Low water-soluble drug gastroresistant coating granules beyond the rumen, and preparation method and application thereof

Abstract

This invention relates to the field of veterinary drug formulation technology, and more particularly to a rumen-coated enteric-coated granule for a low-water-soluble drug, its preparation method, and its application. The coated granule comprises: a core of at least one low-water-soluble active pharmaceutical ingredient, encapsulated by a coating layer surrounding the core; wherein the coating layer includes an inner coating layer and an outer coating layer surrounding the inner coating layer; and the coating layer is formed of a composite coating material of hydrogenated palm oil and oleophilic and hydrophobic nano-active light calcium carbonate. The advantages of this invention are that it utilizes the dual intelligent response mechanism of nano-calcium carbonate—creating pores through acid reaction in the abomasum and producing gas through saponification with fatty acids in the intestine—combined with the barrier effect of the carnauba wax outer coating, to achieve efficient protection of the low-water-soluble drug in the rumen and rapid, complete release in the intestine. In vitro experiments show that its effective release rate can reach over 80%, significantly superior to traditional coatings, and has broad clinical application prospects.

Description

Technical Field

[0001] This invention relates to the field of veterinary drug formulation technology, and in particular to a rumen-coated granule with low water solubility, its preparation method, and its application. Background Technology

[0002] Ruminants have a unique complex stomach structure, including the rumen, reticulum, omasum, and abomasum (true stomach). The rumen environment is complex and contains a large number of microorganisms. Many oral medications, such as antibiotics, can kill the normal rumen flora, harming the animal's health. More importantly, many drugs themselves are degraded by rumen microbial fermentation, making it impossible for them to effectively reach the abomasum and intestinal absorption sites, resulting in extremely low bioavailability.

[0003] To address these issues, rumen-bypass technology emerged. One common and effective physical protection strategy involves coating drugs with materials that remain solid in the rumen environment but can be broken down or dissolved in the abomasum and intestines. Fatty coating materials, such as hydrogenated vegetable oils and stearic acid, are widely used in the preparation of rumen-bypass formulations because they are solid and stable in the neutral environment of the rumen and at body temperature, but can be broken down by intestinal digestive enzymes.

[0004] However, when coating poorly water-soluble drugs, traditional fat coating technology faces an inherent and irreconcilable contradiction. To ensure complete disintegration of the coating in intestinal fluid and full release of the drug core for absorption, the coating is often thin. However, a thin coating is easily damaged or ruptured prematurely by the pressure and friction of rumen contents (coarse fiber), leading to the release of the drug into the rumen and poor rumen stability. On the other hand, increasing the coating thickness to improve rumen stability makes it difficult for the coating to completely disintegrate in intestinal fluid, resulting in insufficient release of the drug from the core. This negates the benefits of rumen protection and ultimately leads to unsatisfactory bioavailability.

[0005] Existing technologies have attempted to improve the performance of fat coatings, such as using mixtures of fats with different melting points or adding inorganic fillers to alter the coating's density and mechanical strength. However, these methods often struggle to achieve an optimal balance between "low rumen dissolution" and "high intestinal release," resulting in either insufficient rumen protection or delayed intestinal release. This contradiction is particularly pronounced for drug molecules with low water solubility.

[0006] Therefore, there is an urgent need in this field to develop a novel rumen-coated particle that can not only provide robust and reliable protection for the low water-soluble core in the complex environment of the rumen, but also be able to be rapidly and effectively triggered after the drug enters the abomasum and intestines, thereby achieving efficient drug release and fundamentally improving the bioavailability of orally administered drugs in ruminants. Summary of the Invention

[0007] The purpose of this invention is to overcome the shortcomings of existing technologies and provide a rumen-coated enteric-coated granule for low water-soluble drugs, its preparation method, and its application. By adding nano-calcium carbonate to the inner coating layer, its reaction with hydrochloric acid in the abomasum dissolves in the coating, forming micropores that increase the contact area with enzymes in intestinal fluid. This promotes the emulsification and decomposition of the hydrogenated palm oil coating under the action of pancreatic enzymes and bile salts. In the small intestine, the nano-calcium carbonate in the coating can further react with the fatty acids from the enzymatic hydrolysis of hydrogenated palm oil to produce gas, further disrupting the coating structure and synergistically promoting drug release. This effectively solves the technical problem of insufficient drug release in the intestine due to a single thick hydrogenated palm oil coating. Simultaneously, to address the common problem of uneven dispersion of nano-sized inorganic fillers in a hydrophobic fatty matrix, this invention selects nano-active light calcium carbonate with surface oleophilic-hydrophobic modification as the functional component. This ensures the high dispersibility of calcium carbonate in hydrogenated palm oil and the uniformity of the coating film. Furthermore, the addition of nano-calcium carbonate to the coating also increases particle hardness and reduces breakage during rumination and chewing. This preparation method is simple and can significantly improve the rumen passage rate and small intestinal release rate of drugs, resulting in high bioavailability. It is suitable for rumen-passing administration of various drugs to ruminants.

[0008] This invention is achieved through the following technical solution: On one hand, it provides a rumen-coated enteric-coated granule for a low-water-soluble drug, comprising:

[0009] The core of at least one low-water-soluble active pharmaceutical ingredient, A coating layer covering the core; The coating layer includes an inner coating layer and an outer coating layer covering the inner coating layer; and the inner coating layer is formed of a composite coating material of hydrogenated palm oil and nano-sized calcium carbonate.

[0010] Furthermore, the weight ratio of the core to the coating layer is 1:1.5~2.5.

[0011] Furthermore, the mass percentage of the nano-calcium carbonate in the composite coating material is 10%-20%; Furthermore, the average particle size of the nano-sized calcium carbonate is no greater than 100 nanometers.

[0012] Furthermore, the outer coating layer comprises carnauba wax; and / or, the weight of the outer coating layer accounts for 8%-18% of the total weight of the entire coated particles.

[0013] Furthermore, the low water-soluble active pharmaceutical ingredient is selected from one or more of antibiotics, vitamins, amino acids, and trace elements.

[0014] Another method for preparing the above-mentioned low water-soluble drug enteric-coated granules includes the following steps: S1. Preparation of a core containing a low-water-soluble pharmaceutical active ingredient; S2. Heat and melt hydrogenated palm oil, add nano-calcium carbonate under high-speed shear, and disperse homogeneously to obtain an inner coating solution; S3. Place the core in a fluidized bed and spray the inner coating liquid onto the surface of the core to form an inner coating layer; S4. Melt carnauba wax and apply a second coating to the particles of the inner coating layer obtained in step S3 to form an outer coating layer, thus obtaining the product.

[0015] Furthermore, in step S2, the rotational speed of the high-speed shearing is 8000-12000 rpm, and the homogenization time is 10-20 minutes; And / or, in step S3, the bed temperature of the fluidized bed is controlled at 30-40°C, and the spray temperature of the coating liquid is maintained at 70-90°C; And / or, in step S4, the spray temperature of the carnauba wax is maintained at 100-120°C.

[0016] A feed additive is also provided, comprising rumen-coated enteric granules containing low water-soluble drugs as described above.

[0017] Finally, the use of the above-mentioned low water-soluble drug rumen-coated enteric-coated granules in the preparation of rumen-targeted release drugs for ruminants is provided.

[0018] Beneficial effects This study utilizes the specific chemical reactions of nano-calcium carbonate in different sections of the digestive tract. In the acidic environment of the stomach, nano-CaCO3 reacts with HCl (CaCO3 + 2HCl → CaCl2 + CO2↑ + H2O), dissolving in the coating layer to form microporous channels and generating gas to initially disrupt the structure. Upon entering the intestines, under the action of lipase, hydrogenated palm oil decomposes into fatty acids, which further undergo saponification with the residual CaCO3 in the coating (2RCOOH + CaCO3 → (RCOO)2Ca + CO2↑ + H2O), again generating gas and forming low-water-soluble saponins, synergistically promoting the complete disintegration of the coating layer. This dual response of acid etching to create pores and saponification to generate gas powerfully drives the rapid release of the core drug components.

[0019] This invention optimizes the content of nano-calcium carbonate in the coating layer (10%-20%), the core-to-wall ratio (1:1.5-1:2.5), and the proportion of the outer coating layer (8%-18%). The particles of this invention exhibit excellent protective properties with a release rate of less than 20% in simulated rumen fluid over 24 hours. Furthermore, they can be rapidly released in subsequent simulated intestinal fluid, with an effective release rate of over 80% after passing through the rumen, perfectly resolving the contradictions in traditional technologies.

[0020] The carnauba wax coating used in this invention has a high melting point, providing a denser and stronger physical barrier to prevent structural damage to particles in the rumen due to friction and compression. The preparation method of this invention is based on a mature fluidized bed coating process, which is easy to industrialize. Attached Figure Description

[0021] Figure 1 This is a schematic diagram of the structure of the rumen-coated granules containing low water-soluble drugs of the present invention. Figure 2 This is a comparison of the cumulative release curves of the particles prepared in Example 1 and Comparative Example 2 in an in vitro simulated digestive environment. Detailed Implementation

[0022] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to specific embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0023] Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without inventive effort are within the scope of protection of this invention. Experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, all percentages, ratios, proportions, or parts are by weight.

[0024] Unless otherwise specified, the reagents and raw materials used in the embodiments and comparative examples of this invention are commercially available.

[0025] Example 1: Preparation of tilmicosin particles coated with nano-calcium carbonate / hydrogenated palm oil / carnauba wax (10% nano-calcium) A method for preparing rumen-coated enteric-coated granules of a drug with low water solubility includes the following steps: S1. Take 300g of tilmicosin raw material, 30g of hydroxypropyl methylcellulose (HPMC), 300g of microcrystalline cellulose, and 370g of corn starch, mix them evenly; add 350mL of purified water to prepare a soft material, and use an extrusion spheroidizer to prepare tilmicosin cores with a particle size of 40-60 mesh, and dry them for later use.

[0026] S2. Take 900 g of hydrogenated palm oil and place it in a container equipped with heating and stirring. Heat it to 90°C until it is completely melted. Separately, take 100 g of nano-calcium carbonate with an average particle size of 100 nm and slowly add it to the molten hydrogenated palm oil while running a high-speed shear press at 10,000 rpm. After the addition is complete, continue high-speed shearing and homogenization for 15 minutes to obtain a uniformly dispersed milky white inner coating solution. Keep it at 90°C and continuously stir slowly to prevent sedimentation.

[0027] S3. Take 500 g of the dried core prepared in S1 and place it in the hopper of a fluidized bed coating machine. Set the fluidized bed inlet air temperature to stabilize the material bed temperature at 35℃ and preheat the core for 10 minutes. Transfer the coating liquid prepared in S2 to a spray tank with an insulation jacket and a stirrer, maintaining the temperature at 90℃. Set the atomization pressure to 30MPa, the peristaltic pump inlet speed to a corresponding rotation speed of 13 r / min, and the fan frequency to 30 Hz. Begin spray coating, strictly controlling the bed temperature at 35±2℃ during the process. Stop coating when the inner coating material increases in weight to twice the weight of the core, obtaining inner-coated particles.

[0028] S4. Take 150 g of carnauba wax and heat it to 130°C to melt it, using it as the outer coating solution. Place 1000 g of the inner-coated particles obtained in step S3 back into the fluidized bed and preheat it to 35°C. Keep the molten carnauba wax at 130°C and perform a second coating by spraying at an atomization pressure of 30 MPa and a pump speed of 8 r / min until the outer coating layer increases in weight to 15% of the total particle weight at this point.

[0029] Step S5: After coating is complete, pass the product through 30-mesh and 50-mesh standard sieves, and collect the coated particles between 30-mesh and 50-mesh to obtain the final product (see...). Figure 1 ).

[0030] Example 2: Preparation of tilmicosin particles coated with nano-calcium carbonate / hydrogenated palm oil / carnauba wax (8% nano-calcium) A method for preparing rumen-coated granules of a drug with low water solubility includes the following steps: S1. Take 300g of tilmicosin raw material, 30g of hydroxypropyl methylcellulose (HPMC), 300g of microcrystalline cellulose, and 370g of corn starch, mix them evenly; add 350mL of purified water to prepare a soft material, and use an extrusion spheroidizer to prepare tilmicosin cores with a particle size of 40-60 mesh, and dry them for later use.

[0031] S2. Take 920 g of hydrogenated palm oil and place it in a container equipped with heating and stirring. Heat it to 90°C until it is completely melted. Separately, take 80 g of nano-calcium carbonate with an average particle size of 100 nm and slowly add it to the molten hydrogenated palm oil while running a high-speed shear press at 10,000 rpm. After the addition is complete, continue high-speed shearing and homogenization for 15 minutes to obtain a uniformly dispersed milky white inner coating solution. Keep it at 90°C and continue to stir slowly to prevent sedimentation.

[0032] S3. Take 500 g of the dried core prepared in S1 and place it in the hopper of a fluidized bed coating machine. Set the fluidized bed inlet air temperature to stabilize the material bed temperature at 35℃ and preheat the core for 10 minutes. Transfer the coating liquid prepared in S2 to a spray tank with an insulation jacket and a stirrer, maintaining the temperature at 90℃. Set the atomization pressure to 30MPa, the peristaltic pump inlet speed to a corresponding rotation speed of 13 r / min, and the fan frequency to 30 Hz. Begin spray coating, strictly controlling the bed temperature at 35±2℃ during the process. Stop coating when the inner coating material increases in weight to twice the weight of the core, obtaining inner-coated particles.

[0033] S4. Take 150 g of carnauba wax and heat it to 130°C to melt it, using it as the outer coating solution. Place 1000 g of the inner-coated particles obtained in step S3 back into the fluidized bed and preheat it to 35°C. Keep the molten carnauba wax at 130°C and perform a second coating by spraying at an atomization pressure of 30 MPa and a pump speed of 8 r / min until the outer coating layer increases in weight to 15% of the total particle weight at this point.

[0034] Step S5: After coating is completed, the product is passed through 30-mesh and 50-mesh standard sieves to collect coated particles between 30-mesh and 50-mesh, which is the final product.

[0035] Example 3: Preparation of tilmicosin particles coated with nano-calcium carbonate / hydrogenated palm oil / carnauba wax (12% nano-calcium) A method for preparing rumen-coated granules of a drug with low water solubility includes the following steps: S1. Take 300g of tilmicosin raw material, 30g of hydroxypropyl methylcellulose (HPMC), 300g of microcrystalline cellulose, and 370g of corn starch, mix them evenly; add 350mL of purified water to prepare a soft material, and use an extrusion spheroidizer to prepare tilmicosin cores with a particle size of 40-60 mesh, and dry them for later use.

[0036] S2. Take 880 g of hydrogenated palm oil and place it in a container equipped with heating and stirring. Heat it to 90°C until it is completely melted. Separately, take 120 g of nano-calcium carbonate with an average particle size of 100 nm and slowly add it to the molten hydrogenated palm oil while running a high-speed shear press at 10,000 rpm. After the addition is complete, continue high-speed shearing and homogenization for 15 minutes to obtain a uniformly dispersed milky white inner coating solution. Keep it at 90°C and continuously stir slowly to prevent sedimentation.

[0037] S3. Take 500 g of the dried core prepared in S1 and place it in the hopper of a fluidized bed coating machine. Set the fluidized bed inlet air temperature to stabilize the material bed temperature at 35℃ and preheat the core for 10 minutes. Transfer the coating liquid prepared in S2 to a spray tank with an insulation jacket and a stirrer, maintaining the temperature at 90℃. Set the atomization pressure to 30MPa, the peristaltic pump inlet speed to a corresponding rotation speed of 13 r / min, and the fan frequency to 30 Hz. Begin spray coating, strictly controlling the bed temperature at 35±2℃ during the process. Stop coating when the inner coating material increases in weight to twice the weight of the core, obtaining inner-coated particles.

[0038] S4. Take 150 g of carnauba wax and heat it to 130°C to melt it, using it as the outer coating solution. Place 1000 g of the inner-coated particles obtained in step S3 back into the fluidized bed and preheat it to 35°C. Keep the molten carnauba wax at 130°C and perform a second coating by spraying at an atomization pressure of 30 MPa and a pump speed of 8 r / min until the outer coating layer increases in weight to 15% of the total particle weight at this point.

[0039] Step S5: After coating is completed, the product is passed through 30-mesh and 50-mesh standard sieves to collect coated particles between 30-mesh and 50-mesh, which is the final product.

[0040] Example 4: Preparation of nano-calcium carbonate / hydrogenated palm oil / carnauba wax coated tilmicosin particles (inner coating to core-wall ratio 1:1.75) A method for preparing rumen-coated granules of a drug with low water solubility includes the following steps: S1. Take 300g of tilmicosin raw material, 30g of hydroxypropyl methylcellulose (HPMC), 300g of microcrystalline cellulose, and 370g of corn starch, mix them evenly; add 350mL of purified water to prepare a soft material, and use an extrusion spheroidizer to prepare tilmicosin cores with a particle size of 40-60 mesh, and dry them for later use.

[0041] S2. Take 787.5 g of hydrogenated palm oil and place it in a container equipped with heating and stirring. Heat it to 90°C until it is completely melted. Separately, take 87.5 g of nano-calcium carbonate with an average particle size of 100 nm and slowly add it to the molten hydrogenated palm oil while running a high-speed shear press at 10,000 rpm. After the addition is complete, continue high-speed shearing and homogenization for 15 minutes to obtain a uniformly dispersed milky white inner coating solution. Keep it at 90°C and continuously stir slowly to prevent sedimentation.

[0042] S3. Take 500 g of the dried core prepared in S1 and place it in the hopper of a fluidized bed coating machine. Set the fluidized bed inlet air temperature to stabilize the material bed temperature at 35℃ and preheat the core for 10 minutes. Transfer the coating liquid prepared in S2 to a spray tank with an insulation jacket and a stirrer, maintaining the temperature at 90℃. Set the atomization pressure to 30MPa, the peristaltic pump inlet speed to a corresponding rotation speed of 13 r / min, and the fan frequency to 30 Hz. Begin spray coating, strictly controlling the bed temperature at 35±2℃ during the process. Stop coating when the inner coating material increases in weight to 1.75 times the weight of the core, obtaining inner-coated particles.

[0043] S4. Take 150 g of carnauba wax and heat it to 130°C to melt it, using it as the outer coating solution. Place 1000 g of the inner-coated particles obtained in step S3 back into the fluidized bed and preheat it to 35°C. Keep the molten carnauba wax at 130°C and perform a second coating by spraying at an atomization pressure of 30 MPa and a pump speed of 8 r / min until the outer coating layer increases in weight to 15% of the total particle weight at this point.

[0044] Step S5: After coating is completed, the product is passed through 30-mesh and 50-mesh standard sieves to collect coated particles between 30-mesh and 50-mesh, which is the final product.

[0045] Example 5: Preparation of nano-calcium carbonate / hydrogenated palm oil / carnauba wax coated tilmicosin particles (core-to-wall ratio 1:2.25) A method for preparing rumen-coated granules of a drug with low water solubility includes the following steps: S1. Take 300g of tilmicosin raw material, 30g of hydroxypropyl methylcellulose (HPMC), 300g of microcrystalline cellulose, and 370g of corn starch, mix them evenly; add 350mL of purified water to prepare a soft material, and use an extrusion spheroidizer to prepare tilmicosin cores with a particle size of 40-60 mesh, and dry them for later use.

[0046] S2. Take 1012.5 g of hydrogenated palm oil and place it in a container equipped with heating and stirring. Heat it to 90°C until it is completely melted. Separately, take 112.5 g of nano-calcium carbonate with an average particle size of 100 nm and slowly add it to the molten hydrogenated palm oil while running a high-speed shear press at 10000 rpm. After the addition is complete, continue high-speed shearing and homogenization for 15 minutes to obtain a uniformly dispersed milky white inner coating solution. Keep it at 90°C and continuously stir slowly to prevent sedimentation.

[0047] S3. Take 500 g of the dried core prepared in S1 and place it in the hopper of a fluidized bed coating machine. Set the fluidized bed inlet air temperature to stabilize the material bed temperature at 35℃ and preheat the core for 10 minutes. Transfer the coating liquid prepared in S2 to a spray tank with an insulation jacket and a stirrer, maintaining the temperature at 90℃. Set the atomization pressure to 30MPa, the peristaltic pump inlet speed to a corresponding rotation speed of 13 r / min, and the fan frequency to 30 Hz. Begin spray coating, strictly controlling the bed temperature at 35±2℃ during the process. Stop coating when the inner coating material increases in weight to 2.25 times the weight of the core, obtaining inner-coated particles.

[0048] S4. Take 150 g of carnauba wax and heat it to 130°C to melt it, using it as the outer coating solution. Place 1000 g of the inner-coated particles obtained in step S3 back into the fluidized bed and preheat it to 35°C. Keep the molten carnauba wax at 130°C and perform a second coating by spraying at an atomization pressure of 30 MPa and a pump speed of 8 r / min until the outer coating layer increases in weight to 15% of the total particle weight at this point.

[0049] Step S5: After coating is completed, the product is passed through 30-mesh and 50-mesh standard sieves to collect coated particles between 30-mesh and 50-mesh, which is the final product.

[0050] Example 6: Preparation of nano-calcium carbonate / hydrogenated palm oil / carnauba wax coated tilmicosin particles (13% coating) A method for preparing rumen-coated granules of a drug with low water solubility includes the following steps: S1. Take 300g of tilmicosin raw material, 30g of hydroxypropyl methylcellulose (HPMC), 300g of microcrystalline cellulose, and 370g of corn starch, mix them evenly; add 350mL of purified water to prepare a soft material, and use an extrusion spheroidizer to prepare tilmicosin cores with a particle size of 40-60 mesh, and dry them for later use.

[0051] S2. Take 900 g of hydrogenated palm oil and place it in a container equipped with heating and stirring. Heat it to 90°C until it is completely melted. Separately, take 100 g of nano-calcium carbonate with an average particle size of 100 nm and slowly add it to the molten hydrogenated palm oil while running a high-speed shear press at 10,000 rpm. After the addition is complete, continue high-speed shearing and homogenization for 15 minutes to obtain a uniformly dispersed milky white inner coating solution. Keep it at 90°C and continuously stir slowly to prevent sedimentation.

[0052] S3. Take 500 g of the dried core prepared in S1 and place it in the hopper of a fluidized bed coating machine. Set the fluidized bed inlet air temperature to stabilize the material bed temperature at 35℃ and preheat the core for 10 minutes. Transfer the coating liquid prepared in S2 to a spray tank with an insulation jacket and a stirrer, maintaining the temperature at 90℃. Set the atomization pressure to 30MPa, the peristaltic pump inlet speed to a corresponding rotation speed of 13 r / min, and the fan frequency to 30 Hz. Begin spray coating, strictly controlling the bed temperature at 35±2℃ during the process. Stop coating when the inner coating material increases in weight to twice the weight of the core, obtaining inner-coated particles.

[0053] S4. Take 130 g of carnauba wax and heat it to 130°C to melt it, using it as the outer coating solution. Place 1000 g of the inner-coated particles obtained in step S3 back into the fluidized bed and preheat it to 35°C. Keep the molten carnauba wax at 130°C and perform a second coating by spraying at an atomization pressure of 30 MPa and a pump speed of 8 r / min until the outer coating layer increases in weight to 13% of the total particle weight at this point.

[0054] Step S5: After coating is completed, the product is passed through 30-mesh and 50-mesh standard sieves to collect coated particles between 30-mesh and 50-mesh, which is the final product.

[0055] Example 7: Preparation of nano-calcium carbonate / hydrogenated palm oil / carnauba wax coated tilmicosin particles (17% coating) A method for preparing rumen-coated granules of a drug with low water solubility includes the following steps: S1. Take 300g of tilmicosin raw material, 30g of hydroxypropyl methylcellulose (HPMC), 300g of microcrystalline cellulose, and 370g of corn starch, mix them evenly; add 350mL of purified water to prepare a soft material, and use an extrusion spheronizer to prepare a core of oxytetracycline hydrochloride with a particle size of 40-60 mesh, and dry it for later use.

[0056] S2. Take 900 g of hydrogenated palm oil and place it in a container equipped with heating and stirring. Heat it to 90°C until it is completely melted. Separately, take 100 g of nano-calcium carbonate with an average particle size of 100 nm and slowly add it to the molten hydrogenated palm oil while running a high-speed shear press at 10,000 rpm. After the addition is complete, continue high-speed shearing and homogenization for 15 minutes to obtain a uniformly dispersed milky white inner coating solution. Keep it at 90°C and continuously stir slowly to prevent sedimentation.

[0057] S3. Take 500 g of the dried core prepared in S1 and place it in the hopper of a fluidized bed coating machine. Set the fluidized bed inlet air temperature to stabilize the material bed temperature at 35℃ and preheat the core for 10 minutes. Transfer the coating liquid prepared in S2 to a spray tank with an insulation jacket and a stirrer, maintaining the temperature at 90℃. Set the atomization pressure to 30MPa, the peristaltic pump inlet speed to a corresponding rotation speed of 13 r / min, and the fan frequency to 30 Hz. Begin spray coating, strictly controlling the bed temperature at 35±2℃ during the process. Stop coating when the inner coating material increases in weight to twice the weight of the core, obtaining inner-coated particles.

[0058] S4. Take 170 g of carnauba wax and heat it to 130°C to melt it, using it as the outer coating solution. Place 1000 g of the inner-coated particles obtained in step S3 back into the fluidized bed and preheat it to 35°C. Keep the molten carnauba wax at 130°C and perform a second coating by spraying at an atomization pressure of 30 MPa and a pump speed of 8 r / min until the outer coating layer increases in weight to 17% of the total particle weight at this point.

[0059] Step S5: After coating is completed, the product is passed through 30-mesh and 50-mesh standard sieves to collect coated particles between 30-mesh and 50-mesh, which is the final product.

[0060] Example 8: Preparation of chlortetracycline particles coated with nano-calcium carbonate / hydrogenated palm oil / carnauba wax A method for preparing rumen-coated granules of a drug with low water solubility includes the following steps: S1. Take 300g of chlortetracycline raw material, 30g of hydroxypropyl methylcellulose (HPMC), 300g of microcrystalline cellulose, and 370g of corn starch, mix them evenly; add 350mL of purified water to prepare a soft material, and use an extrusion rounding machine to prepare a chlortetracycline core with a particle size of 40-60 mesh, and dry it for later use.

[0061] S2. Take 900 g of hydrogenated palm oil and place it in a container equipped with heating and stirring. Heat it to 90°C until it is completely melted. Separately, take 100 g of nano-calcium carbonate with an average particle size of 100 nm and slowly add it to the molten hydrogenated palm oil while running a high-speed shear press at 10,000 rpm. After the addition is complete, continue high-speed shearing and homogenization for 15 minutes to obtain a uniformly dispersed milky white inner coating solution. Keep it at 90°C and continuously stir slowly to prevent sedimentation.

[0062] S3. Take 500 g of the dried core prepared in S1 and place it in the hopper of a fluidized bed coating machine. Set the fluidized bed inlet air temperature to stabilize the material bed temperature at 35℃ and preheat the core for 10 minutes. Transfer the coating liquid prepared in S2 to a spray tank with an insulation jacket and a stirrer, maintaining the temperature at 90℃. Set the atomization pressure to 30MPa, the peristaltic pump inlet speed to a corresponding rotation speed of 13 r / min, and the fan frequency to 30 Hz. Begin spray coating, strictly controlling the bed temperature at 35±2℃ during the process. Stop coating when the inner coating material increases in weight to twice the weight of the core, obtaining inner-coated particles.

[0063] S4. Take 150 g of carnauba wax and heat it to 130°C to melt it, using it as the outer coating solution. Place 1000 g of the inner-coated particles obtained in step S3 back into the fluidized bed and preheat it to 35°C. Keep the molten carnauba wax at 130°C and perform a second coating by spraying at an atomization pressure of 30 MPa and a pump speed of 8 r / min until the outer coating layer increases in weight to 15% of the total particle weight at this point.

[0064] Step S5: After coating is completed, the product is passed through 30-mesh and 50-mesh standard sieves to collect coated particles between 30-mesh and 50-mesh, which is the final product.

[0065] Example 9: Preparation of florfenicol particles coated with nano-calcium carbonate / hydrogenated palm oil / carnauba wax A method for preparing rumen-coated granules of a drug with low water solubility includes the following steps: S1. Take 300g of florfenicol raw material, 30g of hydroxypropyl methylcellulose (HPMC), 300g of microcrystalline cellulose, and 370g of corn starch, mix them evenly; add 350mL of purified water to prepare a soft material, and use an extrusion rounding machine to prepare florfenicol cores with a particle size of 40-60 mesh, and dry them for later use.

[0066] S2. Take 900 g of hydrogenated palm oil and place it in a container equipped with heating and stirring. Heat it to 90°C until it is completely melted. Separately, take 100 g of nano-calcium carbonate with an average particle size of 100 nm and slowly add it to the molten hydrogenated palm oil while running a high-speed shear press at 10,000 rpm. After the addition is complete, continue high-speed shearing and homogenization for 15 minutes to obtain a uniformly dispersed milky white inner coating solution. Keep it at 90°C and continuously stir slowly to prevent sedimentation.

[0067] S3. Take 500 g of the dried core prepared in S1 and place it in the hopper of a fluidized bed coating machine. Set the fluidized bed inlet air temperature to stabilize the material bed temperature at 35℃ and preheat the core for 10 minutes. Transfer the coating liquid prepared in S2 to a spray tank with an insulation jacket and a stirrer, maintaining the temperature at 90℃. Set the atomization pressure to 30MPa, the peristaltic pump inlet speed to a corresponding rotation speed of 13 r / min, and the fan frequency to 30 Hz. Begin spray coating, strictly controlling the bed temperature at 35±2℃ during the process. Stop coating when the inner coating material increases in weight to twice the weight of the core, obtaining inner-coated particles.

[0068] S4. Take 150 g of carnauba wax and heat it to 130°C to melt it, using it as the outer coating solution. Place 1000 g of the inner-coated particles obtained in step S3 back into the fluidized bed and preheat it to 35°C. Keep the molten carnauba wax at 130°C and perform a second coating by spraying at an atomization pressure of 30 MPa and a pump speed of 8 r / min until the outer coating layer increases in weight to 15% of the total particle weight at this point.

[0069] Step S5: After coating is completed, the product is passed through 30-mesh and 50-mesh standard sieves to collect coated particles between 30-mesh and 50-mesh, which is the final product.

[0070] Example 10: Preparation of enrofloxacin particles coated with nano-calcium carbonate / hydrogenated palm oil / carnauba wax A method for preparing rumen-coated granules of a drug with low water solubility includes the following steps: S1. Take 300g of enrofloxacin raw material, 30g of hydroxypropyl methylcellulose (HPMC), 300g of microcrystalline cellulose, and 370g of corn starch, mix them evenly; add 350mL of purified water to prepare a soft material, and use an extrusion rounding machine to prepare florfenicol cores with a particle size of 40-60 mesh, and dry them for later use.

[0071] S2. Take 900 g of hydrogenated palm oil and place it in a container equipped with heating and stirring. Heat it to 90°C until it is completely melted. Separately, take 100 g of nano-calcium carbonate with an average particle size of 100 nm and slowly add it to the molten hydrogenated palm oil while running a high-speed shear press at 10,000 rpm. After the addition is complete, continue high-speed shearing and homogenization for 15 minutes to obtain a uniformly dispersed milky white inner coating solution. Keep it at 90°C and continuously stir slowly to prevent sedimentation.

[0072] S3. Take 500 g of the dried core prepared in S1 and place it in the hopper of a fluidized bed coating machine. Set the fluidized bed inlet air temperature to stabilize the material bed temperature at 35℃ and preheat the core for 10 minutes. Transfer the coating liquid prepared in S2 to a spray tank with an insulation jacket and a stirrer, maintaining the temperature at 90℃. Set the atomization pressure to 30MPa, the peristaltic pump inlet speed to a corresponding rotation speed of 13 r / min, and the fan frequency to 30 Hz. Begin spray coating, strictly controlling the bed temperature at 35±2℃ during the process. Stop coating when the inner coating material increases in weight to twice the weight of the core, obtaining inner-coated particles.

[0073] S4. Take 150 g of carnauba wax and heat it to 130°C to melt it, using it as the outer coating solution. Place 1000 g of the inner-coated particles obtained in step S3 back into the fluidized bed and preheat it to 35°C. Keep the molten carnauba wax at 130°C and perform a second coating by spraying at an atomization pressure of 30 MPa and a pump speed of 8 r / min until the outer coating layer increases in weight to 15% of the total particle weight at this point.

[0074] Step S5: After coating is completed, the product is passed through 30-mesh and 50-mesh standard sieves to collect coated particles between 30-mesh and 50-mesh, which is the final product.

[0075] Comparative Example 1: Preparation of tilmicosin particles coated with hydrogenated palm oil / carnauba wax (0% nano-calcium) A method for preparing coated particles includes the following steps: S1. Take 300g of tilmicosin raw material, 30g of hydroxypropyl methylcellulose (HPMC), 300g of microcrystalline cellulose, and 370g of corn starch, mix them evenly; add 350mL of purified water to prepare a soft material, and use an extrusion rounding machine to prepare tilmicosin cores with a particle size of 40-80 mesh, and dry them for later use.

[0076] S2. Take 1000 g of hydrogenated palm oil and place it in a container equipped with heating and stirring. Heat it to 90°C until it is completely melted, and use it as the inner coating solution.

[0077] S3. Take 500 g of the dried core prepared in S1 and place it in the hopper of a fluidized bed coating machine. Set the fluidized bed inlet air temperature to stabilize the material bed temperature at 35℃ and preheat the core for 10 minutes. Transfer the coating liquid prepared in S2 to a spray tank with an insulated jacket and maintain the temperature at 90℃. Set the atomization pressure to 30MPa, the peristaltic pump inlet speed to a corresponding rotation speed of 13 r / min, and the fan frequency to 30 Hz. Begin spray coating, strictly controlling the bed temperature at 35±2℃ during the process. Stop coating when the coating material weight increases to twice the weight of the core.

[0078] S4. Take 150 g of carnauba wax and heat it to 130°C to melt it, using it as the outer coating solution. Place 1000 g of the inner-coated particles obtained in step S3 back into the fluidized bed and preheat it to 35°C. Keep the molten carnauba wax at 130°C and perform a second coating by spraying at an atomization pressure of 30 MPa and a pump speed of 8 r / min until the outer coating layer increases in weight to 15% of the total particle weight at this point.

[0079] Step S5: After coating is completed, the product is sieved in the same way as in Step S5 of Example 1 to obtain the final product.

[0080] Comparative Example 2: Preparation of tilmicosin particles coated with nano-calcium carbonate / hydrogenated palm oil / carnauba wax (nano-calcium 5%) A method for preparing coated particles includes the following steps: S1, the same as step S1 in Example 1.

[0081] S2. Take 950 g of hydrogenated palm oil and place it in a container equipped with heating and stirring. Heat it to 90°C until it is completely melted. Separately, take 50 g of nano-calcium carbonate with an average particle size of 100 nm and slowly add it to the molten hydrogenated palm oil while running a high-speed shear press at 10,000 rpm. After the addition is complete, continue high-speed shearing and homogenization for 15 minutes to obtain a uniformly dispersed milky white inner coating solution. Keep it at 90°C and continue to stir slowly to prevent sedimentation.

[0082] S3. Take 500 g of the dried core prepared in S1 and place it in the hopper of a fluidized bed coating machine. Set the fluidized bed inlet air temperature to stabilize the material bed temperature at 35℃ and preheat the core for 10 minutes. Transfer the coating liquid prepared in S2 to a spray tank with an insulated jacket and maintain the temperature at 90℃. Set the atomization pressure to 30MPa, the peristaltic pump inlet speed to a corresponding rotation speed of 13 r / min, and the fan frequency to 30 Hz. Begin spray coating, strictly controlling the bed temperature at 35±2℃ during the process. Stop coating when the weight of the inner coating material is twice the weight of the core, obtaining inner-coated particles.

[0083] S4. Take 150 g of carnauba wax and heat it to 130°C to melt it, using it as the outer coating solution. Place 1000 g of the inner-coated particles obtained in step S3 back into the fluidized bed and preheat it to 35°C. Keep the molten carnauba wax at 130°C and perform a second coating by spraying at an atomization pressure of 30 MPa and a pump speed of 8 r / min until the outer coating layer increases in weight to 15% of the total particle weight at this point.

[0084] Step S5: After coating is completed, the product is sieved in the same way as in Step S5 of Example 1 to obtain the final product.

[0085] Comparative Example 3: Preparation of tilmicosin particles coated with nano-calcium carbonate / hydrogenated palm oil / carnauba wax (nano-calcium 20%) A method for preparing coated particles includes the following steps: S1, same as step S1 in Example 1.

[0086] S2. Take 800 g of hydrogenated palm oil and place it in a container equipped with heating and stirring. Heat it to 90°C until it is completely melted. Separately, take 200 g of nano-calcium carbonate with an average particle size of 100 nm and slowly add it to the molten hydrogenated palm oil while running a high-speed shear press at 10,000 rpm. After the addition is complete, continue high-speed shearing and homogenization for 15 minutes to obtain a uniformly dispersed milky white inner coating solution. Keep it at 90°C and continuously stir slowly to prevent sedimentation.

[0087] S3. Take 500 g of the dried core prepared in S1 and place it in the hopper of a fluidized bed coating machine. Set the fluidized bed inlet air temperature to stabilize the material bed temperature at 35℃ and preheat the core for 10 minutes. Transfer the inner coating liquid prepared in S2 to a spray tank with an insulation jacket and a stirrer, maintaining the temperature at 90℃. Set the atomization pressure to 30MPa, the peristaltic pump inlet speed to a corresponding rotation speed of 13 r / min, and the fan frequency to 30 Hz. Begin spray coating, strictly controlling the bed temperature at 35±2℃ during the process. Stop coating when the inner coating material increases in weight to twice the weight of the core, obtaining inner-coated particles.

[0088] S4. Take 150 g of carnauba wax and heat it to 130°C to melt it, using it as the outer coating solution. Place 1000 g of the inner-coated particles obtained in step S3 back into the fluidized bed and preheat it to 35°C. Keep the molten carnauba wax at 130°C and perform a second coating by spraying at an atomization pressure of 30 MPa and a pump speed of 8 r / min until the outer coating layer increases in weight to 15% of the total particle weight at this point.

[0089] Step S5: After coating is completed, the product is sieved in the same way as in Step S5 of Example 1 to obtain the final product.

[0090] Comparative Example 4: Preparation of nano-calcium carbonate / hydrogenated palm oil / carnauba wax coated tilmicosin particles (inner core-to-wall ratio 1:1) A method for preparing coated particles includes the following steps: S1, same as step S1 in Example 1.

[0091] S2. Take 450 g of hydrogenated palm oil and place it in a container equipped with heating and stirring. Heat it to 90°C until it is completely melted. Separately, take 50 g of nano-calcium carbonate with an average particle size of 100 nm and slowly add it to the molten hydrogenated palm oil while running a high-speed shear press at 10,000 rpm. After the addition is complete, continue high-speed shearing and homogenization for 15 minutes to obtain a uniformly dispersed milky white inner coating solution. Keep it at 90°C and continue to stir slowly to prevent sedimentation.

[0092] S3. Take 500 g of the dried core prepared in S1 and place it in the hopper of a fluidized bed coating machine. Set the fluidized bed inlet air temperature to stabilize the material bed temperature at 35℃ and preheat the core for 10 minutes. Transfer the inner coating liquid prepared in S2 to a spray tank with an insulation jacket and a stirrer, maintaining the temperature at 90℃. Set the atomization pressure to 30MPa, the peristaltic pump inlet speed to a corresponding rotation speed of 13 r / min, and the fan frequency to 30 Hz. Begin spray coating, strictly controlling the bed temperature at 35±2℃ during the process. Stop coating when the inner coating material increases in weight to 1 times the weight of the core, obtaining inner-coated particles.

[0093] S4. Take 150 g of carnauba wax and heat it to 130°C to melt it, using it as the outer coating solution. Place 1000 g of the inner-coated particles obtained in step S3 back into the fluidized bed and preheat it to 35°C. Keep the molten carnauba wax at 130°C and perform a second coating by spraying at an atomization pressure of 30 MPa and a pump speed of 8 r / min until the outer coating layer increases in weight to 15% of the total particle weight at this point.

[0094] Step S5: After coating is completed, the product is sieved in the same way as in Step S5 of Example 1 to obtain the final product.

[0095] Comparative Example 5: Preparation of nano-calcium carbonate / hydrogenated palm oil / carnauba wax coated tilmicosin particles (inner core-to-wall ratio 1:3) A method for preparing coated particles includes the following steps: S2. Take 1350 g of hydrogenated palm oil and place it in a container equipped with heating and stirring. Heat it to 90°C until it is completely melted. Separately, take 150 g of nano-calcium carbonate with an average particle size of 100 nm and slowly add it to the molten hydrogenated palm oil while running a high-speed shear press at 10000 rpm. After the addition is complete, continue high-speed shearing and homogenization for 15 minutes to obtain a uniformly dispersed milky white inner coating solution. Keep it at 90°C and continuously stir slowly to prevent sedimentation.

[0096] S3. Take 500 g of the dried core prepared in S1 and place it in the hopper of a fluidized bed coating machine. Set the fluidized bed inlet air temperature to stabilize the material bed temperature at 35℃ and preheat the core for 10 minutes. Transfer the inner coating liquid prepared in S2 to a spray tank with an insulation jacket and a stirrer, maintaining the temperature at 90℃. Set the atomization pressure to 30MPa, the peristaltic pump inlet speed to a corresponding rotation speed of 13 r / min, and the fan frequency to 30 Hz. Begin spray coating, strictly controlling the bed temperature at 35±2℃ during the process. Stop coating when the inner coating material increases in weight to 3 times the weight of the core, obtaining inner-coated particles.

[0097] S4. Take 150 g of carnauba wax and heat it to 130°C to melt it, using it as the outer coating solution. Place 1000 g of the inner-coated particles obtained in step S3 back into the fluidized bed and preheat it to 35°C. Keep the molten carnauba wax at 130°C and perform a second coating by spraying at an atomization pressure of 30 MPa and a pump speed of 8 r / min until the outer coating layer increases in weight to 15% of the total particle weight at this point.

[0098] Step S5: After coating is completed, the product is sieved in the same way as in Step S5 of Example 1 to obtain the final product.

[0099] Comparative Example 6: Preparation of tilmicosin particles coated with nano-calcium carbonate / hydrogenated palm oil / carnauba wax (8% outer coating) A method for preparing coated particles includes the following steps: S1, same as step S1 in Example 1.

[0100] S2. Take 900 g of hydrogenated palm oil and place it in a container equipped with heating and stirring. Heat it to 90°C until it is completely melted. Separately, take 100 g of nano-calcium carbonate with an average particle size of 100 nm and slowly add it to the molten hydrogenated palm oil while running a high-speed shear press at 10,000 rpm. After the addition is complete, continue high-speed shearing and homogenization for 15 minutes to obtain a uniformly dispersed milky white inner coating solution. Keep it at 90°C and continuously stir slowly to prevent sedimentation.

[0101] S3. Take 500 g of the dried core prepared in S1 and place it in the hopper of a fluidized bed coating machine. Set the fluidized bed inlet air temperature to stabilize the material bed temperature at 35℃ and preheat the core for 10 minutes. Transfer the inner coating liquid prepared in S2 to a spray tank with an insulation jacket and a stirrer, maintaining the temperature at 90℃. Set the atomization pressure to 30MPa, the peristaltic pump inlet speed to a corresponding rotation speed of 13 r / min, and the fan frequency to 30 Hz. Begin spray coating, strictly controlling the bed temperature at 35±2℃ during the process. Stop coating when the inner coating material increases in weight to 3 times the weight of the core, obtaining inner-coated particles.

[0102] S4. Take 80 g of carnauba wax and heat it to 130°C to melt it, using it as the outer coating solution. Place 1000 g of the inner-coated particles obtained in step S3 back into the fluidized bed and preheat it to 35°C. Keep the molten carnauba wax at 130°C and perform a second coating by spraying at an atomization pressure of 30 MPa and a pump speed of 8 r / min until the outer coating layer increases in weight to 8% of the total particle weight at this point.

[0103] Step S5: After coating is completed, the product is sieved in the same way as in Step S5 of Example 1 to obtain the final product.

[0104] Comparative Example 7: Preparation of nano-calcium carbonate / hydrogenated palm oil / carnauba wax coated tilmicosin particles (25% outer coating) A method for preparing coated particles includes the following steps: S1, same as step S1 in Example 1.

[0105] S2. Take 900 g of hydrogenated palm oil and place it in a container equipped with heating and stirring. Heat it to 90°C until it is completely melted. Separately, take 100 g of nano-calcium carbonate with an average particle size of 100 nm and slowly add it to the molten hydrogenated palm oil while running a high-speed shear press at 10,000 rpm. After the addition is complete, continue high-speed shearing and homogenization for 15 minutes to obtain a uniformly dispersed milky white inner coating solution. Keep it at 90°C and continuously stir slowly to prevent sedimentation.

[0106] S3. Take 500 g of the dried core prepared in S1 and place it in the hopper of a fluidized bed coating machine. Set the fluidized bed inlet air temperature to stabilize the material bed temperature at 35℃ and preheat the core for 10 minutes. Transfer the inner coating liquid prepared in S2 to a spray tank with an insulation jacket and a stirrer, maintaining the temperature at 90℃. Set the atomization pressure to 30MPa, the peristaltic pump inlet speed to a corresponding rotation speed of 13 r / min, and the fan frequency to 30 Hz. Begin spray coating, strictly controlling the bed temperature at 35±2℃ during the process. Stop coating when the inner coating material increases in weight to 3 times the weight of the core, obtaining inner-coated particles.

[0107] S4. Take 250 g of carnauba wax and heat it to 130°C to melt it, using it as the outer coating solution. Place 1000 g of the inner-coated particles obtained in step S3 back into the fluidized bed and preheat it to 35°C. Keep the molten carnauba wax at 130°C and perform a second coating by spraying at an atomization pressure of 30 MPa and a pump speed of 8 r / min until the outer coating layer increases in weight to 25% of the total particle weight at this point.

[0108] Step S5: After coating is completed, the product is sieved in the same way as in Step S5 of Example 1 to obtain the final product.

[0109] Example 1: Evaluation of in vitro release performance To evaluate the rumen-protective effect and intestinal-targeted release performance of the coated particles prepared in each embodiment and comparative example, a multi-stage in vitro release test was conducted using a biomimetic dissolution system.

[0110] Method: Accurately weigh approximately 1.0 g (accurate to 0.1 mg) of each sample and place it in a pre-prepared 80-mesh nylon bag (6 cm × 9 cm), then seal the bag. Prepare 18 bags in parallel for each sample. First, randomly select 3 bags and determine their total drug content (D0). Immerse the remaining sample bags in dissolution cups containing the corresponding simulated digestion solution (conforming to Method II of the Dissolution Test in the Chinese Pharmacopoeia). Set the dissolution apparatus parameters as follows: paddle speed 50 rpm, temperature 38.0 ± 0.5°C. Change the medium in the following order: (1) The samples were treated in simulated rumen fluid (pH 6.8 buffer, containing microbial enzymes) for 12 hours and 24 hours. Three bags of samples were taken at each time point to determine the remaining drug content and calculate the cumulative release rate.

[0111] (2) Transfer the remaining sample into simulated gastric fluid (pH 2.0 hydrochloric acid buffer) for 2 hours, and take out 3 bags of sample for testing.

[0112] (3) Transfer the remaining samples into simulated small intestinal fluid (pH 6.8 phosphate buffer, containing pancreatic enzymes and bile salts) for 6 hours, and take out 3 bags of samples for testing.

[0113] (4) Transfer the last 3 bags of samples into simulated colon fluid (pH 7.4 phosphate buffer) for 12 hours and then measure them.

[0114] Calculate the average cumulative release rate at each time point.

[0115]

[0116] Rumen release rate = Drug release rate after 12 hours of colonic fluid treatment - Drug release rate after 24 hours of rumen fluid treatment; the larger this value, the higher the proportion of drug effectively released in the abomasum and intestines after bypassing rumen release, and the better the formulation performance. The results are shown in Table 1; Table 1

[0117] As shown in the table above, compared with Comparative Example 1, the rumen-passing release rates of Example 1 and Comparative Example 1 were 85.3% and 68.6%, respectively. This indicates that compared with single hydrogenated palm oil coating, the coated particles with 10% nano-calcium carbonate added to hydrogenated palm oil have a higher intestinal release rate under the same core-to-wall ratio. The rumen-passing release rates of Examples 1, 2, and 3 were 85.3%, 84.7%, and 84.6%, respectively, which were higher than the 73.4% and 77.5% of Comparative Examples 2 and 3. This indicates that under the same core-to-wall ratio and outer coating conditions, when the amount of nano-calcium carbonate added to hydrogenated palm oil is 8%~12%, its overall release effect is better. The rumen-transfer release rates of Examples 1, 4, 6 and Comparative Examples 4, 5 were 85.3%, 82.6%, 83.8%, 73.5%, and 73.1%, respectively, indicating that the overall release effect was best when the core-to-wall ratio was between 1:1.75 and 1:2.25. In addition, the rumen-transfer release rates of Examples 1 to 7 of the present invention were between 80% and 86%, indicating that the seven examples of the present invention had a higher effective drug release rate under in vitro conditions than the comparative examples. Furthermore, the effective release rates of Examples 8, 9, and 10 were all above 80%, demonstrating the universality of the coating.

[0118] Example 2: Evaluation of in vivo release performance To evaluate the rumen-protective properties and intestinal release behavior of the coated granules of this invention in the real digestive tract environment of ruminants, the following in vivo experiments were conducted using a sheep model with a rumen fistula.

[0119] 2.1 Experimental Animals and Materials Three healthy sheep aged 24-29 months with rumen fistulas and similar weights were selected and housed in separate pens. They were allowed to acclimate to the environment for one week before the experiment, with free access to water and a complete diet fed at regular intervals each day.

[0120] Test samples: Tilmicosin rumen-coated granules prepared in Examples 1-10 and Comparative Examples 1-7.

[0121] 2.2 Test Methods 2.21 Rumen stability test: Accurately weigh 0.1 g (accurate to 0.1 mg) of each sample and place it into an 80-mesh nylon mesh bag (6 cm × 9 cm), then seal the bag. Prepare three replicates for each sample at each time point. After morning feeding, insert the nylon bag directly into the rumen sac of the sheep through a rumen fistula (three sample bags are tied to one end of a flexible tube approximately 50 cm long, with the other end of the tube fixed to the fistula cap for easy retrieval). Remove the corresponding nylon bag 24 hours after insertion. Gently rinse the removed sample with distilled water and dry it at 40°C to constant weight. Carefully collect all particles from the nylon bag, determine the residual drug content, and calculate the cumulative release rate in the rumen at that time point.

[0122] 2.22 Whole digestive tract pass-through release test: Take 0.1g of each sample, place it in a nylon bag, and insert it into the rumen. Allow the nylon bag to pass naturally through the digestive tract with the food. Collect all feces daily, and recover the nylon bag by washing and sieving. After washing and drying the recovered samples in the same way, determine the residual drug content and calculate the total cumulative release rate after excretion in the feces.

[0123] 2.23 Data Processing and Indicators Based on the measurement results, the key indicators are calculated using the following formula: Rumen release rate (12h / 24h): = (1 - Residual drug amount in the sample after a specific rumen treatment time / Initial total drug amount in the sample) × 100% Effective release rate = drug release rate after being excreted in feces Drug release rate after 24 hours of rumen treatment. The results of the in vivo release performance evaluation are shown in Table 2 below: Table 2

[0124] As shown in the table above, the cumulative release rate of all Examples 1-5 of this invention in the rumen over 24 hours was controlled below 20%, demonstrating good rumen stability. In contrast, Comparative Examples 4 and 7 had higher rumen release rates (>24%) due to their excessively large core-to-wall ratio or thinner outer coating; Comparative Examples 5 and 7 had lower release rates, but insufficient subsequent intestinal release; Comparative Examples 2 and 3 each had advantages in rumen and intestinal release rates, but their overall rumen-free release rates were low, indicating that both excessively high and low levels of nano-calcium carbonate addition would reduce the rumen-free release rate.

[0125] The rumen-passing release rates of Examples 1-10 all exceeded 80%, significantly higher than those of the comparative examples. This confirms that the coating layer of this invention, consisting of an inner layer of nano-calcium carbonate / hydrogenated palm oil and an outer layer of carnauba wax, can achieve a targeted delivery effect of "low rumen release and high intestinal release." Consistent with the overall in vitro experimental results, in vivo experiments further demonstrated that compared to the single hydrogenated palm oil as the middle coating in Comparative Example 1, adding 10% nano-calcium carbonate in Example 1 increased the rumen-passing release rate from 73.7% to 85.3%. In Examples 1-3, the nano-calcium carbonate content in the range of 8%-12% exhibited the best synergistic release-triggering effect. In Examples 1, 4, and 5, a core-to-wall ratio in the range of 1:1.75-2.25 achieved efficient intestinal release while ensuring rumen protection.

[0126] In summary, the rumen-coated granules of the present invention, which exhibit low water solubility, possess excellent rumen permeability and intestinal-targeted release characteristics. Their rumen-transfer release rate exceeds 80%, significantly superior to traditional single-fat coatings and control samples with inappropriate parameters. This result, corroborated by in vitro release data, fully demonstrates the technical advantages of the present invention's double-layer coating design and the addition of nano-calcium carbonate, providing a solid basis for its practical application in improving the oral bioavailability of drugs in ruminants.

[0127] Finally, it should be noted that the above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A rumen-coated enteric-coated granule for a low-water-soluble drug, characterized in that, include: The core of at least one low-water-soluble active pharmaceutical ingredient, A coating layer covering the core; The coating layer includes an inner coating layer and an outer coating layer covering the inner coating layer; and the inner coating layer is formed of a composite coating material of hydrogenated palm oil and nano-sized calcium carbonate.

2. The low water-soluble drug enteric-coated granules according to claim 1, characterized in that, The weight ratio of the core to the coating layer is 1:1.5~2.

5.

3. The low water-soluble drug enteric-coated granules according to claim 1, characterized in that, The mass percentage of the nano-calcium carbonate in the composite coating material is 10%-20%.

4. The low water-soluble drug enteric-coated granules according to claim 1, characterized in that, The average particle size of the nano-sized calcium carbonate is no greater than 100 nanometers.

5. The low water-soluble drug enteric-coated granules according to claim 1, characterized in that, The outer coating layer contains carnauba wax; and / or, the weight of the outer coating layer accounts for 8%-18% of the total weight of the entire coated particles.

6. The low water-soluble drug enteric-coated granules according to claim 1, characterized in that, The low water-soluble active pharmaceutical ingredient is selected from one or more of antibiotics, vitamins, amino acids, and trace elements.

7. A method for preparing rumen-coated enteric-coated granules of a low water-soluble drug according to any one of claims 1-6, characterized in that, Includes the following steps: S1. Preparation of a core containing a low-water-soluble pharmaceutical active ingredient; S2. Heat and melt hydrogenated palm oil, add nano-calcium carbonate under high-speed shear, and disperse homogeneously to obtain an inner coating solution; S3. Place the core in a fluidized bed and spray the inner coating liquid onto the surface of the core to form an inner coating layer; S4. Melt carnauba wax and apply a second coating to the particles of the inner coating layer obtained in step S3 to form an outer coating layer, thus obtaining the product.

8. The method for preparing rumen-coated enteric-coated granules of low water-soluble drugs according to claim 7, characterized in that, In step S2, the rotation speed of the high-speed shearing is 8000-12000 rpm, and the homogenization time is 10-20 minutes; And / or, in step S3, the bed temperature of the fluidized bed is controlled at 30-40°C, and the spray temperature of the coating liquid is maintained at 70-90°C; And / or, in step S4, the spray temperature of the carnauba wax is maintained at 100-120°C.

9. A feed additive, characterized in that, It contains rumen-coated enteric-coated particles containing low water-soluble drugs as described in any one of claims 1-6.

10. Use of the rumen-exposed enteric-coated granules of any one of claims 1-6 in the preparation of rumen-exposed targeted release drugs for ruminants.

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