Water-soluble drug gastroresistant coating granules, and preparation method and application thereof

Abstract

The present application relates to the technical field of veterinary medicine preparation, and particularly relates to a water-soluble medicine gastro-resistant and enteric-coated granule, a preparation method and application thereof, the coated granule comprising: an inner core of at least one water-soluble medicine active ingredient, a coating layer coated outside the inner core; and the coating layer is formed by a composite coating material of hydrogenated palm oil and lipophilic hydrophobic nano active light calcium carbonate. The present application has the advantages that the nano calcium carbonate is used to form pores in the true stomach by acid reaction and to produce gas by saponification with fatty acids in the intestinal tract, so that the water-soluble medicine is efficiently protected in the rumen and rapidly and completely released in the intestinal tract. In vitro tests show that the effective release rate can reach more than 79%, which is significantly better than the traditional coating, and has a broad clinical application prospect.

Description

Technical Field

[0001] This invention relates to the field of veterinary drug formulation technology, and in particular to a water-soluble drug rumen-coated enteric granule, 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 water-soluble drugs, traditional fat coating technology faces an inherent and irreconcilable contradiction. Water-soluble drugs dissolve readily in rumen fluid, even with trace amounts of water permeating the coating layer, creating a hypertonic solution within the core and generating significant osmotic pressure. This osmotic pressure drives more water in, accelerating drug dissolution and severely impairing rumen protection. Therefore, it is usually necessary to increase the thickness of the coating layer to enhance the barrier effect. However, once this thick coating layer enters the abomasum and intestines, the coating may decompose slowly or incompletely, hindering the timely and sufficient release of the drug, thus reducing the benefits of rumen protection and ultimately leading 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 highly water-soluble drug molecules.

[0006] Therefore, there is an urgent need in this field to develop a novel rumen-coated particle that can not only provide a robust and reliable protection for the core of water-soluble drugs 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 water-soluble drug enteric-coated granule for rumen, its preparation method, and its application. By adding nano-calcium carbonate to the inner coating layer, it reacts with hydrochloric acid in the abomasum, dissolving in the coating to form micropores, increasing 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 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 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, ensuring high dispersibility of calcium carbonate in hydrogenated palm oil and uniformity of the coating film. Furthermore, the addition of nano-calcium carbonate to the coating also increases particle hardness, reducing 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 intestinal administration of various drugs to ruminants.

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

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

[0010] Furthermore, the weight ratio of the core to the inner coating layer is 1:3.5~4.5.

[0011] Furthermore, the mass percentage of the nano-calcium carbonate in the composite coating material is 8%-12%; Furthermore, the average particle size of the nano-sized calcium carbonate is no greater than 100 nanometers.

[0012] Furthermore, the water-soluble active pharmaceutical ingredient is selected from one or more of water-soluble antibiotics, vitamins, amino acids, and trace elements.

[0013] Another method for preparing the above-mentioned water-soluble drug enteric-coated granules includes the following steps: S1. Preparation of a core containing a water-soluble active pharmaceutical ingredient; S2. Heat and melt hydrogenated palm oil, add nano-calcium carbonate under high-speed shear, and disperse homogeneously to obtain a coating solution; S3. Place the core in a fluidized bed and spray the coating liquid onto the surface of the core to form a coating layer, thus obtaining the core.

[0014] 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; A feed additive is also provided, comprising rumen-coated enteric granules of a water-soluble drug as described above.

[0015] Finally, the use of the above-mentioned water-soluble drug rumen-coated enteric particles in the preparation of rumen-targeted release drugs for ruminants is provided.

[0016] 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 water-soluble saponins, synergistically promoting the complete disintegration of the coating layer. This dual response of acid etching for pore creation and saponification for gas production powerfully drives the rapid release of the core drug.

[0017] By optimizing the content of nano-calcium carbonate in the coating layer to 8%-12% and the core-to-wall ratio to 1:3.5-1:4.5, the particles of this invention exhibit excellent protective properties with a 24-hour release rate of less than 15% in simulated rumen fluid. Furthermore, they can be rapidly released in subsequent simulated intestinal fluid, with an effective release rate of over 79% after passing through the rumen, perfectly resolving the contradictions in traditional technologies.

[0018] The preparation method of this invention is based on a mature fluidized bed coating process, which is easy to industrialize. This coating system is suitable for a variety of water-soluble active ingredients that are easily degraded in the rumen, and has strong versatility. Attached Figure Description

[0019] Figure 1 This is a schematic diagram of the structure of the rumen-coated granules of the water-soluble drug of the present invention; Figure 2 This demonstrates the gas production situation of Example 1 and Comparative Example 8 after 2 hours of treatment with real gastric juice according to the present invention; Figure 3This demonstrates the morphological changes of intestinal fluid before and after 6 hours of treatment in Example 1 and Comparative Example 2 of the present invention; Figure 4 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

[0020] 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.

[0021] 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.

[0022] Unless otherwise specified, the reagents and raw materials used in the embodiments and comparative examples of this invention are commercially available.

[0023] Example 1: Preparation of nano-calcium carbonate / hydrogenated palm oil hydrochloride doxycycline-coated microspheres (10% nano-calcium) A method for preparing rumen-coated enteric-coated granules of a water-soluble drug includes the following steps: S1. Take 250g of doxycycline hydrochloride raw material, 30g of hydroxypropyl methylcellulose (HPMC), 300g of microcrystalline cellulose, and 420g of corn starch, mix them evenly, add 350mL of purified water to prepare a soft material, and use an extrusion spheroidizer to prepare doxycycline cores with a particle size of 40-60 mesh, and dry them for later use.

[0024] S2. Take 1800 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 10000 rpm. After the addition is complete, continue high-speed shearing and homogenization for 15 minutes to obtain a uniformly dispersed milky white coating solution. Keep it at 90°C and continuously stir slowly to prevent sedimentation.

[0025] 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 76℃. 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 increases in weight to 4 times the weight of the core, obtaining coated particles.

[0026] Step S4: After coating, pass the product through 20-mesh and 30-mesh standard sieves, and collect the coated particles between 20-mesh and 30-mesh to obtain the final product (see...). Figure 1 ).

[0027] Example 2: Preparation of nano-calcium carbonate / hydrogenated palm oil coated doxycycline hydrochloride particles (12% nano-calcium) A method for preparing rumen-coated granules of a water-soluble drug includes the following steps: S1. Take 250g of doxycycline hydrochloride raw material, 30g of hydroxypropyl methylcellulose (HPMC), 300g of microcrystalline cellulose, and 420g of corn starch, mix them evenly, add 350mL of purified water to prepare a soft material, and use an extrusion spheroidizer to prepare doxycycline cores with a particle size of 40-60 mesh, and dry them for later use.

[0028] S2. Take 1760 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 240 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 coating solution. Keep it at 90°C and continuously stir slowly to prevent sedimentation.

[0029] 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 76℃. 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 increases in weight to 4 times the weight of the core, obtaining coated particles.

[0030] S4. After coating, the product is passed through 20-mesh and 30-mesh standard sieves. Coated particles between 20-mesh and 30-mesh are collected to obtain the final product.

[0031] Example 3: Preparation of nano-calcium carbonate / hydrogenated palm oil coated doxycycline hydrochloride particles (8% nano-calcium) A method for preparing rumen-coated granules of a water-soluble drug includes the following steps: S1. Take 250g of doxycycline hydrochloride raw material, 30g of hydroxypropyl methylcellulose (HPMC), 300g of microcrystalline cellulose, and 420g of corn starch, mix them evenly, add 350mL of purified water to prepare a soft material, and use an extrusion spheroidizer to prepare doxycycline cores with a particle size of 40-60 mesh, and dry them for later use.

[0032] S2. Take 1840 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 160 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 coating solution. Keep it at 90°C and continuously stir slowly to prevent sedimentation.

[0033] 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 76℃. 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 increases in weight to 4 times the weight of the core, obtaining coated particles.

[0034] S5. After coating, the product is passed through 20-mesh and 30-mesh standard sieves. Coated particles between 20-mesh and 30-mesh are collected to obtain the final product.

[0035] Example 4: Preparation of nano-calcium carbonate / hydrogenated palm oil coated doxycycline hydrochloride particles (core-to-wall ratio 1:3.5) A method for preparing rumen-coated granules of a water-soluble drug includes the following steps: S1. Take 250g of doxycycline hydrochloride raw material, 30g of hydroxypropyl methylcellulose (HPMC), 300g of microcrystalline cellulose, and 420g of corn starch, mix them evenly, add 350mL of purified water to prepare a soft material, and use an extrusion spheroidizer to prepare doxycycline cores with a particle size of 40-60 mesh, and dry them for later use.

[0036] S2. Take 1800 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 10000 rpm. After the addition is complete, continue high-speed shearing and homogenization for 15 minutes to obtain a uniformly dispersed milky white 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 76℃. 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 increases in weight to 3.5 times the weight of the core, obtaining coated particles.

[0038] S4. After coating, the product is passed through 20-mesh and 30-mesh standard sieves. Coated particles between 20-mesh and 30-mesh are collected to obtain the final product.

[0039] Example 5: Preparation of nano-calcium carbonate / hydrogenated palm oil coated doxycycline hydrochloride particles (core-to-wall ratio 1:4.5) A method for preparing rumen-coated granules of a water-soluble drug includes the following steps: S1. Take 250g of doxycycline hydrochloride raw material, 30g of hydroxypropyl methylcellulose (HPMC), 300g of microcrystalline cellulose, and 420g of corn starch, mix them evenly, add 350mL of purified water to prepare a soft material, and use an extrusion spheroidizer to prepare doxycycline cores with a particle size of 40-60 mesh, and dry them for later use.

[0040] S2. Take 1800 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 10000 rpm. After the addition is complete, continue high-speed shearing and homogenization for 15 minutes to obtain a uniformly dispersed milky white coating solution. Keep it at 90°C and continuously stir slowly to prevent sedimentation.

[0041] 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 76℃. 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 increases in weight to 4.5 times the weight of the core, obtaining coated particles.

[0042] S4. After coating, the product is passed through 20-mesh and 30-mesh standard sieves. Coated particles between 20-mesh and 30-mesh are collected to obtain the final product.

[0043] Example 6: Preparation of nano-calcium carbonate / hydrogenated palm oil hydrochloride tilmicosin phosphate coated particles A method for preparing rumen-coated granules of a water-soluble drug includes the following steps: S1. Take 250g of tilmicosin hydrochloride raw material, 30g of hydroxypropyl methylcellulose (HPMC), 300g of microcrystalline cellulose, and 420g of corn starch, mix them evenly, add 350mL of purified water to prepare a soft material, and use an extrusion spheroidizer to prepare tilmicosin hydrochloride cores with a particle size of 40-60 mesh, and dry them for later use.

[0044] S2. Take 1800 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 10000 rpm. After the addition is complete, continue high-speed shearing and homogenization for 15 minutes to obtain a uniformly dispersed milky white coating solution. Keep it at 90°C and continuously stir slowly to prevent sedimentation.

[0045] 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 76℃. 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 increases in weight to 4.5 times the weight of the core, obtaining coated particles.

[0046] S4. After coating, the product is passed through 20-mesh and 30-mesh standard sieves. Coated particles between 20-mesh and 30-mesh are collected to obtain the final product.

[0047] Example 7: Preparation of nano-calcium carbonate / hydrogenated palm oil hydrochloride oxytetracycline coated particles A method for preparing rumen-coated granules of a water-soluble drug includes the following steps: S1. Take 250g of oxytetracycline hydrochloride raw material, 30g of hydroxypropyl methylcellulose (HPMC), 300g of microcrystalline cellulose, and 420g of corn starch, mix them evenly, add 350mL of purified water to prepare a soft material, and use an extrusion spheroidizer to prepare an oxytetracycline hydrochloride core with a particle size of 40-60 mesh, and dry it for later use.

[0048] S2. Take 1800 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 10000 rpm. After the addition is complete, continue high-speed shearing and homogenization for 15 minutes to obtain a uniformly dispersed milky white coating solution. Keep it at 90°C and continuously stir slowly to prevent sedimentation.

[0049] 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 76℃. 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 increases in weight to 4.5 times the weight of the core, obtaining coated particles.

[0050] S4. After coating, the product is passed through 20-mesh and 30-mesh standard sieves. Coated particles between 20-mesh and 30-mesh are collected to obtain the final product.

[0051] Example 8: Preparation of nano-calcium carbonate / hydrogenated palm oil tartrate tylosin-coated particles A method for preparing rumen-coated granules of a water-soluble drug includes the following steps: S1. Take 250g of tylosin tartrate raw material, 30g of hydroxypropyl methylcellulose (HPMC), 300g of microcrystalline cellulose, and 420g of corn starch, mix them evenly, add 350mL of purified water to prepare a soft material, and use an extrusion spheroidizer to prepare a tylosin tartrate core with a particle size of 40-60 mesh, and dry it for later use.

[0052] S2. Take 1800 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 10000 rpm. After the addition is complete, continue high-speed shearing and homogenization for 15 minutes to obtain a uniformly dispersed milky white coating solution. Keep it at 90°C and continuously stir slowly to prevent sedimentation.

[0053] 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 76℃. 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 increases in weight to 4.5 times the weight of the core, obtaining coated particles.

[0054] S4. After coating, the product is passed through 20-mesh and 30-mesh standard sieves. Coated particles between 20-mesh and 30-mesh are collected to obtain the final product.

[0055] Example 9: Preparation of nano-calcium carbonate / hydrogenated palm oil vitamin C coated particles A method for preparing rumen-coated granules of a water-soluble drug includes the following steps: S1. Take 250g of vitamin C raw material, 30g of hydroxypropyl methylcellulose (HPMC), 300g of microcrystalline cellulose, and 420g of corn starch, mix them evenly; add 350mL of purified water to prepare a soft material, and use an extrusion spheroidizer to prepare vitamin C kernels with a particle size of 40-60 mesh, and dry them for later use.

[0056] S2. Take 1800 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 10000 rpm. After the addition is complete, continue high-speed shearing and homogenization for 15 minutes to obtain a uniformly dispersed milky white 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 76℃. 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 increases in weight to 4.5 times the weight of the core, obtaining coated particles.

[0058] S4. After coating, the product is passed through 20-mesh and 30-mesh standard sieves. Coated particles between 20-mesh and 30-mesh are collected to obtain the final product.

[0059] Comparative Example 1: Preparation of doxycycline hydrochloride particles coated with single-layer hydrogenated palm oil (core-to-wall ratio 1:3) A method for preparing coated particles includes the following steps: S1. Take 250g of doxycycline hydrochloride raw material, 30g of hydroxypropyl methylcellulose (HPMC), 300g of microcrystalline cellulose, and 420g of corn starch, mix them evenly, add 350mL of purified water to prepare a soft material, and use an extrusion spheroidizer to prepare doxycycline cores with a particle size of 40-60 mesh, and dry them for later use.

[0060] S2. Take 1500 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 a coating solution.

[0061] 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 76℃. 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 increases in weight to three times the weight of the core.

[0062] S4. After coating, the product is passed through 20-mesh and 30-mesh standard sieves. Coated particles between 20-mesh and 30-mesh are collected to obtain the final product.

[0063] Comparative Example 2: Preparation of doxycycline hydrochloride particles coated with single-layer hydrogenated palm oil (core-to-wall ratio 1:4) A method for preparing coated particles includes the following steps: S1, same as step S1 in Comparative Example 1.

[0064] S2. Take 2000 g of hydrogenated palm oil, heat it to 90℃ to melt it, and use it as a coating solution.

[0065] S3. Take 500 g of the dried kernel prepared in S1 above and coat it according to the fluidized bed parameters of step S3 in Comparative Example 1 until the weight of the coating material increases to 4 times the weight of the kernel.

[0066] S4. After coating, the product is sieved in the same way as in step S4 of Comparative Example 1 to obtain the final product.

[0067] Comparative Example 3: Preparation of doxycycline hydrochloride particles coated with single-layer hydrogenated palm oil (core-to-wall ratio 1:5) A method for preparing coated particles includes the following steps: S1, same as step S1 in Comparative Example 1.

[0068] S2. Take 2500 g of hydrogenated palm oil, heat it to 90℃ to melt it, and use it as a coating solution.

[0069] S3. Take 500 g of the dried kernel prepared in S1 above and coat it according to the fluidized bed parameters of step S3 in Comparative Example 1 until the weight of the coating material increases to 5 times the weight of the kernel.

[0070] S4. After coating, the product is sieved in the same way as in step S4 of Comparative Example 1 to obtain the final product.

[0071] Comparative Example 4: Preparation of low-content nano-calcium carbonate / hydrogenated palm oil coated doxycycline hydrochloride particles (nano-calcium 5%) A method for preparing coated particles includes the following steps: S1, same as step S1 in Example 1.

[0072] S2. Take 1900 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 under a high-speed shear press running at 10000 rpm. After the addition is complete, continue high-speed shearing and homogenization for 15 minutes to obtain a coating solution, which is then kept at 90°C.

[0073] S3. Take 500 g of the dried kernel prepared in S1 above, and coat it according to the fluidized bed parameters in step S3 of Example 1 until the weight of the coating material increases to 4 times the weight of the kernel, and then stop to obtain coated particles.

[0074] S4. After coating, the product is sieved in the same way as step S4 in Example 1 to obtain the final product.

[0075] Comparative Example 5: Preparation of high-content nano-calcium carbonate / hydrogenated palm oil coated polyoxyethylene hydrochloride particles (nano-calcium 20%) A method for preparing coated particles includes the following steps: S1, same as step S1 in Example 1.

[0076] S2. Take 1600 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 400 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 coating solution, which is then kept at 90°C.

[0077] S3. Take 500 g of the dried kernel prepared in S1 above, and coat it according to the fluidized bed parameters in step S3 of Example 1 until the weight of the coating material increases to 4 times the weight of the kernel, and then stop to obtain coated particles.

[0078] S4. After coating, the product is sieved in the same way as step S4 in Example 1 to obtain the final product.

[0079] Comparative Example 6: Preparation of high core-to-wall ratio nano-calcium carbonate / hydrogenated palm oil coated doxycycline hydrochloride particles (core-to-wall ratio 1:3) A method for preparing coated particles includes the following steps: S1, same as step S1 in Example 1.

[0080] 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 calcium carbonate with an average particle size of 2 μm 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 coating solution, which is then kept at 90°C.

[0081] S3. Take 500 g of the dried kernel prepared in S1 above, and coat it according to the fluidized bed parameters in step S3 of Example 1 until the weight of the coating material increases to 3 times the weight of the kernel, and then stop to obtain coated particles.

[0082] S4. After coating, the product is sieved in the same way as step S4 in Example 1 to obtain the final product.

[0083] Comparative Example 7: Preparation of low core-to-wall ratio nano-calcium carbonate / hydrogenated palm oil coated doxycycline particles (core-to-wall ratio 1:5) A method for preparing coated particles includes the following steps: S1, same as step S1 in Example 1.

[0084] S2. Take 2250 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 250 g of calcium carbonate with an average particle size of 2 μm 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 coating solution, which is then kept at 90°C.

[0085] S3. Take 500 g of the dried kernel prepared in S1 above, and coat it according to the fluidized bed parameters in step S3 of Example 1 until the weight of the coating material increases to 5 times the weight of the kernel, and then stop to obtain coated particles.

[0086] S4. After coating, the product is sieved in the same way as step S4 in Example 1 to obtain the final product.

[0087] Comparative Example 8: Preparation of micron-sized calcium carbonate / hydrogenated palm oil coated doxycycline hydrochloride particles A method for preparing coated particles includes the following steps: S1, same as step S1 in Example 1.

[0088] S2. Take 1800 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 micron-sized calcium carbonate with an average particle size of less than 2 μm 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 coating solution, which is then kept at 90°C.

[0089] S3. Take 500 g of the dried kernel prepared in S1 above, and coat it according to the fluidized bed parameters in step S3 of Example 1 until the weight of the coating material increases to 4 times the weight of the kernel, and then stop to obtain coated particles.

[0090] S4. After coating, the product is sieved in the same way as step S4 in Example 1 to obtain the final product.

[0091] 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.

[0092] 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.

[0093] (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.

[0094] (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.

[0095] (4) Transfer the last 3 bags of samples into simulated colon fluid (pH 7.4 phosphate buffer) for 12 hours and then measure them.

[0096] Calculate the average cumulative release rate at each time point.

[0097]

[0098] Effective release rate = drug release rate after 12 hours of treatment with colonic fluid - doxycycline release rate after 24 hours of treatment with rumen fluid; the higher this value, the higher the proportion of drug effectively released in the abomasum and intestines after avoiding rumen release, and the better the formulation performance. The results are shown in Table 1; Table 1

[0099] Combining Table 1 above, Figure 3 and Figure 4 It can be seen that, compared with Comparative Example 2, the rumen-passing release rates of Example 1 and Comparative Example 2 were 81.6% and 69.1%, respectively, indicating that compared with single hydrogenated palm oil coating, the coated particles with 10% nano-calcium carbonate added to hydrogenated palm oil had a higher intestinal release rate under the same core-to-wall ratio; the rumen-passing release rates of Examples 1, 2, and 3 were 81.6%, 81.1%, and 79.6%, respectively, which were higher than the 75.9% and 74.7% of Comparative Examples 4 and 5, indicating that under the same core-to-wall ratio, the overall release effect was best when the amount of nano-calcium carbonate added to hydrogenated palm oil was 8%~12%; combined with Figure 2As shown, in the gastric acid environment, Example 1 and Comparative Example 8 produced more gas in the test tubes of nano-sized calcium carbonate particles, indicating that the calcium carbonate in the coating would dissolve and initially destroy the coating in the abomasal environment. Combined with Table 1, the effective release rates of Example 1 and Comparative Example 8 were 81.6% and 74.7%, respectively, indicating that under the same core-to-wall ratio, adding nano-sized calcium carbonate to hydrogenated palm oil resulted in a better overall release effect than micron-sized calcium carbonate. The rumen-crossing release rates of Examples 1, 4, 5 and Comparative Examples 6, 7 were 81.6%, 80.5%, 79.9%, 68.6%, and 72.3%, respectively, indicating that the overall release effect was best between a core-to-wall ratio of 1:3.5 and 1:4.5. Furthermore, the rumen-crossing release rates of the five examples in this invention were between 79% and 82%, indicating that compared to the comparative examples, the five examples of this invention had a higher effective release rate of the drug under in vitro conditions, superior to the comparative examples. In addition, the effective release rates of Examples 6, 7, 8, and 9 were all above 79%, demonstrating the universality of the coating.

[0100] 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.

[0101] 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.

[0102] Test samples: Rumen-coated doxycycline hydrochloride granules prepared in Examples 1-9 and Comparative Examples 1-8.

[0103] 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.

[0104] 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.

[0105] 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

[0106] As shown in the table above, the cumulative release rate in the rumen of all Examples 1-5 of this invention was controlled below 17% over 24 hours, demonstrating good rumen stability. In contrast, Comparative Examples 1 and 6 had higher rumen release rates (>35%) due to their thinner coatings; while Comparative Examples 3 and 7 had lower rumen release rates, their subsequent intestinal release was insufficient.

[0107] The rumen-transfer release rates of Examples 1-5 all exceeded 79%, significantly higher than those of the comparative examples. This confirms that the coating layer composed of nano-calcium carbonate / hydrogenated palm oil in this invention can achieve a targeted delivery effect of "low rumen release and high intestinal release." Consistent with the trend of in vitro experimental results, in vivo experiments further demonstrated that, compared to the single hydrogenated palm oil coating of Comparative Example 2, the addition of 10% nano-calcium carbonate in Example 1 increased the effective release rate from 70.7% to 80.8%. 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 1:3.5-4.5 achieved efficient intestinal release while ensuring rumen protection. The nano-sized calcium carbonate in Example 1 was superior to the micron-sized calcium carbonate in Comparative Example 8.

[0108] In summary, the rumen-coated granules of the present invention exhibit excellent rumen permeability and intestinal-targeted release characteristics. Their rumen-transfer release rate exceeds 79%, 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 hydrogenated palm oil and nano-calcium carbonate composite coating of the present invention, providing a solid basis for its practical application in improving the oral bioavailability of water-soluble drugs in ruminants.

[0109] 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 water-soluble drug with rumen-coated enteric granules, characterized in that, include: The core of at least one water-soluble active pharmaceutical ingredient, A coating layer covering the core; The coating layer is formed of a composite coating material of hydrogenated palm oil and nano-active light calcium carbonate.

2. The water-soluble drug enteric-coated granules according to claim 1, characterized in that, The weight ratio of the core to the coating layer is 1:3.5~4.

5.

3. The water-soluble drug enteric-coated granules according to claim 1, characterized in that, The nano-calcium carbonate accounts for 8%-12% of the mass percentage in the composite coating material.

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

6. A method for preparing rumen-coated enteric-coated granules of a water-soluble drug according to any one of claims 1-5, characterized in that, Includes the following steps: S1. Preparation of a core containing a water-soluble active pharmaceutical ingredient; S2. Heat and melt hydrogenated palm oil, add nano-calcium carbonate under high-speed shear, and disperse homogeneously to obtain a coating solution; S3. Place the core in a fluidized bed and spray the coating liquid onto the surface of the core to form a coating layer, thus obtaining the core.

7. The method for preparing water-soluble drug enteric-coated granules according to claim 6, 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.

8. A feed additive, characterized in that, It contains rumen-coated enteric-coated granules of water-soluble drugs as described in any one of claims 1-5.

9. Use of the water-soluble drug rumen-exposed enteric-coated granules according to any one of claims 1-5 in the preparation of a rumen-exposed targeted release drug for ruminants.

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