CN100579525C - Nicardipine hydrochloride sustained-release preparation and preparation method thereof - Google Patents

Abstract

The nicardipine hydrochloride sustained-release preparation and its preparation method are a kind of sustained-release preparation mainly for treating essential hypertension, coronary heart disease and various types of angina pectoris. Composition of micropills; stomach-soluble micropills and enteric-coated micropills are mixed at a ratio of 1:0.5 to 5 and filled into hollow capsules to prepare sustained-release capsules containing nicardipine hydrochloride, which have a sustained-release effect within 12 hours. The enteric-coated pellets have a sustained-release effect, and their main components are nicardipine hydrochloride, pharmaceutical polymer materials, drug release regulators and some pharmaceutical excipients. The pellets are produced by extrusion-spheronization technique. The slow-release preparation treats essential hypertension, cerebrovascular disease, coronary heart disease and various types of angina pectoris, can make the blood drug concentration quickly reach the therapeutic concentration, maintain stable and effective for a long time, take less times, and have less side effects.

Description

Nicardipine hydrochloride sustained-release preparation and preparation method thereof

technical field

Specifically, the invention relates to a sustained-release preparation of nicardipine hydrochloride for treating essential hypertension, coronary heart disease and various types of angina pectoris, and relates to the technical field of pharmaceutical preparations.

Background technique

Hypertension is an important risk factor for cardiovascular and cerebrovascular diseases. In people of any age and gender, the risk of cardiovascular and cerebrovascular diseases is positively correlated with elevated blood pressure. Therefore, prevention and treatment of high blood pressure should be strengthened to reduce the incidence and mortality of cardiovascular and cerebrovascular diseases. Elderly hypertensive patients have more target organ damage, and are often accompanied by coronary heart disease, angina pectoris, and renal insufficiency. Therefore, many countries have carried out clinical research on drugs for diseases such as hypertension, angina pectoris, and coronary heart disease. At present, there are many kinds of drugs currently used to treat cardiovascular and cerebrovascular diseases such as hypertension, such as diuretics, adrenergic nerve inhibitors, vasodilators, angiotensin converting enzyme inhibitors, 5-hydroxytryptamine receptor antagonists, Ganglion and postganglionic sympathetic inhibitors, β-receptor blockers and calcium ion antagonists, etc., mostly can only achieve 50% to 60% antihypertensive effect, and long-term application may also produce some adverse reactions.

Nicardipine Hydrochloride is a new type of dihydropyridine calcium antagonist, its chemical name is: 2,6-dimethyl 4-(3-nitrophenyl)-1,4-dihydropyridine-3 , 5-dihydroxy acid, 3-[β-(N-benzyl-N-methylamino)] ethyl ester-5-methyl ester hydrochloride; molecular formula: C ₂₆ H ₂₉ N ₃ O ₆ ·HCl; molecular weight For: 515.99. Nicardipine hydrochloride has the advantages of wide range of effects, significant curative effect, little impact on heart function, and few side effects. It is widely used clinically to treat essential hypertension, coronary heart disease, angina pectoris and other diseases. Its main mechanism of action is to inhibit the influx of transmembrane calcium ions in cardiac muscle and vascular smooth muscle without changing the blood calcium concentration; it has a high degree of effect on blood vessels. Selective, the calcium ion antagonistic effect on vascular smooth muscle is stronger than the effect on cardiac muscle; no antiarrhythmic effect, nor arrhythmogenic effect; can improve arterial compliance and delay the occurrence of atherosclerosis; nicardipine hydrochloride It can not only supply myocardial oxygen, but also reduce myocardial oxygen consumption, so it can increase the exercise tolerance of patients with chronic stable angina pectoris and reduce the frequency of angina pectoris. The antihypertensive effect of nicardipine hydrochloride is to dilate arterioles and reduce total peripheral vascular resistance without affecting sympathetic nerve activity.

In the process of treating essential hypertension and other cardiovascular and cerebrovascular diseases, nicardipine hydrochloride has an effective rate of 92.7% in stage I, 90.8% in stage II, and 81.1% in stage III. Long-term application The antihypertensive effect can reach more than 80%, and has no adverse effects on the heart, lung and kidney. It is currently an ideal antihypertensive drug, and it is often used as the first choice for antihypertensive drugs in clinical practice. But the biological half-life of this medicine is short, in order to maintain better curative effect, stabilize patient's blood pressure, need to take medicine on time, cause the patient to take medicine frequently (dosing 3～4 times every day). Because cardiovascular and cerebrovascular diseases are prone to sudden onset, and "drug withdrawal rebound" occurs in some patients who cannot take medicine on time, it often seriously endangers the life safety of patients. Moreover, conventional preparations have large fluctuations in blood drug concentration, and some adverse side effects are prone to occur, which is not conducive to medication for patients.

Nicardipine hydrochloride oral preparations currently on the market include common tablets for rapid release and sustained-release preparations that maintain a long-term curative effect. Since ordinary tablets need to be taken 3 to 4 times a day, and the blood drug concentration fluctuates greatly after taking the medicine, the compliance of taking the medicine is poor, and the adverse reactions are obviously more. Nicardipine hydrochloride sustained-release preparations are widely used clinically. Japan Yamanouchi Pharmaceutical Co., Ltd., which first developed nicardipine hydrochloride sustained-release preparations, launched a product in China: Perdipine sustained-release capsules. The product is made of sustained-release pellets by coating drug powder on blank pellet cores and then wrapping pH-dependent controlled-release membranes. Chinese patent 03110949.7 discloses a sustained-release preparation of nicardipine hydrochloride that can be released in the gastrointestinal tract environment. Laser drilling technology is used to make a drug-release hole on the tablet coating film, which can achieve 24-hour continuous drug release. Effect.

The preparation of nicardipine hydrochloride sustained-release pellets by applying drug powder to the blank core can obtain pellets with regular appearance and easy coating, but the production process requires expensive fluidized bed powder coating equipment. Strictly managed intermediate process control must be carried out, and the yield rate of production is not high. The present invention overcomes the above disadvantages.

Contents of the invention

Technical problem: The object of the present invention is to provide a nicardipine hydrochloride sustained-release preparation and its preparation method. The sustained-release preparation can effectively control the drug release rate, reduce adverse reactions, reduce the number of administrations, and have good medication compliance. The production process of the nicardipine hydrochloride sustained-release preparation should be relatively simple, the production process is easy to control, and the yield is high.

Technical scheme: the nicardipine hydrochloride sustained-release preparation of the present invention is composed of fast-release gastric-coated pellets and sustained-release enteric-coated pellets; the gastric-coated pellets and enteric-coated pellets are mixed into hollow capsules at a ratio of 1:0.5 to 5, Sustained-release capsules containing nicardipine hydrochloride are prepared, and the capsules have a sustained-release effect within 12 hours.

The quick-release gastric-soluble pellets of nicardipine hydrochloride consist of 5-30% of nicardipine hydrochloride; 60-90% of filling agent; 3-10% of disintegrating agent; and 5-32% of other auxiliary materials.

The filler is: a mixture of any one or more of soluble fillers such as lactose, mannitol, sucrose, glucose, sorbitol and microcrystalline cellulose; the disintegrant is: cross-linked polyvinylpyrrolidone, Any one or combination of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, etc.

The composition of nicardipine hydrochloride sustained-release enteric-coated pellets is: nicardipine hydrochloride accounts for 5-30%; pharmaceutical polymer materials account for 5-20%; drug dissolution regulator accounts for 0.1-5.0%; other excipients account for 45-20%. 90%.

Pharmaceutical polymer materials are polymer materials that can be dissolved in the pH environment of the intestinal tract but are difficult to dissolve in gastric juice.

The polymer material is methacrylic acid-methyl methacrylate copolymer and cellulose derivatives.

Methacrylic acid-methyl methacrylate copolymer refers to EUDRAGIT L100-55, EUDRAGIT L100, EUDRAGIT S100 and EUDRAGIT L30D0-55.

Cellulose derivatives refer to hydroxypropylmethylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP) and hydroxypropylmethylcellulose acetate succinate (HPMCAS).

The drug dissolution modifier refers to a salt substance with an acidic aqueous solution, specifically ammonium chloride, potassium dihydrogen phosphate, sodium dihydrogen phosphate, diethylamine hydrochloride and triethylamine hydrochloride.

The preparation is prepared by mixing stomach-coated pellets and enteric-coated pellets at a ratio of 1:0.5 to 5 and then filling them in capsules, wherein the preparation method of nicardipine hydrochloride slow-release enteric-coated pellets is: in addition to drug dissolution adjustment In addition to the agent, the raw materials are dry mixed, and the aqueous solution containing the drug dissolution regulator is used as a wetting agent to obtain a soft material, which is extruded through a mesh plate with a pore size of 0.5-1.5mm, and the rotation speed is 250-600r/min for 5-20min. , dry at 40°C; the preparation method of the quick-release nicardipine hydrochloride stomach-soluble pellets is as follows: after dry mixing each material, water is used as a wetting agent to obtain a soft material, and the aperture is 0.5-1.5mm through a stencil Extrude, rotate at 250-600r/min, spheronize, and dry at 40°C.

Beneficial effects: From the analysis test results, it can be seen that the nicardipine hydrochloride sustained-release capsule has a good sustained-release effect, and can release an effective amount of nicardipine hydrochloride in a short period of time in the hydrochloric acid solution, ensuring a quick onset of action . In the intestinal solution, the nicardipine hydrochloride sustained-release capsules can ensure the steady release of nicardipine hydrochloride for 12 hours, and have a stable blood pressure lowering effect.

Detailed ways

Nicardipine hydrochloride gastric-coated pellets and enteric-coated pellets were prepared by extrusion-spheronization technology. Gastric-coated pellets can quickly release nicardipine hydrochloride in acidic solution, and enteric-coated pellets have sustained-release effect in intestinal solution. Nicardipine hydrochloride stomach-soluble pellets and enteric-coated pellets are mixed at a ratio of 1:0.5-5, and then the mixed pellets are poured into capsules.

The prescription of the sustained-release enteric-coated pellets is as follows, calculated by mass percentage.

Main drug: nicardipine hydrochloride 5～30%

Accessories:

Pharmaceutical polymer materials 5～20%

Drug Dissolution Regulator 0.1～5.0%

Other accessories Balance

The pharmaceutical polymer material in the above prescription refers to a polymer material that can be dissolved in the pH environment of the intestinal tract but is insoluble in gastric juice, such as methacrylic acid-methyl methacrylate copolymer and cellulose derivatives. The methacrylic acid-methyl methacrylate copolymer referred to here can be EUDRAGIT L100-55, EUDRAGIT L100, EUDRAGIT S100 and EUDRAGIT L30D0-55; the cellulose derivative referred to here can be hydroxypropylmethyl phthalate Cellulose (HPMCP), cellulose acetate phthalate (CAP), and hydroxypropylmethylcellulose acetate succinate (HPMCAS).

The drug dissolution regulator in the above prescription refers to the adjustment of the pH value that affects the drug dissolution rate, such as salts that are acidic in the aqueous solution: ammonium chloride, potassium dihydrogen phosphate, sodium dihydrogen phosphate, diethylamine hydrochloride , Triethylamine hydrochloride.

Other excipients in the above prescription refer to commonly used fillers in pharmaceutical preparations: any one or more combinations of lactose, mannitol, sucrose, glucose, sorbitol, starch, modified starch, and microcrystalline cellulose.

The other adjuvants in the above prescription also refer to binders commonly used in pharmaceutical preparations: any one or combination of polyvinylpyrrolidone, hydroxypropylmethylcellulose, etc.

Other excipients in the above prescription also refer to disintegrants commonly used in pharmaceutical preparations: any one of cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, etc. one or more combinations.

Other excipients in the above prescription also refer to lubricants: PEG4000, PEG4000, magnesium stearate, talcum powder, any one or more combinations, micronized silica gel, etc.

In addition to the drug dissolution modifier, the above-mentioned raw materials are fully mixed according to the prescription ratio. The aqueous solution dissolved with the drug dissolution modifier was used as a wetting agent to prepare a soft material, and nicardipine hydrochloride enteric-coated sustained-release pellets were prepared by extrusion-spheronization technology. The hole diameter of the screen for extrusion is 0.5-1.5mm. The rounding speed is 250-600r/min. The rounding time is 5-20min. The optimal mesh aperture for extrusion is 0.8-1.2mm. The best rounding speed is 400-500r/min. The rounding time is 10-12min. The nicardipine hydrochloride enteric-coated pellets prepared by spheronizing are dried with hot air at 40°C until the moisture content is below 3%.

Measure the drug release situation of this nicardipine hydrochloride enteric-coated pellets according to the first method of appendix XD of two appendices of Chinese Pharmacopoeia edition in 2005. The release medium is phosphate buffer (take 6.8g of potassium dihydrogen phosphate and 1g of polysorbate 80, add 900ml of water to dissolve, adjust the pH value to 6.5±0.05 with sodium hydroxide test solution, add water to 1000ml) 900ml, and the speed is 150r /min, sampling and analysis at 1, 2, 4, 6, and 10 hours. The results show that the enteric-coated pellets have a good sustained-release effect, and the total release amount is greater than 80% in 10 hours.

The drug dissolution regulator has a very obvious impact on the drug release, and the pellets made of salts with a lower pH can accelerate the drug release. The type and amount of pharmaceutical polymer materials also have a greater impact on drug release. The desired sustained-release pellets can be obtained by selecting the type and dosage of pharmaceutical polymer materials and drug dissolution regulators. In addition, the rotation speed and spheronization time during spheronization also have a greater impact on drug release.

The prescription of stomach-soluble pellets is as follows, calculated by mass percentage.

Main drug: nicardipine hydrochloride 5～30%

Accessories:

Filler 60～90%

Disintegrant 3～10%

Other accessories Balance

Fillers in the above prescription: any one or more combinations of soluble fillers such as lactose, mannitol, sucrose, glucose, sorbitol, and microcrystalline cellulose.

Disintegrant in the above prescription: any one or combination of cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, etc.

The other auxiliary materials in the above prescription refer to: adhesives, lubricants and other auxiliary materials commonly used in solid oral preparations.

The preparation process of stomach-soluble pellets is the same as the above-mentioned preparation process of enteric-coated pellets, adopting extrusion-spheronization technology, and using water as a wetting agent. The process parameters are also the same as those for the preparation of enteric-coated pellets.

According to the Chinese Pharmacopoeia edition in 2005 two appendices XD the first method is measured the drug release of this nicardipine hydrochloride gastric dissolving pellet. The release medium is 900ml of hydrochloric acid of 0.1mol/L, the rotating speed is 150r/min, and samples are taken and analyzed at 0.25, 0.5, 1, and 2 hours. The results show that the stomach-soluble pellets have 80% drug release in 0.25 hours, and the drug release reaches more than 95% in 1 hour.

The preparation is prepared by mixing stomach-coated pellets and enteric-coated pellets at a ratio of 1:0.5 to 5 and then filling them in capsules, wherein the preparation method of nicardipine hydrochloride slow-release enteric-coated pellets is: in addition to drug dissolution adjustment In addition to the agent, the raw materials are dry mixed, and the aqueous solution containing the drug dissolution regulator is used as a wetting agent to obtain a soft material, which is extruded through a mesh plate with a pore size of 0.5-1.5mm, and the rotation speed is 250-600r/min for 5-20min. , dry at 40°C; the preparation method of the quick-release nicardipine hydrochloride stomach-soluble pellets is as follows: after dry mixing each material, water is used as a wetting agent to obtain a soft material, and the aperture is 0.5-1.5mm through a stencil Extrude, rotate at 250-600r/min, spheronize, and dry at 40°C.

Embodiment 1: the preparation of nicardipine hydrochloride stomach-soluble pellets

prescription

Main drug and excipient name Weight / grams) Nicardipine Hydrochloride 20   Microcrystalline Cellulose 20 Lactose 130 Sodium carboxymethyl starch 18 Polyvinylpyrrolidone K-30 12 purified water 80

Preparation Process

Wetting agent was prepared by dissolving 12 g of polyvinylpyrrolidone K-30 in 80 ml of purified water. Fully mix 20 g of nicardipine hydrochloride, 130 g of lactose, 20 g of microcrystalline cellulose, and 12 g of sodium carboxymethyl starch, and pass through a 60-mesh sieve. Add the wetting agent to the mixed dry powder and stir at high speed for 5 minutes to obtain a soft material. Extrude the soft material through a 1.0mm mesh, and process it on a spheronizer for 10 minutes at a speed of 500 rpm. The obtained wet pellets were air-dried at 40° C. for 4 hours, and 24-40 mesh pellets were sieved, with a yield of 92%.

Embodiment 2: the preparation of nicardipine hydrochloride stomach-soluble pellets

prescription

Main drug and excipient name Weight / grams) Nicardipine Hydrochloride 20   Microcrystalline Cellulose 33 Mannitol 130  Low-substituted hydroxypropyl cellulose 15 Polyvinylpyrrolidone K-30 12 purified water 80

Preparation Process

The preparation process is the same as in Example 1, except that lactose is replaced by mannitol, and sodium carboxymethyl starch is replaced by low-substituted hydroxypropyl cellulose. The yield is 88%.

Example 3: Preparation of nicardipine hydrochloride sustained-release enteric-coated pellets

prescription

Main drug and excipient name Weight / grams) Nicardipine Hydrochloride 40 EUDRAGIT L100-55 25 Potassium dihydrogen phosphate 5   Microcrystalline Cellulose 26 Lactose 89 Sodium carboxymethyl starch 5 Polyvinylpyrrolidone K-30 6 PEG4000 4 purified water 80

Preparation Process

40g of nicardipine hydrochloride; 89g of lactose; 26g of microcrystalline cellulose; EUDRAGIT L100-55, 25g; 5g of sodium carboxymethyl starch; After dissolving 5g of potassium dihydrogen phosphate and 6g of polyvinylpyrrolidone K-30 in 80ml of purified water, add it to the mixed dry powder and stir at high speed for 5 minutes to obtain a soft material. Extruded through a 1.0mm mesh, processed on a spheronizer for 10 minutes at a speed of 400 rpm. The obtained wet pellets were air-dried at 40° C. for 4 hours. Sieve 24-40 mesh pellets. The yield of nicardipine hydrochloride sustained-release enteric-coated pellets was 85%.

The preparation of embodiment 4 nicardipine hydrochloride sustained-release enteric-coated pellets

prescription

Main drug and excipient name Weight / grams) Nicardipine Hydrochloride 40 EUDRAGIT S100 twenty two ammonium chloride 8   Microcrystalline Cellulose 25 Lactose 90 Sodium carboxymethyl starch 5 Polyvinylpyrrolidone K-30 6 PEG4000 4 purified water 80

Preparation Process

The preparation process is the same as in Example 3, except that EUDRAGIT L100-55 is replaced by EUDRAGITS100, and potassium dihydrogen phosphate is replaced by ammonium chloride. The yield of nicardipine hydrochloride sustained-release enteric-coated pellets was 83%.

The preparation of embodiment 5 nicardipine hydrochloride sustained-release enteric-coated pellets

prescription

Main drug and excipient name Weight / grams) Nicardipine Hydrochloride 40 Hydroxypropylmethylcellulose phthalate (HPMCP) 20 Diethylamine Hydrochloride 6   Microcrystalline Cellulose 25 Lactose 60 Mannitol 34 Cross-linked polyvinylpyrrolidone 5 Polyvinylpyrrolidone K-30 10 purified water 80

Preparation Process

40g of nicardipine hydrochloride; 60g of lactose; 34g of lactose; 25g of microcrystalline cellulose; 20g of hydroxypropylmethylcellulose phthalate (HPMCP); After dissolving 6g of diethylamine hydrochloride and 10g of polyvinylpyrrolidone K-30 in 80ml of purified water, add it to the mixed dry powder and stir at high speed for 5 minutes to obtain a soft material. Extruded through a 0.8mm mesh, processed on a spheronizer for 10 minutes at a speed of 450 rpm. The obtained wet pellets were air-dried at 40° C. for 4 hours. Sieve 24-40 mesh pellets. The yield of nicardipine hydrochloride sustained-release enteric-coated pellets was 82%.

Embodiment 6 Preparation of nicardipine hydrochloride sustained-release enteric-coated capsules

prescription

Preparation Process

Fully mix 110 g of nicardipine hydrochloride stomach-coated pellets, 150 g of nicardipine hydrochloride enteric-coated pellets and 2 g of micropowder silica gel. Pack into No. 2 hollow capsules, and fill with about 255 mg of micropills in each capsule. The specification of the nicardipine hydrochloride sustained-release capsules made in this way is: 40 mg/capsule (calculated as nicardipine hydrochloride).

Analysis and comparison

According to the drug standard WS1-(X-316)-2003Z issued by the State Food and Drug Administration, the release analysis of the nicardipine hydrochloride sustained-release capsules was carried out

Dissolution time 1 hour 2 hours 4 hours 8 hours 12 hours Dissolution medium 900ml hydrochloric acid solution (take 14ml hydrochloric acid, add 4g sodium chloride, add water to dissolve, and dilute to 2000ml) 900ml phosphate buffered saline (containing 0.1% polysorbate 80, pH=6.5) The dissolution medium is the same as 2 hours The dissolution medium is the same as 2 hours The dissolution medium is the same as 2 hours Release amount of nicaridine hydrochloride 27% 32% 49% 73% 87%

Note: Release in hydrochloric acid solution for 1 hour, filter out the insoluble matter, and put it into phosphate buffer for release test.

From the analysis test results, it can be seen that the nicardipine hydrochloride sustained-release capsule has a good sustained-release effect, and can release an effective amount of nicardipine hydrochloride in a short period of time in a hydrochloric acid solution to ensure a quick onset of action. In the intestinal solution, the nicardipine hydrochloride sustained-release capsules can ensure the steady release of nicardipine hydrochloride for 12 hours, and have a stable blood pressure lowering effect.

Claims (4)

1. a nicardipine hydrochloride slow-release preparation, it is characterized in that this slow-release preparation is made up of gastric-coated pellets and sustained-release enteric-coated pellets of fast release; Gastric-soluble pellets and enteric-coated pellets Mix and pack into hollow capsules to prepare sustained-release capsules containing nicardipine hydrochloride, which have sustained-release effects within 12 hours; The Nicardipine hydrochloride fast-release stomach-soluble micropills are composed in weight percent: nicardipine hydrochloride accounts for 5-30%; filler accounts for 60-90%; disintegrant accounts for 3-10%; and the balance is other auxiliary materials; The nicardipine hydrochloride slow-release enteric-coated pellets consist of the following components by weight: nicardipine hydrochloride accounts for 5-30%; pharmaceutical polymer materials account for 5-20%; drug dissolution regulator accounts for 0.1-5.0%; the balance is other accessories; The polymer material is methacrylic acid-methyl methacrylate copolymer; The drug dissolution modifier refers to an acidic salt in an aqueous solution, specifically ammonium chloride, potassium dihydrogen phosphate, sodium dihydrogen phosphate, diethylamine hydrochloride or triethylamine hydrochloride. 2. nicardipine hydrochloride sustained-release preparation according to claim 1, is characterized in that described filler is: any one or more in lactose, mannitol, sucrose, glucose, sorbitol and microcrystalline cellulose The mixture; the disintegrating agent is: any one or more combinations of cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and cross-linked sodium carboxymethyl cellulose. 3. Nicardipine hydrochloride sustained release preparation according to claim 1, is characterized in that methacrylic acid-methyl methacrylate copolymer refers to EUDRAGIT L100-55, EUDRAGIT L100, EUDRAGITS100 or EUDRAGIT L30D0-55. 4. a preparation method of nicardipine hydrochloride sustained-release preparation as claimed in claim 1, is characterized in that the preparation is filled in capsules after being mixed by stomach-coated pellets and enteric-coated pellets in a ratio of 1: 0.5～5. Made in China, wherein: the preparation method of nicardipine hydrochloride sustained-release enteric-coated pellets is: except for the drug dissolution regulator, dry-mix the raw materials, and use the aqueous solution dissolved in the drug dissolution regulator as a wetting agent to prepare soft The material is extruded through a 0.5-1.5mm stencil with an aperture of 0.5-1.5mm, and the rotating speed is 250-600r/min, spheronizing for 5-20min, and drying at 40°C; After the materials are dry mixed, water is used as a wetting agent to obtain a soft material, which is extruded through a stencil with a pore size of 0.5-1.5mm, spheronized at a speed of 250-600r/min, and dried at 40°C.