Sustained-release capsule of isosorbide mononitrate and its preparation method

Abstract

The present application provides a kind of isosorbide mononitrate sustained-release capsules and its preparation method, the isosorbide mononitrate sustained-release capsule of the present application, characterized in that, the drug loading layer, sustained-release layer, immediate-release layer and protective layer of the isosorbide mononitrate sustained-release capsule are respectively coated by fluidized bed granulation coating machine.The granular preparation has good stability, small side effect;The preparation process of the isosorbide mononitrate sustained-release capsule of the present application is simple, the equipment is simple and easy to operate, the labor intensity is small, and it is economic and safe.At the same time, the prescription and preparation method are more economical, and are suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a sustained-release capsule of isosorbide mononitrate and its preparation method. Background Technology

[0002] Isosorbide mononitrate can be divided into 5-isosorbide mononitrate and 2-isosorbide mononitrate. Isosorbide mononitrate, also known as 5-isosorbide mononitrate, is a long-acting nitrate antianginal drug with a mechanism of action similar to nitroglycerin, but with a longer duration of action. It is the main active metabolite of isosorbide nitrate in the body, rapidly absorbed orally, with high absolute bioavailability and minimal individual variability. Its main pharmacological effects are relaxing vascular smooth muscle, reducing peripheral vascular resistance, decreasing resistance to left ventricular contraction, thereby reducing myocardial oxygen consumption and improving blood supply to ischemic areas.

[0003] Isosorbide mononitrate has a biological half-life of 4–5 hours and can be used for the prevention and treatment of angina pectoris, long-term treatment of coronary heart disease, prevention of vasospasm and mixed angina, as well as treatment after myocardial infarction and long-term treatment of chronic heart failure. When used in combination with digitalis and / or diuretics, it can treat chronic congestive heart failure and is one of the best drugs for the prevention and treatment of angina pectoris.

[0004] Isosorbide mononitrate was first used clinically in West Germany in 1975. Its chemical name is 3,6-didehydro-D-sorbitol-5-nitrate. It is a white needle-like crystal or crystalline powder, odorless, readily soluble in methanol or acetone, soluble in chloroform or water, and practically insoluble in hexane. It is prone to explosion when heated or impacted. Currently, isosorbide mononitrate is used clinically in conventional dosage forms such as tablets and injections. However, frequent daily dosing leads to large fluctuations in blood drug concentration, and frequent dosing can easily lead to drug tolerance, causing numerous side effects, and even poisoning; or it may fail to exert its effect. Sustained-release formulations, on the other hand, allow the immediate-release layer to quickly achieve blood drug concentration, while the sustained-release layer slowly releases the drug to maintain blood drug concentration, reducing or avoiding peak-trough fluctuations in blood drug concentration. This allows the drug to exert its therapeutic effect more steadily and continuously, improving the safety of clinical use and reducing adverse drug reactions. Isosorbide mononitrate sustained-release formulation is administered once daily, reducing the frequency of dosing and virtually eliminating the risk of drug resistance; thus significantly reducing the probability of nocturnal angina and improving patient compliance.

[0005] Isosorbide mononitrate sustained-release capsules were originally developed by Schwarz Pharma in Germany. In 1992, the isosorbide mononitrate sustained-release capsules manufactured by Schwarz Pharma were approved for marketing in China under the trade name [Brand Name Missing]. In 2007, UCB completed its global acquisition of the German Schwarz Pharmaceuticals Group. In 2008, UCB and Zhuhai Schwarz Pharmaceutical Co., Ltd. completed their merger in China. In 2012, Zhuhai Schwarz Pharmaceutical Co., Ltd. became a wholly-owned subsidiary of UCB. The State Food and Drug Administration of China has approved the marketing of isosorbide mononitrate sustained-release capsules produced by UCB (Zhuhai) Pharmaceutical Co., Ltd. (50mg) as the original drug. Patent 201610630326.1 discloses a method for preparing isosorbide mononitrate capsules. Before preparing microcapsules, the raw materials and fillers are mixed and pulverized using an air jet mill. After pulverization, an immediate-release microcapsule of isosorbide mononitrate is prepared using a multi-functional pelletizing and coating machine, and then a sustained-release microcapsule of isosorbide mononitrate is prepared using the same machine. Finally, the immediate-release and sustained-release microcapsules are mixed and filled into capsules to obtain the final product. However, this method also suffers from high energy consumption and difficulty in large-scale production.

[0006] Patent 201811311153.2 discloses a method for preparing isosorbide mononitrate capsules. First, a soft mass is prepared using a wet granulation machine. Then, the soft mass is used to prepare an immediate-release component using an extrusion-spheronization device and dried. After drying, the immediate-release component is divided into two parts in a 70% and 30% ratio. The 70% immediate-release component is used for further sustained-release coating, while the 30% immediate-release portion is further coated with a release coating using a fluidized bed bottom spray method for later use. Based on the content of the immediate-release component, the content of the sustained-release component, and the mixing ratio, the theoretical filling amount is calculated to fill the capsules. Although this method provides a more stable isosorbide mononitrate sustained-release capsule, the process is still relatively complex and labor-intensive.

[0007] The existing preparation process of isosorbide mononitrate suffers from problems such as crystallization, poor stability, and complex preparation. Therefore, developing a method for preparing isosorbide mononitrate sustained-release capsules to address the shortcomings of the existing technology has become a challenge for researchers. Summary of the Invention

[0008] In view of this, the present invention provides a method for preparing isosorbide mononitrate sustained-release capsules. The drug release is stable, with good stability, few side effects, and the production equipment is simple, easy to operate, easy to scale up, requires little labor, and is economically feasible.

[0009] This invention provides a sustained-release capsule of isosorbide mononitrate, wherein the sustained-release capsule is composed of a drug-loaded layer, a sustained-release layer, an immediate-release layer, and a protective layer.

[0010] More preferably, the drug-loaded layer comprises a blank sucrose pellet core, isosorbide mononitrate, lactose, and purified water; the sustained-release layer comprises ethyl cellulose, the sustained-release layer comprises ethyl cellulose, purified water, and anhydrous ethanol; the release layer comprises isosorbide mononitrate, hydroxypropyl methylcellulose, and purified water; and the protective layer comprises polyvinyl alcohol-polyethylene glycol copolymer, talc, and purified water.

[0011] More preferably, the components of the sustained-release capsule, calculated by weight, are as follows: The drug-loaded layer is:

[0012] 20-25 blank sugar pellet cores

[0013] 30-40 parts of isosorbide mononitrate

[0014] 3-6 parts lactose

[0015] 250.7-399.5 parts purified water;

[0016] The sustained-release layer is:

[0017] 5-8 parts of ethyl cellulose

[0018] The sustained-release layer consists of 2-4 parts ethyl cellulose

[0019] Purified water 5.35-25.67 parts

[0020] Anhydrous ethanol 48.15-231.03 parts;

[0021] The quick-release layer is:

[0022] 10-20 parts of isosorbide mononitrate

[0023] Hydroxypropyl methylcellulose 2.5-7.5 parts

[0024] Composed of 102.5-170 parts purified water;

[0025] The protective layer is:

[0026] 1-5 parts of polyvinyl alcohol-polyethylene glycol copolymer

[0027] 0.5-1 part talcum powder

[0028] 20-50 parts purified water.

[0029] More preferably, the components of the sustained-release capsule, calculated by weight, are as follows: The drug-loaded layer is:

[0030] 20 blank sugar pellet cores

[0031] 35 parts of isosorbide mononitrate

[0032] 3 parts lactose

[0033] 250.7 parts purified water;

[0034] The sustained-release layer is:

[0035] 5 parts ethyl cellulose

[0036] The sustained-release layer consists of 2 parts ethyl cellulose

[0037] 9 parts purified water

[0038] 83 parts of anhydrous ethanol;

[0039] The quick-release layer is:

[0040] 15 parts of isosorbide mononitrate

[0041] 2.5 parts hydroxypropyl methylcellulose

[0042] 105 parts purified water;

[0043] The protective layer is:

[0044] 3 parts of polyvinyl alcohol-polyethylene glycol copolymer

[0045] 0.5 parts talc

[0046] 33 portions of purified water.

[0047] This invention also discloses a method for preparing isosorbide mononitrate sustained-release capsules according to claims 1-4, wherein the preparation steps are as follows:

[0048] (1) Preparation of drug-loaded layer: Isosorbide mononitrate and lactose were added to purified water and stirred until completely dissolved to prepare isosorbide mononitrate and lactose coating solution; blank sucrose pellet cores were placed in a fluidized bed granulation and coating machine for preheating, and the prepared isosorbide mononitrate and lactose coating solution was sprayed onto the preheated blank sucrose pellet cores to prepare drug-loaded micro pellets. The theoretical weight gain of the drug-loaded layer was 152-205%.

[0049] (2) Preparation of sustained-release layer: Ethyl cellulose was slowly added to 90% ethanol solution and stirred to dissolve. Then talc was added and stirred to disperse it fully, so as to prepare a 90% ethanol coating solution of ethyl cellulose and talc. The dried microspheres obtained in step 1 were coated with a sustained-release layer. The theoretical weight gain of the sustained-release microspheres was 10.6%-20.7%.

[0050] (3) Preparation of immediate-release layer: Hydroxypropyl methylcellulose was slowly dispersed in purified water and stirred until completely dissolved. Isosorbide mononitrate was then added and stirred until dissolved to prepare a coating solution of isosorbide mononitrate and hydroxypropyl methylcellulose. The dried microspheres obtained in step 2 were coated with the immediate-release layer. The theoretical weight gain of the immediate-release microspheres was 22.4%-34.6%.

[0051] (4) Preparation of protective layer: Polyvinyl alcohol-polyethylene glycol copolymer is slowly added to purified water and stirred until completely dissolved. Then, talc powder is added and stirred and dispersed to prepare a polyvinyl alcohol-polyethylene glycol copolymer and talc powder coating solution. The dried microspheres obtained in step 3 are coated with a protective layer. The theoretical weight gain of the protective layer is 3.5%-8.5%.

[0052] (5) Capsule filling: Fill capsules according to the content.

[0053] More preferably, in the isosorbide mononitrate sustained-release capsules, the release amounts of isosorbide mononitrate at 0.5, 2, 4, and 8 hours are at least 25%, 38%-58%, 55%-75%, and 80% of the labeled amount, respectively.

[0054] More preferably, the drug-loaded layer, sustained-release layer, immediate-release layer, and protective layer are coated using a fluidized bed granulation and coating machine.

[0055] More preferably, in step (1) when coating the drug-loaded layer, the material temperature is controlled at 39℃±5℃, the atomization pressure at 0.2-0.4MP, the spraying speed at 3-12rpm, and the drying material temperature at 56℃; in step (2) when coating the sustained-release layer, the material temperature is controlled at 29℃±4℃, the atomization pressure at 0.1-0.4MP, the spraying speed at 5-15rpm, and the drying material temperature at 45℃.

[0056] More preferably, in step (3) when coating the immediate release layer, the material temperature is controlled at 39℃±5℃, the atomization pressure at 0.2-0.4MP, the spraying speed at 5-30rpm, and the drying material temperature at 56℃; in step (4) when coating the protective layer, the material temperature is controlled at 41℃±4℃, and the drying material temperature at 56℃.

[0057] The isosorbide mononitrate sustained-release capsules prepared by this invention have good dissolution and are more stable. The preparation method is simpler, more economical, and easier to scale up. Detailed Implementation

[0058] The present invention is specifically implemented through the following embodiments, which further explain and illustrate the present invention, but are not intended to limit the scope of protection of the present invention.

[0059] Example 1

[0060] This embodiment is a specific example of preparing isosorbide mononitrate sustained-release capsule product 1.

[0061] name Dosage (servings) effect Sugar pellet core 20 Starting core Isosorbide mononitrate 35 Active ingredients lactose 3 Osmotic pressure regulator Purified water 250.7 solvent

[0062] name Dosage (servings) effect Ethyl cellulose 5 Sustained-release materials talcum powder 2 Anti-adhesive Purified water 9.3 solvent Anhydrous ethanol 83.7 solvent

[0063] name Dosage (servings) effect Isosorbide mononitrate 15 Active ingredients Hydroxypropyl methylcellulose 2.5 adhesives Purified water 105 solvent

[0064] name Dosage (servings) effect Polyvinyl alcohol-polyethylene glycol copolymer 3 Film-forming materials talcum powder 0.5 Anti-adhesive Purified water 33.75 solvent

[0065] 1. Preparation of the drug-loaded layer: Isosorbide mononitrate and lactose were dissolved in water and stirred until completely dissolved to prepare an aqueous solution of isosorbide mononitrate and lactose. Blank sucrose pellet cores were preheated in a fluidized bed granulation and coating machine. The prepared coating solution was sprayed onto the preheated blank sucrose pellet cores for coating. The theoretical weight gain of the drug-loaded layer was 190%. 2. Sustained-release coating: Ethyl cellulose was slowly added to a 90% ethanol solution and stirred until dissolved. Talc was then added and stirred thoroughly to disperse the cellulose, preparing a 90% ethanol solution of ethyl cellulose and talc. The dried pellets obtained in step 1 were coated with a sustained-release layer. The theoretical weight gain of the sustained-release pellets was 12.1%.

[0066] 3. Immediate-release coating: Hydroxypropyl methylcellulose was slowly dispersed in purified water and stirred until completely dissolved. Isosorbide mononitrate was then added and stirred until dissolved to prepare an aqueous solution of isosorbide mononitrate and hydroxypropyl methylcellulose. The dried microspheres obtained in step 2 were coated with an immediate-release coating. The theoretical weight gain of the immediate-release microspheres was 26.9%.

[0067] 4. Protective coating: Slowly add the polyvinyl alcohol-polyethylene glycol copolymer to purified water and stir until completely dissolved. Then add talc powder and stir thoroughly to disperse, preparing an aqueous solution of polyvinyl alcohol-polyethylene glycol copolymer and talc powder. Coat the dried microspheres obtained in step 3 with a protective coating. The theoretical weight gain of the protective coating is 4.2%.

[0068] Capsule filling: Fill capsules according to the required content.

[0069] Example 2

[0070] This embodiment is a specific example of preparing isosorbide mononitrate sustained-release capsule product 1.

[0071] name Dosage (servings) effect Sugar pellet core 23 Starting core Isosorbide mononitrate 38 Active ingredients lactose 5 Osmotic pressure regulator Purified water 310 solvent

[0072] name Dosage (servings) effect Ethyl cellulose 6 Sustained-release materials talcum powder 3 Anti-adhesive Purified water 11.1 solvent Anhydrous ethanol 99.9 solvent

[0073] name Dosage (servings) effect Isosorbide mononitrate 15 Active ingredients Hydroxypropyl methylcellulose 5.5 adhesives Purified water 129.5 solvent

[0074] name Dosage (servings) effect Polyvinyl alcohol-polyethylene glycol copolymer 5 Film-forming materials talcum powder 0.75 Anti-adhesive Purified water 44.25 solvent

[0075] 1. Preparation of the drug-loaded layer: Isosorbide mononitrate and lactose were dissolved in water and stirred until completely dissolved to prepare an aqueous solution of isosorbide mononitrate and lactose. Blank sucrose pellet cores were preheated in a fluidized bed granulation and coating machine. The prepared coating solution was sprayed onto the preheated blank sucrose pellet cores for coating. The theoretical weight gain of the drug-loaded layer was 165%. 2. Sustained-release coating: Ethyl cellulose was slowly added to a 90% ethanol solution and stirred until dissolved. Talc was then added and stirred thoroughly to disperse the cellulose, preparing a 90% ethanol solution of ethyl cellulose and talc. The dried pellets obtained in step 1 were coated with a sustained-release layer. The theoretical weight gain of the sustained-release pellets was 14.3%.

[0076] 3. Immediate-release coating: Hydroxypropyl methylcellulose was slowly dispersed in purified water and stirred until completely dissolved. Isosorbide mononitrate was then added and stirred until dissolved to prepare an aqueous solution of isosorbide mononitrate and hydroxypropyl methylcellulose. The dried microspheres obtained in step 2 were coated with an immediate-release coating. The theoretical weight gain of the immediate-release microspheres was 28.5%.

[0077] 4. Protective coating: Slowly add the polyvinyl alcohol-polyethylene glycol copolymer to purified water and stir until completely dissolved. Then add talc powder and stir thoroughly to disperse, preparing an aqueous solution of polyvinyl alcohol-polyethylene glycol copolymer and talc powder. Coat the dried microspheres obtained in step 3 with a protective coating. The theoretical weight gain of the protective coating is 6.2%. Capsule filling: Fill capsules according to the content.

[0078] Example 3

[0079] This embodiment is a specific example of preparing isosorbide mononitrate sustained-release capsule product 1.

[0080] name Dosage (servings) effect Sugar pellet core 25 Starting core Isosorbide mononitrate 33 Active ingredients lactose 6 Osmotic pressure regulator Purified water 396.5 solvent

[0081] name Dosage (servings) effect Ethyl cellulose 8 Sustained-release materials talcum powder 4 Anti-adhesive Purified water 25.47 solvent Anhydrous ethanol 229.23 solvent

[0082] name Dosage (servings) effect Isosorbide mononitrate 15 Active ingredients Hydroxypropyl methylcellulose 7.5 adhesives Purified water 165 solvent

[0083] name Dosage (servings) effect Polyvinyl alcohol-polyethylene glycol copolymer 6 Film-forming materials talcum powder 1 Anti-adhesive Purified water 68 solvent

[0084] 1. Preparation of the drug-loaded layer: Isosorbide mononitrate and lactose were dissolved in water and stirred until completely dissolved to prepare an aqueous solution of isosorbide mononitrate and lactose. Blank sucrose pellet cores were preheated in a fluidized bed granulation and coating machine. The prepared coating solution was sprayed onto the preheated blank sucrose pellet cores for coating. The theoretical weight gain of the drug-loaded layer was 164%. 2. Sustained-release coating: Ethyl cellulose was slowly added to a 90% ethanol solution and stirred until dissolved. Talc was then added and stirred thoroughly to disperse the cellulose, preparing a 90% ethanol solution of ethyl cellulose and talc. The dried pellets obtained in step 1 were coated with a sustained-release layer. The theoretical weight gain of the sustained-release pellets was 18.2%.

[0085] 3. Immediate-release coating: Hydroxypropyl methylcellulose was slowly dispersed in purified water and stirred until completely dissolved. Isosorbide mononitrate was then added and stirred until dissolved to prepare an aqueous solution of isosorbide mononitrate and hydroxypropyl methylcellulose. The dried microspheres obtained in step 2 were coated with an immediate-release coating. The theoretical weight gain of the immediate-release microspheres was 28.8%.

[0086] 4. Protective coating: Slowly add the polyvinyl alcohol-polyethylene glycol copolymer to purified water and stir until completely dissolved. Then add talc powder and stir thoroughly to disperse, preparing an aqueous solution of polyvinyl alcohol-polyethylene glycol copolymer and talc powder. Coat the dried microspheres obtained in step 3 with a protective coating. The theoretical weight gain of the protective coating is 7.0%.

[0087] Capsule filling: Fill capsules according to the required content.

[0088] After capsule filling, the release rate of isosorbide mononitrate was tested. The release rates of isosorbide mononitrate at 0.5, 2, 4, and 8 hours should be ≥24%, 38%-58%, 55%-75%, and ≥80% of the labeled amount, respectively.

[0089] The statistical results of the release rate of isosorbide dinitrate sustained-release capsules are shown in Table 13.

[0090] Time (hours) 0.5 2 4 8 standard ≥25％ 38％-58％ 55％-75％ ≥80％ Example 1 32 46 66 89 Example 2 31 48 69 91 Example 3 30 45 67 87

[0091] The results showed that the formulation process has low labor intensity, low production cost, is easy to scale up, and produces products with good stability and stable drug release. The immediate-release layer releases drugs rapidly and can quickly reach blood drug concentrations. The sustained-release layer releases drugs slowly, prolonging the effective duration of action, reducing fluctuations in blood drug concentrations, reducing the occurrence of adverse drug reactions, and improving the safety of clinical drug use.

Claims

1. A method for preparing isosorbide mononitrate sustained-release capsules, characterized in that, The sustained-release capsule comprises a drug-loaded layer, a sustained-release layer, an immediate-release layer, and a protective layer; the drug-loaded layer includes a blank sucrose core, isosorbide mononitrate, lactose, and purified water; the sustained-release layer contains ethyl cellulose, purified water, and anhydrous ethanol; the immediate-release layer contains isosorbide mononitrate, hydroxypropyl methylcellulose, and purified water; and the protective layer contains polyvinyl alcohol-polyethylene glycol copolymer, talc, and purified water. The components of the sustained-release capsule are calculated by weight as follows: The drug-loaded layer consists of 20-25 parts of blank sucrose pellet core, 30-40 parts of isosorbide mononitrate, 3-6 parts of lactose, and 250.7-399.5 parts of purified water. The sustained-release layer consists of 5-8 parts ethyl cellulose, 5.35-25.67 parts purified water, and 48.15-231.03 parts anhydrous ethanol. The immediate-release layer consists of 10-20 parts isosorbide mononitrate, 2.5-7.5 parts hydroxypropyl methylcellulose, and 102.5-170 parts purified water. The protective layer consists of 1-5 parts of polyvinyl alcohol-polyethylene glycol copolymer, 0.5-1 part of talc, and 20-50 parts of purified water. The preparation steps are as follows: (1) Preparation of drug-loaded layer: Isosorbide mononitrate and lactose were added to purified water and stirred until completely dissolved to prepare isosorbide mononitrate and lactose coating solution; blank sucrose pellet cores were placed in a fluidized bed granulation and coating machine for preheating, and the prepared isosorbide mononitrate and lactose coating solution was sprayed onto the preheated blank sucrose pellet cores to prepare drug-loaded microgranules. The theoretical weight gain of the drug-loaded layer was 152-205%. (2) Preparation of sustained-release layer: Ethyl cellulose was slowly added to 90% ethanol solution and stirred to dissolve. Then, talc powder was added and stirred to disperse thoroughly to prepare a 90% ethanol coating solution of ethyl cellulose and talc powder. The dried microspheres obtained in step (1) were coated with a sustained-release layer. The theoretical weight gain of the sustained-release microspheres was 10.6%-20.7%. (3) Preparation of the immediate-release layer: Hydroxypropyl methylcellulose was slowly dispersed in purified water and stirred until completely dissolved. Isosorbide mononitrate was then added and stirred until dissolved to prepare a coating solution of isosorbide mononitrate and hydroxypropyl methylcellulose. The dried microspheres obtained in step (2) were coated with the immediate-release layer. The theoretical weight gain of the immediate-release microspheres was 22.4%-34.6%. (4) Preparation of protective layer: Polyvinyl alcohol-polyethylene glycol copolymer is slowly added to purified water and stirred until completely dissolved. Then, talc powder is added and stirred thoroughly to disperse, thus preparing a polyvinyl alcohol-polyethylene glycol copolymer and talc powder coating solution. The dried microspheres obtained in step (3) are coated with a protective layer, and the theoretical weight gain of the protective layer is 3.5%-8.5%. (5) Capsule filling: Fill capsules according to the content; The drug-loaded layer, sustained-release layer, immediate-release layer, and protective layer are coated using a fluidized bed granulation and coating machine. In step (1), the material temperature is controlled at 39℃±5℃, the atomization pressure at 0.2-0.4MPa, the spraying speed at 3-12rpm, and the temperature of the dried material at 56℃ during the drug-loaded coating process; in step (2), the material temperature is controlled at 29℃±4℃, the atomization pressure at 0.1-0.4MPa, the spraying speed at 5-15rpm, and the temperature of the dried material at 45℃ during the sustained-release coating process.

2. The preparation method according to claim 1, characterized in that, The components of the sustained-release capsule are calculated in parts by weight as follows: The drug-loaded layer consists of: 20 parts blank sucrose pellet core, 35 parts isosorbide mononitrate, 3 parts lactose, and 250.7 parts purified water; The sustained-release layer consists of: 5 parts ethyl cellulose, 9 parts purified water, and 83 parts anhydrous ethanol. The immediate-release layer is composed of: 15 parts isosorbide mononitrate, 2.5 parts hydroxypropyl methylcellulose, and 105 parts purified water. The protective layer consists of 3 parts polyvinyl alcohol-polyethylene glycol copolymer, 0.5 parts talc, and 33 parts purified water.

3. The preparation method according to claim 1, characterized in that, In the isosorbide mononitrate sustained-release capsules, the release amounts of isosorbide mononitrate at 0.5, 2, 4, and 8 hours are at least 25%, 38%-58%, 55%-75%, and 80% of the labeled amount, respectively.

4. The preparation method according to claim 1, characterized in that, In step (3), the material temperature is controlled at 39℃±5℃, the atomization pressure at 0.2-0.4MPa, the spraying speed at 5-30rpm, and the material temperature at 56℃ during the coating of the immediate release layer. In step (4), the material temperature is controlled at 41℃±4℃, and the material temperature at 56℃ during the coating of the protective layer.