Taste-masking enteric-coated acetylisovaleryltylosin tartrate tablet and preparation method thereof

Abstract

The invention relates to taste-masking enteric-coated acetylisovaleryltylosin tartrate tablets, which are characterized by comprising 1000 tablets, the acetylisovaleryltylosin tartrate tablet comprises the following main components by weight: 25 to 75 g of acetylisovaleryltylosin tartrate, 75 to 225 g of hydroxypropyl-beta-cyclodextrin, 7 to 9 g of a pork liver flavoring agent, 18 to 22 g of a microcrystalline cellulose-silicification compound, 6 to 20 g of origanum oil nano-emulsion, 13 to 14 g of Eudragit L100-55, 5 to 6 g of nano-zinc oxide, 2 to 3 g of polyethylene glycol, 1 to 2 g of magnesium stearate and 0 to 45 g of lactose. The acetylisovaleryltylosin tartrate tablet can effectively improve the palatability of drugs, improve the bioavailability and stability, ensure the mixing uniformity of raw materials, and better manage the drug resistance problem, thereby improving the application effect of acetylisovaleryltylosin tartrate in animal husbandry.

Description

Technical Field

[0001] This invention belongs to the field of veterinary drug formulation technology, specifically relating to a taste-masked enteric-coated tylosin tablet and its preparation method. Background Technology

[0002] Tylosin tartrate is a typical third-generation macrolide antibiotic with broad-spectrum antibacterial activity. It primarily works by inhibiting bacterial protein synthesis and exhibits significant antibacterial effects against a variety of Gram-positive bacteria and some Gram-negative bacteria. It has gained widespread recognition and application in the veterinary field, particularly for its remarkable efficacy in preventing and treating diseases such as mycoplasma infection, porcine reproductive and respiratory syndrome (PRRS), and porcine proliferative enteritis. Compared to tylosin, its antibacterial potency is 5-10 times higher, it is more sensitive to mycoplasma, and it can also enhance the animal's own immune function.

[0003] Currently, the use of tylosin tartrate is steadily increasing in both the global and domestic markets, with strong market demand. However, in clinical applications, it suffers from problems such as poor palatability, unstable bioavailability, risks related to mixing uniformity, and insufficient management of drug resistance, which affect its therapeutic effects in aquaculture and thus limit the realization of its application potential.

[0004] Based on this, this application was developed. This application addresses the aforementioned problems by developing a novel taste-masked enteric-coated tylosin tablet. The successful development of this formulation effectively improves the palatability of the drug, enhances bioavailability and stability, ensures uniform mixing of raw materials, and better manages drug resistance issues, thereby improving the efficacy of tylosin tartrate in livestock farming. This innovation has profound significance for promoting its widespread application in livestock farming, protecting animal health, and improving breeding efficiency. Summary of the Invention

[0005] The purpose of this invention is to overcome the shortcomings of existing technologies and provide a taste-masked enteric-coated tivalvicine tablet. This tivalvicine tablet can effectively improve the palatability of the drug, enhance bioavailability and stability, ensure the uniformity of raw material mixing, and better manage drug resistance issues, thereby improving the application effect of tivalvicine tartrate in animal husbandry.

[0006] Another object of the present invention is to provide a method for preparing the above-mentioned taste-masked enteric-coated tylosin tablets.

[0007] A third objective of this invention is to provide laboratory and clinical trial analyses of the above-mentioned taste-masked enteric-coated tylosin tablets.

[0008] To achieve the above objectives, the present invention adopts the following technical solution: A flavor-masked enteric-coated tivalmics tablet, wherein, based on 1000 tablets, the main components and weight ratio of the tivalmics tablet are as follows: tivalmics tartrate 25-75g, hydroxypropyl-β-cyclodextrin 75-225g, pork liver flavoring agent 7-9g, microcrystalline cellulose-silicified complex 18-22g, oregano oil nanoemulsion 6-20g, Eudragit L100-55 13-14g, nano zinc oxide 5-6g, polyethylene glycol (PEG6000) 2-3g, magnesium stearate 1-2g, and lactose 0-45g.

[0009] More preferably, the mass ratio of tartrate tylosin to hydroxypropyl-β-cyclodextrin can be 1:2-3, preferably 1:3.

[0010] Specifically, in the aforementioned taste-masked enteric-coated tylosin tablets, the microcrystalline cellulose-silicified complex can be prepared by the following steps: dispersing nano-silica in anhydrous ethanol, and spraying microcrystalline cellulose in a fluidized bed to obtain the product.

[0011] Furthermore, the concentration of the nano-silica in anhydrous ethanol is 5-10% w / v; during spray coating, the inlet air temperature is 40-60℃ and the atomization pressure is 0.8-1.5 bar.

[0012] Specifically, in the above-mentioned taste-masked enteric-coated tylosin tablets, the oregano oil nanoemulsion can be prepared by the following steps: oregano oil, polyoxyethylene hydrogenated castor oil and anhydrous ethanol are mixed and homogenized, a freeze-drying protectant is added, and the mixture is pre-frozen at -40±5℃ for 2-4 hours, and then vacuum dried until the moisture content is ≤1.5%.

[0013] Furthermore, the mass ratio of oregano oil, polyoxyethylene hydrogenated castor oil, and ethanol can be 10:12-18:4-6, preferably 10:15:5. The oregano oil contains ≥85% carvacrol.

[0014] Furthermore, high-pressure homogenization can be used at a pressure of 1500±200 bar, cyclically 4-6 times; the freeze-drying protectant can be composed of mannitol and lactose in a mass ratio of 1:1-2. The mass ratio of the freeze-drying protectant to oregano oil can be 1.5-3:1.

[0015] This invention provides a method for preparing the above-mentioned taste-masked enteric-coated tylosin tablets, which specifically includes the following steps: 1) Dissolve tartrate tylosin and hydroxypropyl-β-cyclodextrin in a 20-40% ethanol aqueous solution (this can be achieved by magnetically stirring at 400-600 rpm in a water bath at 40±5℃ until completely dissolved, then transferring to an ultrasonic reactor and ultrasonically vibrating at 35-45 kHz at 35-45℃ for 20-45 min to promote uniform dissolution and dispersion), to obtain a solution system with a solid content concentration of 0.2-0.6 g / mL, and then spray-dry to obtain a white inclusion powder; 2) The inclusion powder obtained in step 1), microcrystalline cellulose-silicified complex, pork liver flavoring agent, oregano oil nanoemulsion, and lactose are mixed evenly in a three-dimensional mixer and then extruded into granules. 3) After mixing the granules obtained in step 2) with magnesium stearate evenly, compress the mixture into tablets; 4) Disperse Eudragit L100-55, nano zinc oxide, and polyethylene glycol in a 60-80% ethanol aqueous solution to obtain a system with a total concentration of 0.10-0.12 g / mL of the three raw materials. After ball milling, the system is used to coat tablets. 5) A CO2 laser (wavelength 10.6 μm) is used to drill a transverse hole on one side of the tablet sidewall, with a hole diameter of 50±5 μm and a hole depth of 200±10 μm (penetrating the enteric coating layer to the tablet core). The tablet is then packaged to obtain the product of this invention.

[0016] Furthermore, in step 1), during spray drying, the inlet air temperature is 50-70℃ and the outlet air temperature is 30-40℃; in step 2), a twin-screw dry granulator is used for extrusion granulation with a pressure of 10-20 kN and a screw speed of 15-25 rpm; in step 3), a rotary tablet press is used for tableting with a pressure of 8-10 kN.

[0017] Further, in step 4), the particles are ball-milled until the particle size D90 ≤ 5 μm (approximately 2-3 hours of ball milling is required); during coating, the inlet air temperature is 30-40℃, the material temperature is ≤ 30℃, the spraying rate is 3-8 mL / min, and the atomization pressure is 0.5-1.0 bar. In step 5), the core purpose of laser perforation is to achieve "targeted controlled release" of the tablets. By creating micropores of a specific size on the enteric coating layer, the drug can be programmed to be released in the intestinal environment (pH ≥ 5.5). This invention involves transverse perforation through the curved surface (sidewall) of a cylindrical tablet to penetrate to the tablet core.

[0018] Compared with the prior art, the present invention has the following unique advantages and significant beneficial effects: (1) The present invention uses molecular inclusion masking technology to mask the unpleasant taste of drugs, improve palatability, and facilitate animal acceptance and administration; (2) The present invention introduces advanced nano-enteric coating protection technology, so that the drug is not destroyed in gastric acid and is released under specific pH conditions in the intestine, thereby improving stability and bioavailability; (3) The present invention uses laser precision controlled release technology to artificially create a "release channel". When the tablet enters the small intestine (pH≥5.5), the coating layer dissolves slowly. At this time, the micropores allow the internal drug to continuously seep out through the osmotic pressure gradient (similar to the structure of an osmotic pump). Thus, the drug release rate can be precisely controlled so that it is released at a preset rate and time point to achieve the ideal drug effect. (4) This invention achieves breakthroughs in both materials science and process innovation, and has both clinical application value and industrial production feasibility, providing large-scale pig farms with a new administration method of tylosin that is "highly compliant and lowly resistant". Detailed Implementation

[0019] The technical solution of the present invention will be further described in detail below with reference to the embodiments, but the scope of protection of the present invention is not limited thereto.

[0020] In the following examples, all raw materials used are common commercially available products that can be purchased directly, or can be prepared using conventional techniques in the art. For example, the pork liver flavoring agent was purchased from Guangzhou Huabao Flavoring Co., Ltd., model HB-Liver-SP103, and Eudragit L100-55 was purchased from Huzhou Zhanwang Pharmaceutical Co., Ltd., model Wangit®L100C.

[0021] Examples 1, 2, and 3: A taste-masked enteric-coated tylosin tablet The main components and weight ratios (based on 1000 tablets) of the tylosin tablets described in Examples 1 to 3 are shown in the table below.

[0022] The preparation method of the taste-masked enteric-coated tylosin tablets described in Examples 1 to 3 above is as follows: 1. Dissolve tartrate tylosin and hydroxypropyl-β-cyclodextrin in 30% ethanol aqueous solution (500 mL). Stir magnetically in a 40℃ water bath (500 rpm) until completely dissolved. Then transfer to an ultrasonic reactor (frequency 40 kHz) and sonicate at 40℃ for 30 min. Finally, spray dry (inlet air temperature 60℃, outlet air temperature 35℃) to obtain a white inclusion powder. 2. Place the inclusion powder obtained in step 1, microcrystalline cellulose-silicified complex, pork liver flavoring agent, oregano oil nanoemulsion, and lactose into a three-dimensional mixer and mix for 10 minutes to ensure uniform mixing. Then, extrude the mixture into granules using a twin-screw dry granulator (pressure 15kN, screw speed 20rpm). 3. Mix the granules obtained in step 2 with magnesium stearate for 1 minute to ensure uniform mixing, and then compress the mixture into tablets using a rotary tablet press (pressure 8-10 kN). 4. Disperse Eudragit L100-55, nano zinc oxide, and PEG6000 in a 70% (v / v) ethanol aqueous solution (200 mL), and ball mill until the particle size D90 ≤ 5 μm (approximately 2 hours of ball milling). Then, coat the tablets (inlet air temperature 35℃, material temperature ≤ 30℃, spray rate 5 mL / min, atomization pressure 0.8 bar). 5. A CO2 laser (wavelength 10.6μm) is used to drill a transverse hole on one side of the tablet sidewall, with a hole diameter of 50±5μm and a hole depth of 200±10μm (penetrating the enteric coating layer to the tablet core). The tablet is then packaged to obtain the product of this invention.

[0023] Among them: 1. The mass ratio of tartrate tylosin to hydroxypropyl-β-cyclodextrin is 1:3; 2. Preparation method of microcrystalline cellulose-silicified composite: Disperse nano-silica in anhydrous ethanol (system concentration 5% w / v), and spray-coat microcrystalline cellulose in a fluidized bed (inlet air temperature 50℃, atomization pressure 1.0 bar) to obtain the composite.

[0024] 3. Preparation method of oregano oil nanoemulsion: Take oregano oil (carvacrol ≥ 85%), polyoxyethylene hydrogenated castor oil, and anhydrous ethanol (weight ratio of 10:15:5) and perform high-pressure homogenization treatment (pressure 1500 bar, cycle 5 times). Add a freeze-drying protectant (mannitol: lactose = 1:1, mass ratio, the mass ratio of freeze-drying protectant to oregano oil is 2:1). After pre-freezing at -40℃ for 3 hours, vacuum dry for 24 hours (moisture content ≤ 1.5%) to obtain the nanoemulsion.

[0025] Comparative Example 1: 25mg / tablet (200mg / tablet) [Process Adjustment] Cancellation of the antibacterial synergist, oregano oil nanoemulsion. A tivalmiculin tablet, the composition and weight of raw materials used (based on 1000 tablets) are as follows: tivalmiculin tartrate 25.0g, hydroxypropyl-β-cyclodextrin 75.0g, pork liver flavoring agent 8.0g, microcrystalline cellulose-silicified complex 20.0g, Eudragit L100-55 13.2g, nano zinc oxide 5.3g, PEG6000 2.6g, magnesium stearate 1.3g, and lactose 49.6g.

[0026] The preparation method of the above-mentioned tylosin tablets is as follows: 1. Dissolve tartrate tylosin and hydroxypropyl-β-cyclodextrin in 30% ethanol aqueous solution (500 mL). Stir magnetically in a 40℃ water bath (500 rpm) until completely dissolved. Then transfer to an ultrasonic reactor (frequency 40 kHz) and sonicate at 40℃ for 30 min. Finally, spray dry (inlet air temperature 60℃, outlet air temperature 35℃) to obtain a white incorporation powder. 2. Place the inclusion powder obtained in step 1, microcrystalline cellulose-silicified complex, pork liver flavoring agent, and lactose into a three-dimensional mixer and mix for 10 minutes. Then, extrude the mixture into granules using a twin-screw dry granulator (pressure 15kN, screw speed 20rpm). 3. After mixing the granules obtained in step 2 with magnesium stearate for 1 minute, compress the mixture into tablets using a rotary tablet press (pressure 8-10 kN, tablet weight 200 ± 5 mg). 4. Disperse Eudragit L100-55, nano zinc oxide, and PEG6000 in a 70% (v / v) ethanol aqueous solution (200 mL), and ball mill until the particle size D90 ≤ 5 μm (approximately 2 hours of ball milling). Then, coat the tablets (inlet air temperature 35℃, material temperature ≤ 30℃, spray rate 5 mL / min, atomization pressure 0.8 bar). 5. A CO2 laser (wavelength 10.6μm) is used to drill a transverse hole on one side of the tablet sidewall, with a hole diameter of 50±5μm and a hole depth of 200±10μm (penetrating the enteric coating layer to the tablet core). The tablet is then packaged to obtain the product of this invention.

[0027] Comparative Example 2: 25 mg / tablet (200 mg / tablet) [Process Adjustment] Laser controlled release technology cancelled. A tivalmiculin tablet, the composition and weight of raw materials used (based on 1000 tablets) are as follows: 25.0g talcum tartrate, 75.0g hydroxypropyl-β-cyclodextrin, 8.0g pork liver flavoring agent, 20.0g microcrystalline cellulose-silicified complex, 6.25g oregano oil nanoemulsion, 13.2g Eudragit L100-55, 5.3g nano zinc oxide, 2.6g PEG6000, 1.3g magnesium stearate, and 43.35g lactose.

[0028] The preparation method of the above-mentioned tylosin tablets is as follows: 1. Dissolve tartrate tylosin and hydroxypropyl-β-cyclodextrin in 30% ethanol aqueous solution (500 mL). Stir magnetically in a 40°C water bath (500 rpm) until completely dissolved. Then transfer to an ultrasonic reactor (40 kHz frequency) and ultrasonically vibrate at 40°C for 30 min. Finally, spray dry (inlet air temperature 60°C, outlet air temperature 35°C) to obtain a white incorporation powder. 2. Place the inclusion powder obtained in step 1, microcrystalline cellulose-silicified complex, pork liver flavoring agent, oregano oil nanoemulsion, and lactose into a three-dimensional mixer and mix for 10 minutes. Then, extrude the mixture into granules using a twin-screw dry granulator (pressure 15kN, screw speed 20rpm). 3. After mixing the granules obtained in step 2 with magnesium stearate for 1 minute, compress the mixture into tablets using a rotary tablet press (pressure 8-10 kN, tablet weight 200 ± 5 mg). 4. Disperse Eudragit L100-55, nano zinc oxide, and PEG6000 in a 70% (v / v) ethanol aqueous solution (200 mL), and ball mill until the particle size D90 ≤ 5 μm (approximately 2 hours). Then, coat the tablets (inlet air temperature 35℃, material temperature ≤ 30℃, spray rate 5 mL / min, atomization pressure 0.8 bar), and package them to obtain the product of this invention.

[0029] Comparative Example 3: 25mg / tablet (200mg / tablet) [Process Adjustment] The raw materials no longer contain Eudragit L100-55, nano zinc oxide, or PEG6000, and the enteric coating process and laser controlled release technology have been discontinued. A tivalmiculin tablet, the composition and weight of raw materials used (based on 1000 tablets) are as follows: 25.0g talcum tartrate, 75.0g hydroxypropyl-β-cyclodextrin, 8.0g pork liver flavoring agent, 20.0g microcrystalline cellulose-silicified complex, 6.25g oregano oil nanoemulsion, 1.3g magnesium stearate, and 64.45g lactose.

[0030] The preparation method of the above-mentioned tylosin tablets is as follows: 1. Dissolve tartrate tylosin and hydroxypropyl-β-cyclodextrin in 30% ethanol aqueous solution (500 mL). Stir magnetically in a 40℃ water bath (500 rpm) until completely dissolved. Then transfer to an ultrasonic reactor (frequency 40 kHz) and sonicate at 40℃ for 30 min. Finally, spray dry (inlet air temperature 60℃, outlet air temperature 35℃) to obtain a white incorporation powder. 2. Place the inclusion powder obtained in step 1, microcrystalline cellulose-silicified complex, pork liver flavoring agent, oregano oil nanoemulsion, and lactose into a three-dimensional mixer and mix for 10 minutes. Then, extrude the mixture into granules using a twin-screw dry granulator (pressure 15kN, screw speed 20rpm). 3. After mixing the granules obtained in step 2 with magnesium stearate for 1 minute, the mixture is compressed into tablets using a rotary tablet press (pressure 8-10 kN, tablet weight 200 ± 5 mg), and then packaged to obtain the product of this invention.

[0031] Comparative Example 4 25mg / tablet A tivalmiculin tablet, the composition of which and the weight of raw materials used in 1000 finished tablets are: 25.0g tivalmiculin tartrate, 108.5g starch, 50.0g sucrose, 1.5g magnesium stearate, and 15.0g enteric coating.

[0032] The preparation of the above-mentioned tylosin tablets adopts the traditional wet granulation method. Specifically, tylosin tartrate, starch and sucrose are mixed in a wet granulator for 10 minutes. A 30% ethanol aqueous solution (20% of the total powder weight) is added as a binder to form a soft mass. The soft mass is extruded through a 14-mesh sieve and granulated. The wet granules are dried in a fluidized bed at 55℃±2℃ until the moisture content is ≤3%. After granulation through a 16-mesh sieve, magnesium stearate is added and mixed for 3 minutes. The tablets are then compressed into uncoated tablets (200mg / tablet) using a rotary tablet press. Finally, the tablets are spray-coated in a coating pan with an enteric coating solution (15% solid content) to obtain the finished product.

[0033] Test case 1. Test materials The products prepared in Examples 1, 2, and 3; Comparative Example 1: Oregano oil nanoemulsion was removed; Comparative Example 2: Laser controlled release technology was removed (enteric coating was retained); Comparative Example 3: Enteric coating and laser controlled release were removed (ordinary tablet compression). Comparative Example 4: Traditional wet granulation (60℃ drying + non-functional coating).

[0034] 2. Experimental methods and results 2.1 Pharmacokinetic Studies Experimental animals: 70 healthy Landrace pigs (weight 20±2kg) were randomly divided into 7 groups of 10 pigs each. The pre-experiment period was 7 days. They were fed a uniform basal diet to exclude diseases and drug residues.

[0035] Dosage regimen: For Examples 1 and Comparative Examples 1, 2, 3, and 4, one tablet was taken orally once; for Example 2, 1 / 2 tablet was taken orally once; and for Example 3, 1 / 3 tablet was taken orally once. All were taken on an empty stomach in the morning with 10 mL of water.

[0036] Blood samples were collected from the anterior vena cava at 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, and 24h after drug administration, and the blood drug concentration was measured.

[0037] The relative bioavailability (F) was calculated using Example 1 as the reference formulation.

[0038] The experimental results are shown in Table 1.

[0039] Table 1 Pharmacokinetic test data As shown in Table 1, the peak plasma concentrations (C) of Examples 1, 2, and 3 are as follows: maxThe average value was 3.14, which was 12.14%, 6.44%, 53.17%, and 73.48% higher than that of Comparative Examples 1, 2, 3, and 4, respectively. The average relative bioavailability of Examples 1, 2, and 3 was 100.17, which was 22.91%, 19.53%, 47.96%, and 89.36% higher than that of Comparative Examples 1, 2, 3, and 4, respectively.

[0040] Therefore, the use of oregano oil nanoemulsion technology, enteric coating technology, and dry granulation process can significantly improve the bioavailability of tivalmiculin tablets. The combined application of these technologies optimizes the drug release mechanism, enhances in vivo absorption efficiency, and makes the therapeutic effect of tivalmiculin tablets more significant.

[0041] 2.2 Palatability Test Experimental animals: Sixty healthy Landrace pigs (weighing 20±2kg) were randomly divided into 6 groups of 10 each. During the 24-hour pre-experiment period, they were fed a uniform basal diet and their feed intake was recorded.

[0042] Experimental method: The test tablets were crushed and passed through a 40-mesh sieve. They were then evenly mixed into the basal diet at a ratio of 1 tablet / kg of feed. 1kg of medicated feed was weighed and placed into the feed trough. The feed intake (accurate to 0.1g) and the time of first contact with the feed (s) within 0-30 minutes were recorded. The rejection rate (%) and feeding rate (g / min) were calculated. The blank group was the group without added drug.

[0043] Refusal rate = (1 - intake of medicated feed / intake of basal feed) × 100%.

[0044] Feeding rate = 30 min feed intake / 30.

[0045] The test results are shown in Table 2.

[0046] Table 2 Palatability test data As shown in Table 2, the refusal rate of Example 1 was reduced by 84.32% and 88.31% compared to Comparative Examples 3 and 4, respectively; the first contact time was reduced by 82.22% and 87.50% compared to Comparative Examples 3 and 4, respectively; and the feeding rate was increased by 20.45% and 55.12% compared to Comparative Examples 3 and 4, respectively. The refusal rates of Example 1, Comparative Examples 1 and 2 were similar, and the first contact time and feeding rate were similar to those of the control group. Compared to Comparative Example 4, Comparative Example 3 showed a 25.45% reduction in refusal rate and a 29.69% reduction in first contact time, and a 28.78% increase in feeding rate.

[0047] It is evident that by employing hydroxypropyl-β-cyclodextrin (HP-β-CD) inclusion technology, combined with pork liver flavoring agents and enteric coating for taste masking, this series of core technologies has demonstrated significant effectiveness in improving the taste of drugs.

[0048] 2.3 Intestinal-targeted release efficiency: Experimental Groups: This experiment consisted of 7 groups: 3 example groups (Example 1, Example 2, Example 3) and 4 comparative groups (Comparative Example 1, Comparative Example 2, Comparative Example 3, Comparative Example 4). Each group had 6 parallel samples for subsequent testing.

[0049] Experimental methods: Preparation of simulated pig gastric juice: Accurately measure a certain volume of 0.1M hydrochloric acid solution, add pepsin at a ratio of 3.2g / L, and stir evenly to obtain simulated pig gastric juice.

[0050] Preparation of simulated pig intestinal fluid: Prepare a phosphate buffer solution with pH 6.8, add trypsin at a ratio of 10 g / L, stir thoroughly to dissolve, and you will get the simulated pig intestinal fluid.

[0051] Release experiment: Tylenol tablets prepared in each example and comparative example were placed in dissolution vessels, and 900 mL of simulated porcine gastric fluid was added to each vessel. The dissolution vessels were placed in a dissolution apparatus, and the release experiment was conducted at 37℃±0.5℃ with a stirring rate of 50 rpm for 2 hours. The simulated porcine intestinal fluid experiment was conducted using the same method for 10 hours.

[0052] Calculation of gastric juice degradation rate: After releasing the solution into simulated pig gastric juice for 2 hours, a suitable amount of solution was filtered. The content of tylosin in the filtrate was determined by high performance liquid chromatography (HPLC) and denoted as C. 胃液 Simultaneously, a reference standard containing the same amount of tylosin tartrate as that in the tablets was accurately weighed and prepared into a solution of the same concentration. Its content was then determined by HPLC and denoted as C. 对照 Gastric juice degradation rate (%) = (C 对照 - C 胃液 ) / C 对照 ×100%.

[0053] Intestinal fluid dissolution calculation: After releasing the solution into simulated pig intestinal fluid for 10 hours, a suitable amount of solution was filtered. The filtrate was then analyzed by HPLC to determine the content of tylosin, denoted as C. 肠液 Intestinal fluid dissolution rate (%) = C 肠液 / C 对照 ×100%.

[0054] The above calculations were performed on 6 parallel samples in each group, and the final result was the average value. Table 3 Release rate data (%) As shown in Table 3, the average gastric juice degradation rate of Examples 1, 2 and 3 was 3.2%, which was 96.15% and 96.63% lower than that of Comparative Examples 3 and 4, respectively; the average intestinal juice dissolution rate was 97.3%, which was 24.27% and 34.21% higher than that of Comparative Examples 3 and 4, respectively.

[0055] Therefore, by employing the experimental method of this invention, the taste-masked enteric-coated tylosin tablets can effectively achieve targeted drug release in the intestine, thereby significantly reducing the degradation process of the drug in the stomach. This method not only improves drug utilization efficiency but also reduces drug loss due to gastric degradation, ensuring the effective concentration of the drug in the intestine and providing more precise drug release control for treatment.

Claims

1. A taste-masked enteric-coated tylosin tablet, characterized in that, Based on 1000 tablets, the main components and weight ratio of the tivamectin tablets are as follows: tivamectin tartrate 25-75g, hydroxypropyl-β-cyclodextrin 75-225g, pork liver flavoring agent 7-9g, microcrystalline cellulose-silicified complex 18-22g, oregano oil nanoemulsion 6-20g, Eudragit L100-55 13-14g, nano zinc oxide 5-6g, polyethylene glycol 2-3g, magnesium stearate 1-2g, and lactose 0-45g.

2. The taste-masked enteric-coated tylosin tablets as described in claim 1, characterized in that, The mass ratio of tartrate tylosin to hydroxypropyl-β-cyclodextrin is 1:2-3.

3. The taste-masked enteric-coated tylosin tablets as described in claim 1, characterized in that, The microcrystalline cellulose-silicified composite was prepared by the following steps: dispersing nano-silica in anhydrous ethanol and spraying it onto microcrystalline cellulose in a fluidized bed.

4. The taste-masked enteric-coated tylosin tablets as described in claim 3, characterized in that, The concentration of the nano-silica in anhydrous ethanol is 5-10% w / v; during spray coating, the inlet air temperature is 40-60℃ and the atomization pressure is 0.8-1.5 bar.

5. The taste-masked enteric-coated tylosin tablets as described in claim 1, characterized in that, The oregano oil nanoemulsion was prepared by the following steps: oregano oil, polyoxyethylene hydrogenated castor oil and anhydrous ethanol were mixed and homogenized, a freeze-drying protectant was added, and the mixture was pre-frozen at -40±5℃ and then vacuum dried until the moisture content was ≤1.5%.

6. The taste-masked enteric-coated tylosin tablets as described in claim 5, characterized in that, The mass ratio of oregano oil, polyoxyethylene hydrogenated castor oil, and ethanol is 10:12-18:4-6.

7. The taste-masked enteric-coated tylosin tablets as described in claim 5, characterized in that, High-pressure homogenization is adopted at a pressure of 1500±200 bar, and the cycle is 4-6 times. The freeze-drying protectant is composed of mannitol and lactose in a mass ratio of 1:1-2, and the mass ratio of freeze-drying protectant to oregano oil is 1.5-3:

1.

8. The method for preparing the taste-masked enteric-coated tylosin tablets according to any one of claims 1 to 7, characterized in that, Includes the following steps: 1) Dissolve tartrate tylosin and hydroxypropyl-β-cyclodextrin in a 20-40% ethanol aqueous solution, and then spray dry to obtain a white inclusion powder; 2) After uniformly mixing the inclusion powder obtained in step 1), microcrystalline cellulose-silicified complex, pork liver flavoring agent, oregano oil nanoemulsion, and lactose, extrude and granulate. 3) After mixing the granules obtained in step 2) with magnesium stearate evenly, compress the mixture into tablets; 4) Disperse Eudragit L100-55, nano zinc oxide, and polyethylene glycol in a 60-80% ethanol aqueous solution, ball mill, coat the tablets, punch a transverse hole on one side of the tablet sidewall, and package them to obtain the final product.

9. The method for preparing taste-masked enteric-coated tylosin tablets as described in claim 8, characterized in that, In step 1), during spray drying, the inlet air temperature is 50-70℃ and the outlet air temperature is 30-40℃; in step 2), a twin-screw dry granulator is used for extrusion granulation, with a pressure of 10-20 kN and a screw speed of 15-25 rpm; in step 3), a rotary tablet press is used for tableting, with a pressure of 8-10 kN.

10. The method for preparing taste-masked enteric-coated tylosin tablets as described in claim 8, characterized in that, In step 4), the particles are ball-milled until the particle size D90 ≤ 5 μm; during coating, the inlet air temperature is 30-40℃, the material temperature is ≤ 30℃, the spraying rate is 3-8 mL / min, and the atomization pressure is 0.5-1.0 bar.

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