A sirolimus enteric microcapsule granule and a preparation method thereof

Abstract

The application relates to the field of medicine preparation, in particular to a sirolimus enteric microcapsule granule and a preparation method thereof. The sirolimus enteric microcapsule granule comprises the following components in parts by weight: 0.1-0.5 parts of sirolimus, 50-80 parts of microcrystalline cellulose, 5-10 parts of an inner layer coating material and 3-8 parts of an outer layer coating material; the inner layer coating material comprises carboxymethylcellulose, and the outer layer coating material comprises Eudragit L100-55. The application is characterized in that the outer layer coating is composed of Eudragit L100-55, so that the granule can smoothly pass through the stomach and reach the intestines; the inner layer coating material is composed of carboxymethylcellulose, after the outer layer coating is dissolved in the intestines, the carboxymethylcellulose absorbs water and expands to form a viscous gel layer, so that the drug release is delayed, and the blood drug concentration can be maintained for a long time.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical preparation, specifically to a sirolimus enteric-coated microcapsule granule and its preparation method. Background Technology

[0002] Sirolimus is a third-generation immunosuppressant commonly used clinically to suppress immune rejection after organ transplantation, such as liver and kidney transplantation. It belongs to Class II biopharmaceuticals. Sirolimus's bioavailability is reduced because it first passes through the stomach and is partially degraded in the acidic environment of the stomach. Gastric emptying rate is greatly affected by food intake, leading to absorption fluctuations, and direct contact with the gastric mucosa can easily cause ulcers. This is one of the significant drawbacks of sirolimus in clinical use. Currently, only a small number of sirolimus formulations are available for human use, including liquid oral formulations and intravenous injections. Convenient and easily administered solid dosage forms of sirolimus are urgently needed. Summary of the Invention

[0003] To address the issue of preparing convenient and readily available sirolimus solid dosage forms, this application provides an enteric-coated sirolimus microcapsule granule formulation.

[0004] In a first aspect, this application provides a sirolimus enteric-coated microcapsule granule formulation, employing the following technical solution: A sirolimus enteric-coated microcapsule granule formulation comprises the following components in parts by weight: Sirolimus 0.1-0.5 parts, microcrystalline cellulose 50-80 parts, inner coating material 5-10 parts, outer coating material 3-8 parts; the inner coating material includes carboxypropyl methylcellulose, and the outer coating material includes Eudragit L100-55.

[0005] By employing the above-mentioned technical solution, the intestinal pH is close to neutral, resulting in high drug stability; the large intestinal surface area enhances absorption efficiency, making it more suitable for the absorption and utilization of sirolimus. Eudragit L100-55 is an acrylic resin-based enteric-coating material that remains stable and insoluble in the acidic environment of the stomach (pH<3), ensuring the coating passes through the stomach intact; after entering the small intestine, it dissolves rapidly, releasing sirolimus and achieving intestinal localization. If sirolimus is released in the intestine in a short period of time, it can easily trigger the body's regulatory mechanisms, leading to widespread metabolism by the CYP3A4 isoenzyme in the intestinal wall, thus lowering the concentration of sirolimus in the blood. This can cause a rapid rise and fall in the concentration of sirolimus in the blood, requiring patients to take the medication multiple times to maintain the blood concentration, and increasing the likelihood of side effects. In contrast, carboxypropyl methylcellulose absorbs water and swells upon contact with water, forming a viscous gel layer. Through diffusion and dissolution mechanisms, it delays drug release, effectively avoiding rapid rises and falls in blood concentration, maintaining blood concentration for a longer period, and reducing the burden of medication for patients.

[0006] This application uses Eudragit L100-55 as the outer coating material to allow the granules to pass smoothly through the stomach and reach the intestines. The inner coating material is composed of carboxypropyl methylcellulose. After the outer coating dissolves in the intestines, the carboxypropyl methylcellulose absorbs water and swells to form a viscous gel layer, which can delay drug release and thus maintain blood drug concentration for a long time.

[0007] Preferably, the inner coating thickness is 50-100μm.

[0008] By adopting the above technical solution, when the inner coating is too thin, the gel layer formed by carboxypropyl methylcellulose is discontinuous or easily broken, making it difficult to achieve the sustained release effect; when the inner coating is too thick, cracks are more likely to appear on the surface of the inner coating. When carboxypropyl methylcellulose absorbs water and swells, the gel layer is not dense enough, and multiple water channels are dispersed in the middle, which accelerates the dissolution of sirolimus and fails to achieve the sustained release effect. Therefore, after a lot of research and experimental verification, the applicant finally determined that the inner coating thickness of this application is as described above.

[0009] Preferably, the outer coating thickness is 30-60 μm.

[0010] By adopting the above technical solution, when the outer coating is too thin, it begins to dissolve in the gastric acid environment, reducing the amount of drug released into the intestines; when the outer coating is too thick, cracks are more likely to appear on the surface of the outer coating. When passing through the gastric acid environment, the gastric acid can easily dissolve the inner coating through the cracks in the outer coating, thereby increasing the amount of drug released in the gastric acid environment and reducing the amount of drug released into the intestines. Therefore, after extensive research and experimental verification, the applicant finally determined that the outer coating thickness of this application is preferably as described above.

[0011] Preferably, the inner coating material further includes triethyl citrate.

[0012] By employing the above technical solution, triethyl citrate, an environmentally friendly plasticizer, can intercalate between carboxypropyl methylcellulose polymer chains, weakening intermolecular forces, lowering the glass transition temperature, and making the coating film more flexible and preventing brittleness. The flexible coating film can resist the mechanical stress generated by intestinal peristalsis, ensuring the integrity of the gel layer and maintaining a stable sustained-release rate.

[0013] Preferably, the mass ratio of carboxypropyl methylcellulose to triethyl citrate is 9:0.5-1.5.

[0014] By adopting the above technical solution, when the content of triethyl citrate is too low, the promoting effect on the gel layer composed of carboxypropyl methylcellulose is reduced, thereby reducing the promoting effect on sirolimus sustained release; when the content of triethyl citrate is too high, the coating film is not strong enough and is prone to cracking during coating, causing sirolimus to flow out from the cracked channels formed in the inner coating in the intestine, reducing the sustained release effect. Therefore, after extensive research and experimental verification, the applicant finally determined that the mass ratio of carboxypropyl methylcellulose to triethyl citrate in this application is preferably as described above.

[0015] Preferably, the outer coating material further includes talc.

[0016] By employing the above technical solution, Eudragit L100-55 granules are prone to sticking together during the drying process due to their viscosity. Talc, as inert microparticles, is embedded in the polymer coating film, reducing surface adhesion through physical isolation and ensuring coating integrity. The talc microparticles, dispersed as a filler within the coating film, can buffer against intestinal peristalsis or external impacts during tableting, reducing the risk of coating rupture.

[0017] Preferably, the mass ratio of Eudragit L100-55 to talc is 8:1-3.

[0018] By adopting the above technical solution, when the talc content is too low, the promoting effect on the outer coating is reduced, thereby reducing the targeted release effect of sirolimus in the intestine; when the talc content is too high, the relative content of Eudragit L100-55 is reduced, the resistance effect in gastric acid is reduced, and thus it is easier to release more of the drug in gastric acid. Therefore, after extensive research and experimental verification, the applicant finally determined that the mass ratio of Eudragit L100-55 to talc in this application is preferably as described above.

[0019] Secondly, this application provides a method for preparing sirolimus enteric-coated microcapsule granules, using the following technical solution: A method for preparing sirolimus enteric-coated microcapsule granules, comprising the following steps: Granulation: Mix the formulated amounts of sirolimus and microcrystalline cellulose to obtain raw material granules; Coating: The raw material particles are sequentially coated with an inner coating and an outer coating to obtain sirolimus enteric-coated microcapsule granules.

[0020] Preferably, in the granulation step, the formulated amounts of sirolimus and microcrystalline cellulose are stirred and mixed, and then a PVP aqueous solution is added to mix and form a soft material, which is then granulated through a 20-mesh sieve and dried to obtain raw material granules.

[0021] By employing the above-mentioned technical solution, sirolimus and microcrystalline cellulose are granulated using a wet granulation process, primarily considering the low-dose, highly hydrophobic, and easily aggregated characteristics of sirolimus. Polyvinylpyrrolidone (PVP) plays a crucial role as a binder in this process. Utilizing the capillary adsorption of microcrystalline cellulose, the drug is drawn into the porous structure during the dry mixing stage, and then the dispersion is locked in through wet granulation to prevent subsequent migration. The pyrrolidone groups of PVP form hydrogen bonds with the hydroxyl groups of microcrystalline cellulose, encapsulating the drug particles to form "adhesive bridges." In the enteric double-layer coating system, the particle porosity controlled by PVP synergistically works with the gel layer of carboxypropyl methylcellulose to ensure the uniform release of sirolimus in the intestine.

[0022] Preferably, the PVP concentration in the PVP aqueous solution is 2-7 wt%.

[0023] By adopting the above technical solution, when the PVP concentration is low, the overall promoting effect is insufficient; when the PVP concentration is high, PVP easily forms a continuous hydration layer, establishes hydrophilic channels, and the carbonyl group of PVP and the hydroxyl group of sirolimus easily form a hydrogen bond network, reducing the drug diffusion barrier, which in turn promotes the release of sirolimus and reduces the sustained-release effect. Therefore, after extensive research and experimental verification, the applicant finally determined that the PVP concentration in the PVP aqueous solution of this application should be as described above.

[0024] In summary, this application has the following beneficial effects: Because this application uses Eudragit L100-55 as the outer coating, the granules can pass smoothly through the stomach and reach the intestines. The inner coating material is composed of carboxypropyl methylcellulose. After the outer coating dissolves in the intestines, the carboxypropyl methylcellulose absorbs water and swells to form a viscous gel layer, which can delay drug release and thus maintain blood drug concentration for a long time. The inner coating material of this application also includes triethyl citrate. Triethyl citrate can be inserted between carboxypropyl methylcellulose polymer chains, weakening intermolecular forces, lowering the glass transition temperature, making the coating film more flexible and preventing brittleness. The flexible coating film can resist the mechanical stress generated by intestinal peristalsis, ensuring the integrity of the gel layer and maintaining a stable sustained-release rate. The outer coating material of this application also includes talc. Talc, as an inert microparticle, is embedded in the polymer coating film. It reduces surface adhesion through physical isolation and ensures the integrity of the coating. The talc microparticles are dispersed in the coating film as a filler, which can buffer intestinal peristalsis or external force impact during tableting and reduce the risk of coating film rupture. Detailed Implementation

[0025] The raw materials in this application include the following: Sirolimus: Uses a commercially available product with CAS number 52123-88-9; Microcrystalline cellulose: Commercially available product with CAS number 9004-34-6; Carboxypropyl methylcellulose: Uses commercially available products with CAS number 9004-65-3; Eudragit L100-55: Commercially available product; Triethyl citrate: Use the commercially available product with CAS number 77-93-0; Talc powder: Uses commercially available product with CAS number 14807-96-6; Polyvinylpyrrolidone: Use commercially available products with CAS number 9003-39-8; The present application will be further described in detail below with reference to embodiments and comparative examples. Example 1

[0026] A method for preparing sirolimus enteric-coated microcapsule granules includes the following steps: Granulation: Mix 65g sirolimus and 0.3g microcrystalline cellulose to obtain raw material granules; Coating: The raw material particles were sequentially coated with an inner coating and an outer coating in a fluidized bed. The inner coating material was 8g of carboxypropyl methylcellulose with a thickness of 80μm. The outer coating material was 5g of Eudragit L100-55 with a thickness of 50μm, thus obtaining sirolimus enteric-coated microcapsule granules. Example 2-3

[0027] Example 2, based on the preparation method of Example 1, adjusted the content of each component of the sirolimus enteric-coated microcapsule granules, as shown in Table 1. Additionally, the inner coating thickness was 50 μm and the outer coating thickness was 30 μm.

[0028] Example 3, based on the preparation method of Example 1, adjusted the content of each component of the sirolimus enteric-coated microcapsule granules, as shown in Table 1. Additionally, the inner coating thickness was 100 μm and the outer coating thickness was 60 μm.

[0029] Comparative Examples 1-3 Comparative Example 1 was prepared using the same method as in Example 1, but without the inner coating layer.

[0030] Comparative Example 2 is prepared using the same method as in Example 1, but without the outer coating.

[0031] Comparative Example 3, based on the preparation method of Example 1, adjusted the inner coating thickness to 50 μm and the inner coating material to 5 g of Eudragit L100-55; the outer coating thickness to 50 μm and the outer coating material to 8 g of carboxypropyl methylcellulose.

[0032] Performance testing The sirolimus enteric-coated microcapsule granules of Examples 1-3 and Comparative Examples 1-3 were subjected to the following performance tests, and the test results are shown in Table 1.

[0033] 1. Dissolution level in hydrochloric acid solution Following the method for dissolution and release determination (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II), a dissolution medium of 900 mL of 0.1 mol / L hydrochloric acid solution was used, and the rotation speed was 75 rpm. The dissolution amount A of sirolimus after 2 hours was recorded. The proportion of the dissolution amount A in the total sirolimus was calculated.

[0034] 2. Dissolution level under neutral conditions Following the dissolution and release assay method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II), sirolimus was first dissolved in 900 mL of 0.1 mol / L hydrochloric acid solution at 75 rpm for 2 hours. The amount of sirolimus dissolved (A) after 2 hours was recorded. Then, using pH 7.4 phosphate buffer as the dissolution medium at 75 rpm, the dissolution curve was determined. The amount of sirolimus dissolved (B) after 1 hour and (C) after 6 hours was recorded. The total amount of sirolimus (D) in neutral solution was obtained by subtracting the amount of sirolimus dissolved (A) from the total amount of sirolimus. Finally, the proportions of dissolved amounts (B and C) in the total amount of sirolimus (D) were calculated.

[0035] 3. Stability The samples were placed under accelerated conditions (temperature 40℃±2℃, RH 75%±5%) for 6 months. Then, following the dissolution and release assay (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II), the dissolution medium was pH 7.4 phosphate buffer, and the dissolution rate was 75 rpm. The amount of sirolimus dissolved (E) after 6 hours was recorded. Finally, the proportion of the dissolved amount (E) in the total sirolimus was calculated.

[0036] Table 1. Content (g) and performance test results of each component in sirolimus enteric-coated microcapsule granules of Examples 1-3 and Comparative Examples 1-3. Referring to Table 1, comparing Examples 1-3 and Comparative Examples 1-3, it is evident that sirolimus enteric-coated microcapsules require an inner coating of carboxypropyl methylcellulose and an outer coating of Eudragit L100-55 to ensure the sirolimus enteric-coated microcapsules can first stably pass through a strongly acidic environment, and then be slowly released in a neutral environment. This is because Eudragit L100-55 is an acrylic resin-based enteric coating material, which remains stable and insoluble in the acidic environment of the stomach (pH < 3), ensuring the coating's complete passage through the strongly acidic environment; upon entering the neutral environment, it dissolves rapidly, releasing sirolimus and achieving intestinal localization.

[0037] Carboxypropyl methylcellulose is easily decomposed in a strong acid environment, while Eudragit L100-55 dissolves rapidly in a neutral environment. Comparative Example 3 involved exchanging the inner and outer coating materials, which prevented sirolimus from being slowly released even in a neutral environment after passing through a strong acid environment.

[0038] Furthermore, comparing Examples 1-3, it was found that Example 1 had the best performance; therefore, Example 1 was preferred. Examples 4-5

[0039] Examples 4-5 are based on the preparation method of Example 1, but the thickness of the inner coating is adjusted. The specific adjustments are shown in Table 2.

[0040] The sirolimus enteric-coated microcapsule granules from Examples 4-5 were subjected to the performance tests described above, and the test results are shown in Table 2.

[0041] Table 2. Inner coating thickness and performance test results for Examples 1 and 4-5. Referring to Table 2, a comparison of Examples 1 and 4-5 shows that as the inner coating thickness increases, the dissolution level of sirolimus enteric-coated microcapsules in phosphate buffer exhibits a trend of first decreasing and then increasing. This is because as the inner coating thickness increases, the gel layer formed by carboxypropyl methylcellulose gradually becomes continuous, controlling the release rate of sirolimus and achieving a sustained-release effect. However, beyond a certain range, cracks are more likely to appear on the surface of the inner coating. When carboxypropyl methylcellulose absorbs water and swells, the gel layer becomes insufficiently dense, with multiple water channels dispersed in the middle, which actually accelerates the dissolution of sirolimus and fails to achieve the sustained-release effect. Examples 6-9

[0042] In Example 6, based on the preparation method of Example 1, the inner coating material was adjusted to an inner layer mixture of 8g of carboxypropyl methylcellulose and triethyl citrate, with a mass ratio of carboxypropyl methylcellulose to triethyl citrate of 9:1.

[0043] Example 7: Based on the preparation method of Example 1, the inner coating material was adjusted to be 5g of a mixture of carboxypropyl methylcellulose and triethyl citrate, with a mass ratio of carboxypropyl methylcellulose to triethyl citrate of 9:1. The inner coating thickness was 50μm.

[0044] In Examples 8-9, based on the preparation method of Example 7, the total mass of carboxypropyl methylcellulose and triethyl citrate was 5g. The mass ratio of carboxypropyl methylcellulose to triethyl citrate was adjusted, and the specific adjustments are shown in Table 3.

[0045] The sirolimus enteric-coated microcapsule granules of Examples 6-9 were subjected to the above performance tests, and the test results are shown in Table 3.

[0046] Table 3. Mass ratio and performance test results of carboxypropyl methylcellulose and triethyl citrate in Examples 1 and 6-9. Referring to Table 3, a comparison of Examples 1 and 6-9 shows that the sirolimus enteric-coated microcapsule granules using a mixture of carboxypropyl methylcellulose and triethyl citrate as the inner layer material exhibit better sustained-release performance. This is because triethyl citrate is an environmentally friendly plasticizer that can insert into the carboxypropyl methylcellulose polymer chains, weakening intermolecular forces, lowering the glass transition temperature, and making the coating film more flexible and preventing brittleness. Since the adjusted inner layer performs better, the impact of a lower inner layer thickness is reduced. The sustained-release performance of sirolimus enteric-coated microcapsule granules with an inner layer thickness of 50 μm and 80 μm is comparable. For cost considerations, using sirolimus enteric-coated microcapsule granules with an inner layer thickness of 50 μm is more suitable.

[0047] As the proportion of triethyl citrate increases, the dissolution level of sirolimus enteric-coated microcapsules in phosphate buffer shows a trend of first decreasing and then increasing. This is because as the proportion of triethyl citrate increases, the coating becomes more flexible, preventing brittleness and cracking, resulting in a denser gel layer, thus achieving a sustained-release effect. However, beyond a certain range, the carboxypropyl methylcellulose content becomes too low, leading to insufficient coating film strength and making it prone to cracking during encapsulation. When carboxypropyl methylcellulose absorbs water and swells, the gel layer becomes insufficiently dense, with multiple water channels dispersed within, which actually accelerates sirolimus dissolution and fails to achieve the sustained-release effect. Examples 10-11

[0048] Examples 10-11 are based on the preparation method of Example 1, but the thickness of the outer coating is adjusted. The specific adjustments are shown in Table 4.

[0049] The sirolimus enteric-coated microcapsule granules of Examples 10-11 were subjected to the above performance tests, and the test results are shown in Table 4.

[0050] Table 4. Outer coating thickness and performance test results for Examples 1 and 10-11 Referring to Table 4, a comparison of Examples 1 and 10-11 shows that as the outer coating thickness increases, the dissolution level of sirolimus enteric-coated microcapsules in hydrochloric acid solution initially decreases and then increases. This is because, with increasing outer coating thickness, the enteric coating composed of Eudragit L100-55 better hinders hydrochloric acid erosion, reducing the release amount in hydrochloric acid solution. However, beyond a certain range, cracks are more likely to appear on the outer coating surface. When exposed to a strong acid environment, the strong acid can easily dissolve the inner coating through these cracks, thereby increasing the drug release in the strong acid environment and decreasing the drug release in the neutral environment. Examples 12-14

[0051] Example 12 is based on the preparation method of Example 1, the outer coating material is adjusted to be 5g of Eudragit L100-55 and talc powder outer layer mixture, the mass ratio of Eudragit L100-55 to talc powder in the outer layer mixture is 8:2.

[0052] Examples 13-14 are based on the preparation method of Example 12, but the mass ratio of Eudragit L100-55 to talc is adjusted. The specific adjustments are shown in Table 5.

[0053] The sirolimus enteric-coated microcapsule granules of Examples 12-14 were subjected to the above performance tests, and the test results are shown in Table 5.

[0054] Table 5. Mass ratio of Eudragit L100-55 to talc and performance test results in Examples 1 and 12-14. Referring to Table 5, a comparison of Examples 1 and 12-14 shows that adding talc to the outer coating material is more effective in reducing the dissolution level of sirolimus enteric microcapsules in hydrochloric acid solution. This is because Eudragit L100-55 particles are prone to sticking together during the drying process due to their viscosity. Talc, as inert microparticles embedded in the polymer coating, reduces surface adhesion through physical isolation, ensuring coating integrity. The talc microparticles, dispersed as a filler in the coating, can buffer external impacts during tableting, reducing the risk of coating rupture.

[0055] As the proportion of talc increases, the dissolution level of sirolimus enteric-coated microcapsules in hydrochloric acid solution initially decreases and then increases. This is because a higher proportion of talc reduces particle adhesion and strengthens the coating, thus lowering the dissolution level of sirolimus enteric-coated microcapsules in hydrochloric acid solution. Beyond a certain range, the relative content of Eudragit L100-55 decreases, reducing its resistance to strong acids and making it easier to release more of the drug in strong acids. Examples 15-18

[0056] Example 15 adjusts the granulation step based on the preparation method of Example 1 as follows: Granulation: Mix 65g sirolimus and 0.3g microcrystalline cellulose, then add 3mL of PVP aqueous solution to prepare a soft mass. The PVP concentration in the aqueous solution is 5wt%. Granulate through a 20-mesh sieve, and dry in a fluidized bed at 50℃ until the moisture content is ≤2%. After granulation, control the bulk density to 0.45±0.05g / cm³. 3 , to obtain raw material granules.

[0057] Examples 16-17 are based on the preparation method of Example 15, but the PVP concentration is adjusted. The specific adjustments are shown in Table 6.

[0058] Example 18, based on the preparation method of Example 15, adjusts the inner coating material to an inner layer mixture of 5g of carboxypropyl methylcellulose and triethyl citrate, with a mass ratio of carboxypropyl methylcellulose to triethyl citrate of 9:1. The inner coating thickness is 50μm. The outer coating material is adjusted to an outer layer mixture of 5g of Eudragit L100-55 and talc, with a mass ratio of Eudragit L100-55 to talc of 8:2.

[0059] The sirolimus enteric-coated microcapsule granules of Examples 15-18 were subjected to the above performance tests, and the test results are shown in Table 6.

[0060] Table 6. PVP concentration and performance test results for Examples 1 and 15-18. Referring to Table 6, a comparison of Examples 1 and 15-18 shows that wet granulation with PVP aqueous solution yields better results. This is because wet granulation of sirolimus and microcrystalline cellulose is primarily chosen to address sirolimus's low dosage, high hydrophobicity, and tendency to aggregate. Polyvinylpyrrolidone (PVP) plays a crucial role as a binder in this process. Utilizing the capillary adsorption of microcrystalline cellulose, the drug is drawn into the porous structure during the dry mixing stage, and then the dispersion is locked in through wet granulation, preventing subsequent migration. The pyrrolidone groups of PVP form hydrogen bonds with the hydroxyl groups of microcrystalline cellulose, encapsulating the drug particles to form "adhesive bridges." In the enteric double-layer coating system, the particle porosity controlled by PVP synergistically works with the gel layer of carboxypropyl methylcellulose to ensure uniform release of sirolimus under neutral conditions.

[0061] As the concentration of PVP increased, the dissolution levels of sirolimus enteric-coated microcapsules in phosphate buffer and phosphate buffer both showed a trend of first decreasing and then increasing. This is because, with increasing PVP concentration, the PVP-controlled particle porosity synergizes better with the carboxypropyl methylcellulose gel layer, thus promoting the sustained-release effect. However, beyond a certain range, PVP tends to form a continuous hydration layer, establishing hydrophilic channels, and the carbonyl groups of PVP easily form hydrogen bond networks with the hydroxyl groups of sirolimus, lowering the drug diffusion barrier and conversely promoting sirolimus release, thus reducing the sustained-release effect.

[0062] This specific embodiment is merely an explanation of this application and is not intended to limit it. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they fall within the scope of the claims of this application.

Claims

1. A sirolimus enteric-coated microcapsule granule formulation, characterized in that, The components include the following parts by weight: Sirolimus 0.1-0.5 parts, microcrystalline cellulose 50-80 parts, inner coating material 5-10 parts, outer coating material 3-8 parts; the inner coating material includes carboxypropyl methylcellulose, and the outer coating material includes Eudragit L100-55.

2. The sirolimus enteric-coated microcapsule granules according to claim 1, characterized in that: The inner coating thickness is 50-100μm.

3. The sirolimus enteric-coated microcapsule granules according to claim 1, characterized in that: The outer coating thickness is 30-60μm.

4. The sirolimus enteric-coated microcapsule granules according to claim 1, characterized in that: The inner coating material also includes triethyl citrate.

5. The sirolimus enteric-coated microcapsule granules according to claim 4, characterized in that: The mass ratio of carboxypropyl methylcellulose to triethyl citrate is 9:0.5-1.

5.

6. The sirolimus enteric-coated microcapsule granules according to claim 1, characterized in that: The outer coating material also includes talc.

7. The sirolimus enteric-coated microcapsule granules according to claim 6, characterized in that: The mass ratio of Eudragit L100-55 to talc is 8:1-3.

8. The method for preparing sirolimus enteric-coated microcapsule granules according to any one of claims 1-7, characterized in that, Includes the following steps: Granulation: Mix the formulated amounts of sirolimus and microcrystalline cellulose to obtain raw material granules; Coating: The raw material particles are sequentially coated with an inner coating and an outer coating to obtain sirolimus enteric-coated microcapsule granules.

9. The method for preparing sirolimus enteric-coated microcapsule granules according to claim 8, characterized in that: In the granulation step, the formulated amounts of sirolimus and microcrystalline cellulose are stirred and mixed, and then PVP aqueous solution is added to mix and form a soft material. The mixture is then granulated through a 20-mesh sieve and dried to obtain raw material granules.

10. The method for preparing sirolimus enteric-coated microcapsule granules according to claim 9, characterized in that: The PVP concentration in the PVP aqueous solution is 2-7 wt%.

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