Urapidil sustained-release capsule and preparation method thereof

Abstract

The present invention provides a sustained-release capsule of urapidil, comprising sustained-release micropellets and a hollow gelatin capsule shell; the sustained-release micropellets comprise a blank core, a drug-loading layer and a sustained-release layer, and an isolation layer is further provided between the drug-loading layer and the sustained-release layer; the drug-loading layer comprises urapidil API and a binder; the isolation layer is hydroxypropyl methylcellulose and / or hydroxypropyl cellulose; the sustained-release layer comprises a sustained-release material, an enteric material and a pore-forming agent. The urapidil sustained-release capsule of the present invention has a stable API crystal form, the prepared product has good stability, and the dissolution is stable during the accelerated test process, thus solving the problems of API crystal form transformation and low drug loading efficiency during the drug loading process of the drug-loading layer, as well as the problem of rapid dissolution during the stability test of the sustained-release capsule. The present invention also provides a method for preparing urapidil sustained-release capsules, which improves the stability of the preparation by adding an isolation layer and screening a suitable sustained-release layer prescription, thereby ensuring the safety and effectiveness of the drug.

Description

Technical Field

[0001] The invention belongs to the technical field of medicine, and particularly relates to an urapidil sustained-release capsule and a preparation method thereof. Background Art

[0002] The main indications of urapidil sustained-release capsules are essential hypertension, renal hypertension, hypertension caused by pheochromocytoma; urinary disorders associated with benign prostatic hyperplasia; and urinary disorders associated with neurogenic bladder.

[0003] Urapidil sustained-release capsules were approved for marketing in Japan in January 1989, in the European Union in June 1983, and in Germany in May 1995. Currently, Xi'an Yuanda Detian Pharmaceutical Co., Ltd. and Huayu (Wuxi) Pharmaceutical Co., Ltd. manufacture and sell Urapidil sustained-release capsules in China, but neither has passed the generic drug quality and efficacy consistency evaluation.

[0004] In the current patents or literature reports on urapidil sustained-release capsules, the preparation of the loaded pellets mostly uses water as the solvent, using fluidized bed layering, wet powdering, or wet centrifugal granulation. Although urapidil API is insoluble in water, it may form urapidil hydrosolvate in the presence of water, undergoing a crystal transformation and increasing crystal size. A microscopic image of urapidil API is attached. Figure 1 The microscopic picture of the water solvate formed when the raw material meets water is attached. Figure 2 , the microscope picture of the raw material drug solution after drying is attached Figure 3 The figure clearly shows that the crystal form of urapidil has changed. The crystal form transition may affect the bioavailability in the human body, thereby affecting the safety and efficacy of the drug.

[0005] To address the issue of drug crystal formation, some companies use high-speed dispersion and emulsification to break up the large crystals formed when the urapidil raw material comes into contact with water. However, this method, affected by the dispersion speed and time, results in uneven crystal size after crushing. Furthermore, the crystals further change during the coating process, making it impossible to prevent crystal growth throughout the coating process. Therefore, preventing the crystal form changes caused by urapidil coming into contact with water is a pressing issue in formulation research.

[0006] The study also found that the original formulation of urapidil sustained-release capsules dissolves faster during the accelerated stability test. The stability dissolution data are shown in the table below. Changes in stability dissolution can affect product release and absorption in the body, thereby affecting the safety and efficacy of the drug.

[0007]

[0008] Therefore, it is urgent to develop an urapidil sustained-release capsule with stable urapidil raw material crystal form, high formulation stability, and safer and more effective clinical use. Summary of the Invention

[0009] The purpose of the present invention is to provide a urapidil sustained-release capsule and a preparation method thereof in view of the drawbacks of the prior art.

[0010] The technical solution adopted by the present invention to solve its technical problem is:

[0011] A sustained-release capsule of urapidil, comprising a sustained-release pellet and a hollow gelatin capsule shell; the sustained-release pellet comprises a blank pellet core, a drug-loaded layer and a sustained-release layer, and an isolation layer is further provided between the drug-loaded layer and the sustained-release layer;

[0012] The drug-carrying layer comprises urapidil API and a binder, wherein the binder is hydroxypropyl cellulose and / or povidone;

[0013] The isolation layer is hypromellose and / or hydroxypropyl cellulose;

[0014] The sustained-release layer comprises a sustained-release material, an enteric material and a pore-forming agent, wherein the sustained-release material is ethyl cellulose, the enteric material is hydroxypropyl methylcellulose phthalate, and the pore-forming agent is hydroxypropyl cellulose or povidone.

[0015] The particle size of the urapidil raw material is controlled at 8 μm to 50 μm.

[0016] In the drug-carrying layer, the weight ratio of urapidil raw material to the binder is 1:0.4-0.8; and the solvent of the drug-carrying layer is anhydrous ethanol.

[0017] The isolation layer uses anhydrous ethanol as a solvent; compared with the sum of the masses of the blank pill core and the drug-loaded layer, the isolation layer increases in weight by 7% to 15%.

[0018] In the sustained-release layer, the weight ratio of the sustained-release material, the enteric material and the pore-forming agent is 1:0.4-0.8:0.1-0.4; compared with the sum of the weights of the blank pill core, the drug-loaded layer and the isolation layer, the sustained-release layer increases in weight by 8%-15%.

[0019] The preparation method of the urapidil sustained-release capsules comprises the following steps:

[0020] S1. Grind the urapidil API to 8 μm to 50 μm, disperse the prescribed amount of the urapidil API and a binder in anhydrous ethanol to obtain a drug-loaded coating solution; spray the drug-loaded coating solution onto blank pill cores through a fluidized bed to obtain drug-loaded pills;

[0021] S2. Dissolving a prescribed amount of hydroxypropyl cellulose and / or hydroxypropyl methylcellulose in anhydrous ethanol to obtain a sealing layer coating solution; applying the sealing layer coating solution to the loaded pills in a fluidized bed to obtain sealing layer pills;

[0022] S3, dissolving the sustained-release material, enteric material and pore-forming agent in 80% ethanol to obtain a sustained-release layer coating solution; spraying the sustained-release layer coating solution onto the surface of the isolation layer pellets through a fluidized bed to obtain sustained-release pellets;

[0023] S4. Fill the urapidil sustained-release micropellets into the hollow gelatin capsule shell to obtain the urapidil sustained-release capsules.

[0024] In step S1, the amount of the solvent anhydrous ethanol is 8 to 20 times the weight of the raw material drug; during the preparation of the drug-loaded pills, the fluidized bed material temperature is controlled to be 28 to 40° C., and the atomization pressure is controlled to be 0.8 to 1.5 bar.

[0025] In step S2, the amount of the solvent anhydrous ethanol is 10 to 20 times the weight of hydroxypropyl cellulose / hydroxypropyl methylcellulose; during the preparation of the loaded pills, the fluidized bed material temperature is controlled to be 28 to 40° C., and the atomization pressure is controlled to be 0.8 to 1.5 bar.

[0026] In step S3, the amount of the solvent 80% ethanol is 20 to 30 times the total weight of the sustained-release material, the enteric material, and the pore-forming agent; during the preparation of the loaded pills, the fluidized bed material temperature is controlled at 30 to 42° C., and the atomization pressure is controlled at 0.8 to 1.5 bar.

[0027] Through the above technical solution, the beneficial effects obtained by the present invention are:

[0028] The present invention discloses an urapidil sustained-release capsule. By screening the drug solvent for the drug-loading layer of the urapidil sustained-release capsule, screening the type of adhesive, and controlling the particle size of the raw drug, the problems of the raw drug crystal form change and low drug loading efficiency during the drug loading process of the urapidil sustained-release capsule are solved. By adding an isolation layer and optimizing the formulation and process of the sustained-release layer of the urapidil sustained-release capsule, the problem of rapid dissolution during the accelerated stability test of the urapidil sustained-release capsule is solved. The urapidil sustained-release capsule prepared using this formulation and process has a stable raw drug crystal form during the preparation process, good product stability, and stable dissolution during the accelerated test with no significant increase. The urapidil sustained-release capsule prepared using this process has improved drug safety and efficacy, improved product quality, and ensured the safety of people's medication.

[0029] The present invention avoids direct contact between alkaline urapidil raw materials and enteric materials by adding an isolation layer coating, effectively prevents degradation of the enteric materials, improves the stability of the preparation, and effectively solves the problem of rapid dissolution during the stability process of urapidil sustained-release capsules.

[0030] By adjusting the ratio of the sustained-release material, enteric material, and porogen during the preparation of the sustained-release layer, a smooth and effective release of urapidil can be achieved. The urapidil sustained-release capsules prepared by the present invention have a zero-day dissolution profile that is highly consistent with the original formulation, enabling them to replace the original product. The product's stability is superior to that of the original product, with little change in dissolution during the accelerated process.

[0031] The present invention also discloses a method for preparing urapidil sustained-release capsules. By controlling the particle size of the API and the binder ratio, the drug coating bonding efficiency is improved, thereby increasing the drug application rate. Anhydrous ethanol is used as a solvent in the preparation of both the drug-loaded and isolation-layered pellets to prevent the urapidil API from contacting water. This solves the problem of urapidil API undergoing crystal transformation and increasing particle size upon contact with water, thereby ensuring the drug's bioavailability in humans. By adding an isolation layer and selecting a suitable sustained-release layer formulation, the stability of the formulation is improved, ensuring the drug's safety and effectiveness. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 This is a photo of the crystal structure of urapidil API under a microscope;

[0033] Figure 2 This is a photo of the crystal structure of urapidil aqueous solution under a microscope;

[0034] Figure 3 This is a photo of the crystal structure of the dried urapidil aqueous solution under a microscope. DETAILED DESCRIPTION

[0035] The technical solution of the present invention is described in detail below.

[0036] A sustained-release capsule of urapidil comprises sustained-release pellets and a hollow capsule shell, wherein the sustained-release pellets are filled in the hollow capsule shell. The hollow capsule shell is a hollow gelatin capsule shell. The sustained-release pellets are composed, from the inside out, of a blank pellet core, a drug-loading layer, an isolation layer, and a sustained-release layer.

[0037] The blank pellet core is a sucrose pellet core or a mannitol pellet core with a particle size of 500-800 μm. The particle size of the blank pellet core can be selected from 500-600 μm, 600-700 μm, or 700-800 μm. The weight of the blank pellet core is 2-4 times the weight of the urapidil API, preferably 2.75-3.05 times, and most preferably 2.85 times.

[0038] The drug-carrying layer comprises the urapidil API, a binder, and a solvent for dispersion (the solvent evaporates during coating). The urapidil API has a purity of no less than 99.5%, and its particle size is controlled to be between 8 μm and 50 μm. The binder is hydroxypropyl cellulose and / or povidone, wherein the molecular weight of hydroxypropyl cellulose is controlled to be between 40,000 and 95,000, and the molecular weight of povidone is controlled to be between 34,000 and 58,000; preferably, hydroxypropyl cellulose. The solvent used in the drug-carrying layer is anhydrous ethanol.

[0039] In the drug-carrying layer, the weight ratio of the urapidil API to the binder is 1:0.4-0.8, preferably 1:0.5-0.8, and most preferably 1:0.7. The amount of anhydrous ethanol added is 8-20 times, preferably 10-12 times, of the urapidil API.

[0040] The isolation layer is made of hypromellose and / or hydroxypropyl cellulose. The hypromellose is substituted 2910 with a molecular weight of 400,000 to 746,000; the hydroxypropyl cellulose has a molecular weight of 40,000 to 95,000; preferably, hypromellose. The isolation layer uses anhydrous ethanol as the solvent. The isolation layer is weight-added by 7% to 15% over the blank core and drug-loaded layer. The amount of anhydrous ethanol added is 10 to 20 times, preferably 10 times, the weight of the isolation layer material.

[0041] The sustained-release layer includes a sustained-release material, an enteric material, and a pore-forming agent. The sustained-release material is ethyl cellulose with a molecular weight of 65,000 to 140,000. The enteric material is hydropropyl methylcellulose phthalate, preferably HP50 or HP55. The pore-forming agent is hydroxypropyl cellulose or povidone, preferably hydroxypropyl cellulose; the molecular weight of hydroxypropyl cellulose is 40,000 to 95,000, and the molecular weight of povidone is 34,000 to 58,000.

[0042] In the sustained-release layer, the weight ratio of the sustained-release material, enteric material, and pore-forming agent is 1:0.4-0.8:0.1-0.4, preferably 1:0.4-0.5:0.1-0.3, and more preferably 1:0.5:0.1 and 1:0.5:0.25. The sustained-release layer is weight-added by 8% to 15% relative to the blank core, drug-loaded layer, and isolation layer. The amount of 80% ethanol used is 20 to 30 times, preferably 20 to 26 times, the combined weight of the sustained-release material, enteric material, and pore-forming agent.

[0043] The preparation method of the urapidil sustained-release capsules comprises the following steps:

[0044] S1. Grind the urapidil API to 8 μm to 50 μm, disperse the prescribed amount of the urapidil API and a binder in a solvent to obtain a drug-loaded coating solution; spray the drug-loaded coating solution onto blank pill cores through a fluidized bed to obtain drug-loaded pills;

[0045] S2. Dissolving a prescribed amount of hydroxypropyl cellulose and / or hydroxypropyl methylcellulose in a solvent to obtain a separation layer coating solution; spraying the separation layer coating solution onto the surface of the drug-loaded pills through a fluidized bed to obtain separation layer pills;

[0046] S3, dissolving the sustained-release material, enteric material and pore-forming agent in a solvent to obtain a sustained-release layer coating solution; spraying the sustained-release layer coating solution onto the surface of the isolation layer pellets through a fluidized bed to obtain sustained-release pellets;

[0047] S4. Fill the urapidil sustained-release micropellets into the hollow gelatin capsule shell to obtain the urapidil sustained-release capsules.

[0048] In step S1, the solvent used is anhydrous ethanol. The binder is dissolved in the anhydrous ethanol, and the urapidil API is dispersed in the anhydrous ethanol to form a suspension. The solids content of the urapidil API in the drug-loaded coating solution is controlled to be between 5% and 12%. During the preparation of the drug-loaded pills, the fluidized bed material temperature is controlled to be between 28°C and 40°C, and the atomization pressure is controlled to be between 0.8 and 1.5 bar.

[0049] In step S2, the solvent used is anhydrous ethanol. During the preparation of the isolation layer pellets, the fluidized bed material temperature is controlled at 28-40°C, the atomization pressure is controlled at 0.8-1.5 bar, and the isolation layer weight is increased by 7%-15%.

[0050] In step S3, the solvent used is ethanol at a concentration of 75% to 85%, preferably 80%, as the enteric material has good solubility at this concentration. During the preparation of the sustained-release pellets, the fluidized bed material temperature is controlled at 30 to 42°C, the atomization pressure is controlled at 0.8 to 1.5 bar, and the sustained-release layer weight gain is controlled at 8 to 15%.

[0051] After the coating of the drug-loaded pellets, isolation layer pellets and sustained-release pellets is completed, they are all dried in a fluidized bed for 30 minutes before proceeding to the next step.

[0052] The technical solutions of the present invention will be clearly and completely described below in conjunction with specific embodiments. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. All other embodiments obtained by ordinary technicians in this field based on the embodiments of the present invention without making any creative efforts shall fall within the scope of protection of the present invention.

[0053] In the following examples, the manufacturers and specifications of the raw and auxiliary materials used are shown in the table below.

[0054] name factory Specification Urapidil Hebei Yipin Pharmaceutical Co., Ltd. N / A Sucrose pellets Hangzhou Gaocheng Bio-Nutrition Technology Co., Ltd. 600～700 Hydroxypropylcellulose Ashland Specialty Ingredients GP LF Ethyl cellulose The Dow Chemical Company 20 Hydroxypropyl methylcellulose phthalate Shin-Etsu Chemical Co., Ltd. HP55 Povidone ISP Technologies, Inc. K29 / 32 Hydroxypropyl methylcellulose Ashland Specialty Ingredients GP E4M

[0055] The anhydrous ethanol and 80% ethanol used both meet the requirements for medicinal use.

[0056] Example 1

[0057] Urapidil sustained-release capsules prescription:

[0058]

[0059] Preparation process:

[0060] S1. Preparation of drug-loaded pellets

[0061] Preparation of drug-loaded coating solution: dissolve the prescribed amount of hydroxypropyl cellulose in anhydrous ethanol, then add the prescribed amount of urapidil API and disperse evenly to obtain drug-loaded coating solution;

[0062] Preparation of drug-loaded pills: Blank pill cores are placed in a fluidized bed, and the drug-loaded coating liquid is layered onto the blank pill cores through the fluidized bed to obtain drug-loaded pills.

[0063] S2. Preparation of isolation layer pellets

[0064] Preparation of isolation layer coating liquid: dissolve the isolation layer prescription amount of hydroxypropyl cellulose in anhydrous ethanol to obtain isolation layer coating liquid;

[0065] Seal layer coating: The seal layer coating liquid is sprayed onto the drug-loaded pills obtained in step S1 through a fluidized bed to obtain seal layer pills.

[0066] S3. Preparation of sustained-release pellets

[0067] Preparation of sustained-release layer coating solution: Dissolve the prescribed amount of hydroxypropyl cellulose, ethyl cellulose, and hydroxypropyl methylcellulose phthalate in 80% ethanol to obtain the sustained-release layer coating solution;

[0068] Sustained-release layer coating: The sustained-release layer coating liquid is sprayed onto the isolation layer pellets obtained in step S2 through a fluidized bed to obtain sustained-release pellets.

[0069] S4. Fill the sustained-release micropellets into hollow gelatin capsules to obtain urapidil sustained-release capsules.

[0070] Example 2

[0071] Urapidil sustained-release capsules prescription:

[0072]

[0073] Preparation process:

[0074] S1. Preparation of drug-loaded pellets

[0075] Preparation of drug-loaded coating solution: dissolve the prescribed amount of hydroxypropyl cellulose in anhydrous ethanol, then add the prescribed amount of urapidil API and disperse evenly to obtain drug-loaded coating solution;

[0076] Preparation of drug-loaded pills: Blank pill cores are placed in a fluidized bed, and the drug-loaded coating liquid is layered onto the blank pill cores through the fluidized bed to obtain drug-loaded pills.

[0077] S2. Preparation of isolation layer pellets

[0078] Preparation of isolation layer coating liquid: Dissolve the isolation layer prescription amount of hypromellose in anhydrous ethanol to obtain isolation layer coating liquid;

[0079] Seal layer coating: The seal layer coating liquid is sprayed onto the drug-loaded pills obtained in step S1 through a fluidized bed to obtain seal layer pills.

[0080] S3. Preparation of sustained-release pellets

[0081] Preparation of sustained-release layer coating solution: Dissolve the prescribed amount of hydroxypropyl cellulose, ethyl cellulose, and hydroxypropyl methylcellulose phthalate in 80% ethanol to obtain the sustained-release layer coating solution;

[0082] Sustained-release layer coating: The sustained-release layer coating liquid is sprayed onto the isolation layer pellets obtained in step S2 through a fluidized bed to obtain sustained-release pellets.

[0083] S4. Fill the sustained-release micropellets into hollow gelatin capsules to obtain urapidil sustained-release capsules.

[0084] Example 3

[0085] Urapidil sustained-release capsules prescription:

[0086]

[0087] Preparation process:

[0088] S1. Preparation of drug-loaded pellets

[0089] Preparation of drug-loaded coating solution: Dissolve the prescribed amount of hydroxypropyl cellulose and povidone in anhydrous ethanol, then add the prescribed amount of urapidil API and disperse evenly to obtain drug-loaded coating solution;

[0090] Preparation of drug-loaded pills: Blank pill cores are placed in a fluidized bed, and the drug-loaded coating liquid is layered onto the blank pill cores through the fluidized bed to obtain drug-loaded pills.

[0091] S2. Preparation of isolation layer pellets

[0092] Preparation of isolation layer coating liquid: Dissolve the isolation layer prescription amount of hypromellose in anhydrous ethanol to obtain isolation layer coating liquid;

[0093] Seal layer coating: The seal layer coating liquid is sprayed onto the drug-loaded pills obtained in step S1 through a fluidized bed to obtain seal layer pills.

[0094] S3. Preparation of sustained-release pellets

[0095] Preparation of sustained-release layer coating solution: Dissolve the prescribed amount of hydroxypropyl cellulose, ethyl cellulose, and hydroxypropyl methylcellulose phthalate in 80% ethanol to obtain the sustained-release layer coating solution;

[0096] Sustained-release layer coating: The sustained-release layer coating liquid is sprayed onto the isolation layer pellets obtained in step S2 through a fluidized bed to obtain sustained-release pellets.

[0097] S4. Fill the sustained-release micropellets into hollow gelatin capsules to obtain urapidil sustained-release capsules.

[0098] Example 4

[0099] Urapidil sustained-release capsules prescription:

[0100]

[0101]

[0102] Preparation process:

[0103] S1. Preparation of drug-loaded pellets

[0104] Preparation of drug-loaded coating solution: dissolve the prescribed amount of hydroxypropyl cellulose in anhydrous ethanol, then add the prescribed amount of urapidil API and disperse evenly to obtain drug-loaded coating solution;

[0105] Preparation of drug-loaded pills: Blank pill cores are placed in a fluidized bed, and the drug-loaded coating liquid is layered onto the blank pill cores through the fluidized bed to obtain drug-loaded pills.

[0106] S2. Preparation of isolation layer pellets

[0107] Preparation of isolation layer coating liquid: dissolve the isolation layer prescription amount of hydroxypropyl cellulose in anhydrous ethanol to obtain isolation layer coating liquid;

[0108] Seal layer coating: The seal layer coating liquid is sprayed onto the drug-loaded pills obtained in step S1 through a fluidized bed to obtain seal layer pills.

[0109] S3. Preparation of sustained-release pellets

[0110] Preparation of sustained-release layer coating solution: Dissolve the prescribed amount of hydroxypropyl cellulose, ethyl cellulose, and hydroxypropyl methylcellulose phthalate in 80% ethanol to obtain the sustained-release layer coating solution;

[0111] Sustained-release layer coating: The sustained-release layer coating liquid is sprayed onto the isolation layer pellets obtained in step S2 through a fluidized bed to obtain sustained-release pellets.

[0112] S4. Fill the sustained-release micropellets into hollow gelatin capsules to obtain urapidil sustained-release capsules.

[0113] Example 5

[0114] Urapidil sustained-release capsules prescription:

[0115]

[0116] Preparation process:

[0117] S1. Preparation of drug-loaded pellets

[0118] Preparation of drug-loaded coating solution: dissolve the prescribed amount of hydroxypropyl cellulose in anhydrous ethanol, then add the prescribed amount of urapidil API and disperse evenly to obtain drug-loaded coating solution;

[0119] Preparation of drug-loaded pills: Blank pill cores are placed in a fluidized bed, and the drug-loaded coating liquid is layered onto the blank pill cores through the fluidized bed to obtain drug-loaded pills.

[0120] S2. Preparation of isolation layer pellets

[0121] Preparation of isolation layer coating liquid: dissolve the isolation layer prescription amount of hydroxypropyl cellulose in anhydrous ethanol to obtain isolation layer coating liquid;

[0122] Seal layer coating: The seal layer coating liquid is sprayed onto the drug-loaded pills obtained in step S1 through a fluidized bed to obtain seal layer pills.

[0123] S3. Preparation of sustained-release pellets

[0124] Preparation of sustained-release layer coating solution: Dissolve the prescribed amount of hydroxypropyl cellulose, ethyl cellulose, and hydroxypropyl methylcellulose phthalate in 80% ethanol to obtain the sustained-release layer coating solution;

[0125] Sustained-release layer coating: The sustained-release layer coating liquid is sprayed onto the isolation layer pellets obtained in step S2 through a fluidized bed to obtain sustained-release pellets.

[0126] S4. Fill the sustained-release micropellets into hollow gelatin capsules to obtain urapidil sustained-release capsules.

[0127] The performance of the urapidil sustained-release capsules prepared in Examples 1 to 5 was tested below.

[0128] (1) Investigation of dissolution curve

[0129] The inventors measured the dissolution rates of the urapidil sustained-release capsules prepared in Examples 1 to 5 of the present invention and compared the in vitro dissolution curves with those of the original formulation.

[0130] The original preparation is urapidil sustained-release capsules produced by Kakyo Pharmaceutical Co., Ltd., with a specification of 30 mg and batch number: I34170.

[0131] The determination method is as follows: Dissolution and Release Method II of the General Rules of the Chinese Pharmacopoeia (2020 edition), using 900 ml of 0.01 N hydrochloric acid solution as the dissolution medium at a speed of 50 rpm / min. 1 ml of sample was collected at 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 16 hours of dissolution, without rehydration, to serve as the test solution.

[0132] According to the HPLC method in the Chinese Pharmacopoeia 2020 edition 0512, the peak area of ​​the test solution was determined, and the dissolution amount of each urapidil sustained-release capsule at different times was calculated. The results are shown in Table 1.

[0133] Table 1 In vitro dissolution results of Examples 1-5

[0134]

[0135] As can be seen from the above table, the in vitro dissolution curves of the urapidil sustained-release capsules prepared in Examples 1-5 of the present invention are basically consistent with the in vitro dissolution curve of the original preparation. In 0.01N hydrochloric acid medium, the urapidil sustained-release capsules of the present invention have been completely released within 16 hours.

[0136] (2) Investigation of product batch reproducibility

[0137] Three batches of urapidil sustained-release capsules were prepared according to the formulation and process of Example 5, and then subjected to in vitro dissolution investigation according to the above-mentioned dissolution curve method. The results are shown in Table 2.

[0138] Table 2 Reproducible sample dissolution results

[0139]

[0140] As can be seen from the above table, there is no significant difference between batches of the urapidil sustained-release capsules prepared by the present invention, indicating that the preparation method provided by the present invention is process-stable.

[0141] (3) Stability investigation

[0142] The sample of Example 5 of the present invention and the original preparation were placed at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5% for 6 months. Samples were taken at 1, 2, 3, and 6 months, respectively, to examine the changes in the dissolution curves. The results are shown in Table 3.

[0143] Table 3 Dissolution results of stability samples

[0144]

[0145] The above data show that the dissolution curve of the urapidil sustained-release capsules prepared by the present invention did not change significantly after being placed under accelerated conditions for 6 months, but the dissolution of the original preparation was significantly faster after being accelerated for 6 months, indicating that the stability of the homemade product is better than that of the original product.

[0146] In summary, the 0-day dissolution curve of the urapidil sustained-release capsules prepared by the present invention is consistent with that of the original formulation, the sustained-release effect is good, the product quality is stable during the stability process, and the stability is better than that of the original product, which can replace the original product.

[0147] The urapidil sustained-release capsules provided by the present invention have good dissolution performance and good stability. Anhydrous ethanol is used as a solvent in the preparation process of the loaded pills, which effectively solves the problem of crystal transformation of the urapidil raw material when water is used as a solvent in the prior art. By adding an isolation layer coating to avoid contact between the enteric material and the urapidil raw material, the degradation of the enteric material is effectively slowed down, thereby improving product stability.

[0148] The above description is only a preferred embodiment of the present invention. All equivalent changes and modifications made according to the scope of the patent application of the present invention should fall within the scope of the present invention.

Claims

1. A sustained-release capsule of urapidil, characterized in that: The invention comprises sustained-release micropellets and hollow gelatin capsule shells; the sustained-release micropellets comprise a blank core, a drug-loaded layer and a sustained-release layer, and an isolation layer is provided between the drug-loaded layer and the sustained-release layer; The drug-carrying layer comprises urapidil API and a binder, wherein the binder is hydroxypropyl cellulose and / or povidone; in the drug-carrying layer, the weight ratio of urapidil API to the binder is 1:0.4-0.8; and the solvent of the drug-carrying layer is anhydrous ethanol; The isolation layer is made of hypromellose and / or hydroxypropyl cellulose, wherein the hypromellose is substituted 2910 with a molecular weight of 400,000 to 746,000; the molecular weight of hydroxypropyl cellulose is 40,000 to 95,000; the isolation layer uses anhydrous ethanol as a solvent; The sustained-release layer comprises a sustained-release material, an enteric material and a pore-forming agent, wherein the sustained-release material is ethyl cellulose, the enteric material is hydroxypropyl methylcellulose phthalate, and the pore-forming agent is hydroxypropyl cellulose or povidone; in the sustained-release layer, the weight ratio of the sustained-release material, the enteric material and the pore-forming agent is 1:0.4-0.8:0.1-0.4; The preparation method of the urapidil sustained-release capsules comprises the following steps: S1. Grind the urapidil API to 8 μm to 50 μm, disperse the prescribed amount of the urapidil API and a binder in anhydrous ethanol to obtain a drug-loaded coating solution; spray the drug-loaded coating solution onto blank pill cores through a fluidized bed to obtain drug-loaded pills; S2. Dissolving a prescribed amount of hydroxypropyl cellulose and / or hydroxypropyl methylcellulose in anhydrous ethanol to obtain a sealing layer coating solution; applying the sealing layer coating solution to the loaded pills in a fluidized bed to obtain sealing layer pills; S3, dissolving the sustained-release material, enteric material and pore-forming agent in 80% ethanol to obtain a sustained-release layer coating solution; spraying the sustained-release layer coating solution onto the surface of the isolation layer pellets through a fluidized bed to obtain sustained-release pellets; S4. Fill the urapidil sustained-release micropellets into the hollow gelatin capsule shell to obtain the urapidil sustained-release capsules.

2. The urapidil sustained-release capsule according to claim 1, characterized in that: The particle size of the urapidil raw material is controlled at 8 μm to 50 μm.

3. The urapidil sustained-release capsule according to claim 1, wherein: Compared with the sum of the mass of the blank pellet core and the drug-loaded layer, the isolation layer increases in weight by 7% to 15%.

4. The urapidil sustained-release capsule according to claim 1, characterized in that: Compared with the sum of the weight of the blank pill core, the drug-loaded layer, and the isolation layer, the sustained-release layer increases in weight by 8% to 15%.

5. The urapidil sustained-release capsule according to claim 1, characterized in that: In step S1, the amount of anhydrous ethanol used is 8 to 20 times the weight of the raw material drug; during the preparation of the drug-loaded pills, the fluidized bed material temperature is controlled to be 28 to 40° C., and the atomization pressure is controlled to be 0.8 to 1.5 bar.

6. The urapidil sustained-release capsule according to claim 1, characterized in that: In step S2, the amount of anhydrous ethanol used is 10 to 20 times the weight of hydroxypropyl cellulose / hydroxypropyl methylcellulose; during the preparation of the loaded pills, the fluidized bed material temperature is controlled to be 28 to 40° C., and the atomization pressure is controlled to be 0.8 to 1.5 bar.

7. The urapidil sustained-release capsule according to claim 1, characterized in that: In step S3, the amount of 80% ethanol is 20 to 30 times the total weight of the sustained-release material, the enteric material, and the pore-forming agent; during the preparation of the drug-loaded pills, the fluidized bed material temperature is controlled at 30 to 42° C., and the atomization pressure is controlled at 0.8 to 1.5 bar.

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