "preparation") starts from the origin and continuously rises, and the rising rate gradually increases, reaching about 80% at 5 hours; the red solid line (representing the "control") slowly rises in the early stage, and remains basically stable after 2 hours, maintaining at about 17%, indicating that the sustained-release effect of the preparation is much better than that of the control sample. The results show that the florfenicol suspension of Comparative Example 1 basically tends to be flat after 2.5 hours, and the total cumulative release rate at 5 hours is 17.02%. In contrast, the veterinary florfenicol enteric sustained-release gel capsule prepared in Example 1 shows continuous release during the entire 5-hour observation period, and the total cumulative release rate at 5 hours is 80.42%. The data show that in the simulated intestinal environment, the gel matrix structure formed by the content of the preparation of the present application can control the release rate of florfenicol, achieving sustained release of the drug over a long period of time, thereby showing sustained-release characteristics.

[0071] 4.2 Release kinetics model fitting To quantitatively describe the release mechanism of florfenicol from the gel matrix, the in vitro cumulative release data of the formulation samples measured in Section 4.1 were fitted with various drug release kinetic models, including Zero order, First order, Higuchi, Korsmeyer-Peppas, Hixson-Crowell and Weibull, respectively. The release behavior of the drug was determined by comparing the fitting equations and correlation coefficients (r) of each model.

[0072] Table 12. Kinetic model fitting results of in vitro release data of the formulation

[0073] The fitting results of each kinetic model are shown in Table 12. By comparing the correlation coefficients (r), the r value of the Weibull model is 0.9990, which is closest to 1, indicating that this model can most accurately describe the in vitro release process of the formulation of the present application. The fitting results show that the release of florfenicol from the gel matrix composed of Carbopol 940 and hypromellose is a complex process dominated by the dissolution mechanism, which is consistent with the mechanism that the gel matrix gradually swells and is eroded in the release medium to release the drug.

Claims

1. A veterinary florfenicol enteric-coated sustained-release gel capsule, characterized in that, include: Enteric-coated capsule shell and gel powder filling the enteric-coated capsule shell; The gel powder is made from a mixture of carbomer 940, hydroxypropyl methylcellulose, florfenicol and sodium dodecyl sulfate; The weight ratio of carbomer 940, hydroxypropyl methylcellulose, florfenicol and sodium dodecyl sulfate is (1.8-2.2):(2.7-3.3):(3.6-4.4):(4.5-5.5).

2. The veterinary florfenicol enteric-coated sustained-release gel capsule according to claim 1, characterized in that, The weight ratio of carbomer 940, hydroxypropyl methylcellulose, florfenicol, and sodium dodecyl sulfate is 2:3:4:

5.

3. The veterinary florfenicol enteric-coated sustained-release gel capsule according to claim 1, characterized in that, The enteric-coated capsule shell is an animal-specific enteric-coated capsule shell, which consists of a capsule shell body made of gelatin or hydroxypropyl methylcellulose and an enteric coating layer covering the capsule shell body. The enteric coating layer is composed of one or more of acrylic resin or cellulose acetate phthalate.

4. The veterinary florfenicol enteric-coated sustained-release gel capsule according to claim 1, characterized in that, The carbomer 940 and the hydroxypropyl methylcellulose together constitute the gel matrix.

5. The veterinary florfenicol enteric-coated sustained-release gel capsule according to claim 1, characterized in that, The weight ratio of florfenicol to sodium dodecyl sulfate is in the range of 1:(1.02-1.53).

6. A method for preparing veterinary florfenicol enteric-coated sustained-release gel capsules as described in any one of claims 1-5, characterized in that, Includes the following steps: S1. Carbomer 940, hydroxypropyl methylcellulose, florfenicol and sodium dodecyl sulfate are provided and mixed to obtain a mixed powder; S2. The mixed powder obtained in step S1 is stirred at room temperature at a speed of 800 r / min to 1200 r / min for 8 min to 15 min to obtain gel powder. S3. The gel powder obtained in step S2 is filled into an enteric capsule shell to obtain the veterinary florfenicol enteric-coated sustained-release gel capsule.

7. The method for preparing a veterinary florfenicol enteric-coated sustained-release gel capsule according to claim 6, characterized in that, The stirring speed in step S2 is 900 r / min to 1100 r / min.

8. The method for preparing a veterinary florfenicol enteric-coated sustained-release gel capsule according to claim 6, characterized in that, The stirring time in step S2 is 9 to 12 minutes.

9. The method for preparing a veterinary florfenicol enteric-coated sustained-release gel capsule according to claim 6, characterized in that, The stirring process parameters in step S2 are: a rotation speed of 900 r / min to 1100 r / min and a time of 9 min to 12 min.

10. The method for preparing a veterinary florfenicol enteric-coated sustained-release gel capsule according to claim 6, characterized in that, The stirring in step S2 continues until the mixed powder is visually observed to form a uniform gel powder.

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