Urapidil sustained-release capsule and preparation method thereof

Abstract

The invention provides an urapidil sustained-release capsule. The urapidil sustained-release capsule comprises a sustained-release pellet and a hollow gelatin capsule shell, the sustained-release pellet comprises a blank pellet core, a medicine carrying layer and a sustained-release layer, wherein an isolating layer is also arranged between the medicine carrying layer and the sustained-release layer; the medicine carrying layer comprises an urapidil raw material medicine and an adhesive, and the isolating layer is hydroxypropyl methylcellulose and / or hydroxypropyl cellulose; the sustained-release layer comprises a sustained-release material, an enteric-coated material and a pore-foaming agent. The urapidil sustained-release capsule is stable in bulk drug crystal form, the prepared product is good in stability and stable in dissolution in the accelerated test process, and the problems that the bulk drug crystal form is changed in the drug loading process of a drug carrying layer and the drug loading efficiency is low are solved, and the problem that dissolution is fast in the accelerated test stability process of the sustained-release capsule is solved. The invention further provides a preparation method of the urapidil sustained-release capsule, by adding the isolating layer and screening a proper sustained-release layer prescription, the stability of the preparation is improved, and the safety and effectiveness of the medicine are ensured.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, 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 primary hypertension, renal hypertension, hypertension caused by pheochromocytoma; urinary disorders associated with prostatic hypertrophy; 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. produce 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, water is mostly used as the solvent for the preparation of drug-loaded pills, using fluidized bed layering, wet powdering or wet centrifugal granulation. Although urapidil API is insoluble in water, urapidil may form urapidil water solvate in the presence of water, undergoing a crystal transformation, and the crystals grow larger. See the attached microscope picture of urapidil API. Figure 1 The microscopic picture of the water solvate formed when the API meets water is attached. Figure 2 , the microscope picture of the raw material drug solution after drying is attached Figure 3 It can be clearly seen in the figure 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 effectiveness of the drug.

[0005] In order to solve the problem of drug crystal form, some companies use high-speed dispersion and emulsification to break up the large-sized crystals formed by the urapidil raw material in water. However, this method is affected by the dispersion speed and dispersion time, and the crystal size after crushing is uneven. In addition, the crystal will further change during the coating process, and it is impossible to prevent the growth of crystals during the entire coating process. Therefore, how to avoid the change of crystal form caused by urapidil in water is also a problem that needs to be solved in the formulation research process.

[0006] At the same time, the study found that the original formulation of urapidil sustained-release capsules dissolved faster during the accelerated stability test. The dissolution data during the stability process are shown in the table below. Changes in dissolution during the stability process will affect the release and absorption of the product in the body, thereby affecting the safety and effectiveness of the drug.

[0007]

[0008] Therefore, it is urgent to develop a sustained-release capsule of urapidil 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 sustained-release pellets and a hollow gelatin capsule shell; the sustained-release pellets comprising 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 hydroxypropyl methylcellulose 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 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 solvent; compared with the sum of the masses of the blank pill core and the drug-carrying 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 capsule comprises the following steps:

[0020] S1. Grind the urapidil API to 8 μm to 50 μm, disperse the prescribed amount of 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 an isolation layer coating solution; and subjecting the isolation layer coating solution to isolation layer coating on the drug-loaded pills through a fluidized bed to obtain isolation layer pills;

[0022] S3, dissolving the sustained-release material, the enteric material and the 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 micropellets;

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

[0024] In the 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 the 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 drug-loaded pills, the fluidized bed material temperature is controlled to be 28 to 40° C., and the atomization pressure is 0.8 to 1.5 bar.

[0026] In step S3, the amount of the solvent 80% ethanol is 20 to 30 times the sum of the weights 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.

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

[0028] The 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 problem of the change of the raw drug crystal form and low drug loading efficiency during the drug loading process of the urapidil sustained-release capsule is solved. By adding an isolation layer, optimizing the prescription and process of the sustained-release layer of the urapidil sustained-release capsule, the problem of faster dissolution during the stability test of the urapidil sustained-release capsule is solved. The urapidil sustained-release capsule prepared by the prescription process has a stable raw drug crystal form during the preparation process, good stability of the prepared product, and stable dissolution during the accelerated test without obvious growth. The urapidil sustained-release capsule prepared by the process improves the safety and effectiveness of the drug, improves the product quality, and ensures 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 enteric materials, improves preparation stability, and effectively solves the problem of faster dissolution during the stability process of urapidil sustained-release capsules.

[0030] By adjusting the ratio of the sustained-release material, the enteric material and the pore-forming agent during the preparation of the sustained-release layer, a stable and effective release of urapidil can be achieved. The 0-day dissolution curve of the urapidil sustained-release capsule prepared by the present invention is highly consistent with that of the original preparation, and the original product can be replaced. The product stability is better than that of the original product, and the accelerated dissolution process is basically unchanged.

[0031] The invention also discloses a method for preparing urapidil sustained-release capsules. By controlling the particle size of the raw medicine and the ratio of the adhesive, the drug coating bonding efficiency is improved, and the drug application rate is improved. In the preparation process of the drug-carrying pills and the isolation layer pills, anhydrous ethanol is used as a solvent to avoid the contact of the urapidil raw medicine with water, solve the problem of crystal transformation and particle size enlargement of the urapidil raw medicine after contacting water, and ensure the human bioavailability of the drug. By adding an isolation layer and selecting a suitable sustained-release layer prescription, the stability of the preparation is improved, and the safety and effectiveness of the drug are guaranteed. 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 sequentially composed of a blank pellet core, a drug-loading layer, an isolation layer and a sustained-release layer from the inside to the outside.

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

[0038] The drug-carrying layer includes urapidil API and adhesive, and a solvent for dispersion (the solvent evaporates during coating). The purity of the urapidil API is not less than 99.5%, and its particle size is controlled at 8 μm to 50 μm. The adhesive is hydroxypropyl cellulose and / or povidone, wherein the molecular weight of hydroxypropyl cellulose is controlled at 40,000 to 95,000, and the molecular weight of povidone is controlled at 34,000 to 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 the amount of the urapidil API, preferably 10-12 times.

[0040] The isolation layer is hydroxypropyl methylcellulose and / or hydroxypropyl cellulose, wherein hydroxypropyl methylcellulose is substituted type 2910 with a molecular weight of 400,000 to 746,000; the molecular weight of hydroxypropyl cellulose is 40,000 to 95,000; preferably hydroxypropyl methylcellulose. The isolation layer uses anhydrous ethanol as a solvent. On the basis of the blank pill core and the drug-carrying layer, the isolation layer is increased in weight by 7% to 15%. The amount of anhydrous ethanol added is 10 to 20 times the weight of the isolation layer material, preferably 10 times.

[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 hydroxypropyl methylcellulose phthalate, and its model is preferably HP50 or HP55. The pore-forming agent is hydroxypropyl cellulose or povidone, preferably hydroxypropyl cellulose; wherein 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, the enteric material and the 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. On the basis of the blank pill core, the drug-carrying layer and the isolation layer, the sustained-release layer is increased by 8% to 15%. The amount of the 80% ethanol is 20 to 30 times the sum of the weight of the three components of the sustained-release material, the enteric material and the pore-forming agent, preferably 20 to 26 times.

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

[0044] S1. Grind the urapidil API to 8 μm to 50 μm, disperse the prescribed amount of 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 methyl cellulose in a solvent to obtain an isolation layer coating solution; spraying the isolation layer coating solution onto the surface of the drug-loaded pills through a fluidized bed to obtain isolation layer pills;

[0046] S3, dissolving the sustained-release material, the enteric material and the 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 micropellets;

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

[0048] In the step S1, the solvent used is anhydrous ethanol. The binder is dissolved in anhydrous ethanol, and the urapidil API is dispersed in anhydrous ethanol to form a suspension, and the solid content of the urapidil API in the drug-loaded coating liquid is controlled at 5% to 12%. During the preparation of the drug-loaded pills, the fluidized bed material temperature is controlled at 28 to 40° C., and the atomization pressure is controlled at 0.8 to 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 to be 28-40°C, the atomization pressure is 0.8-1.5 bar, and the isolation layer weight gain is 7%-15%.

[0050] In step S3, the solvent used is ethanol with a concentration of 75% to 85%, preferably ethanol with a concentration of 80%, at which the enteric material has good solubility. 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 is increased by 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 solution of the present invention will be clearly and completely described below in conjunction with specific embodiments. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are 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 Biological 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 liquid: 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 liquid;

[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 a 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 microcapsules 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 liquid: 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 liquid;

[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 hydroxypropyl methylcellulose 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 a 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 microcapsules 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 liquid: 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 liquid;

[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 hydroxypropyl methylcellulose 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 a 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 microcapsules 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 liquid: 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 liquid;

[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 a 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 microcapsules 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 liquid: 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 liquid;

[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 a 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 microcapsules 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] (I) 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 preparation.

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

[0131] The determination method is: according to the second method of dissolution and release of the general rules of the 2020 edition of the Chinese Pharmacopoeia, 900ml of 0.01N hydrochloric acid solution is used as the dissolution medium, the speed is 50rpm / min, and the operation is carried out in accordance with the law. 1ml of samples are taken at 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, and 16h of dissolution, without rehydration, as the test solution.

[0132] According to the high performance liquid chromatography method of 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] It can be seen from the above table that the in vitro dissolution curves of the urapidil sustained-release capsules prepared in Examples 1-5 of the present invention are substantially consistent with the in vitro dissolution curve of the original preparation, and the urapidil sustained-release capsules of the present invention are completely released in 16 hours in a 0.01N hydrochloric acid medium.

[0136] (II) 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 the in vitro dissolution was investigated according to the above dissolution curve method. The results are shown in Table 2.

[0138] Table 2 Reproducible sample dissolution results

[0139]

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

[0141] (III) 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 the 1st, 2nd, 3rd and 6th month, 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 has no obvious change after being placed under accelerated conditions for 6 months, but the dissolution of the original preparation for comparison becomes 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 preparation, 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, so the original product can be replaced.

[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 urapidil raw materials when water is used as a solvent in the prior art. The contact between the enteric material and the urapidil raw material is avoided by adding an isolation layer coating, which effectively slows down the degradation of the enteric material and improves the 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: It comprises sustained-release pellets and hollow gelatin capsule shells; the sustained-release pellets comprise blank pellet cores, 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; The drug-carrying layer comprises urapidil API and a binder, wherein the binder is hydroxypropylcellulose and / or povidone; 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, 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.

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

4. The urapidil sustained-release capsule according to claim 1, characterized in that: The isolation layer uses anhydrous ethanol as solvent; compared with the sum of the masses of the blank pill core and the drug-carrying layer, the isolation layer increases in weight by 7% to 15%.

5. The urapidil sustained-release capsule according to claim 1, characterized in that: 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%.

6. The method for preparing the urapidil sustained-release capsule according to any one of claims 1 to 5, characterized in that The following steps are involved: S1. Grind the urapidil API to 8 μm to 50 μm, disperse the prescribed amount of 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 an isolation layer coating solution; and subjecting the isolation layer coating solution to isolation layer coating on the drug-loaded pills through a fluidized bed to obtain isolation layer pills; S3, dissolving the sustained-release material, the enteric material and the 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 micropellets; S4. Fill the urapidil sustained-release microcapsules into the hollow gelatin capsule shells to obtain urapidil sustained-release capsules.

7. The method for preparing urapidil sustained-release capsules according to claim 6, characterized in that: In the 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.

8. The method for preparing urapidil sustained-release capsules according to claim 6, characterized in that: In the 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 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.

9. The method for preparing urapidil sustained-release capsules according to claim 6, characterized in that: In the step S3, the amount of 80% ethanol is 20 to 30 times the sum of the weights 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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