CN1931166A - medications for high blood pressure - Google Patents

Abstract

The invention discloses an enteric-coated tablet (trade name: an aranidipine enteric-coated tablet) for treating hypertension, which is prepared by taking aranidipine ((+/-) 1, 4-dihydro-2, 6-dimethyl-4- (2-nitrophenyl) -3, 5-dipicolinic acid methyl-2-oxypropyl ester) as an active ingredient, wherein a tablet core is prepared by taking aranidipine, acrylic resin (L100), acrylic resin (S100), lactose, starch, microcrystalline cellulose, hydroxypropyl methyl cellulose and magnesium stearate as raw auxiliary materials. Has the advantages of high bioavailability, long-lasting action, one-time daily administration, convenient use, greatly improved compliance of patients, and good curative effect for treating hypertension.

Description

medications for high blood pressure

technical field

The invention relates to the technical field of chemical medicines, in particular to an enteric-coated tablet (trade name: aredipine enteric-coated tablet) for treating hypertension prepared by using aredipine as an active ingredient.

Background technique

Aredipine, its chemical structural formula is:

Molecular formula: C ₁₉ H ₂₀ N _2O N ₂ O ₇

Molecular weight: 388.37

Chemical name: (±) 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylate methyl-2-oxypropyl ester

Aredipine was developed by Taiho Pharmaceutical Co., Ltd. of Japan in the early stage (the status quo of new drug research and development in the world, page 9 in 2001) and was first approved to be marketed in Japan in 1996 (page 185, issue 47, issue of recent 1999), and has been successively published in Listed in the United States, according to literature reports, a multi-center, double-blind trial conducted in Japan showed that the effective rate of taking aledipine was 89.1% (368 cases/413 cases) in 413 hypertensive patients. They are as follows:

Indications Efficient mild to moderate essential hypertension 90.9% (314 cases/349 cases) Severe hypertension 88.9% (32 cases/36 cases) Hypertension with renal impairment 78.6% (22 cases/28 cases)

Long-term use shows that the antihypertensive effect is good, and the effective rate is 88.3% (53 cases/60 cases); orally once a day, it is a vasodilator and calcium channel blocker for the treatment of hypertension, with high curative effect and good tolerance , a potent, long-acting calcium antagonist with greater potency and duration of action than nifedipine and nicardipine without affecting heart rate (Pharma projects September 2002), and activity in opening potassium channels . Clinically, it has a good curative effect on essential hypertension, reduces peripheral resistance of blood vessels, controls cardiac hypertrophy, and enhances ejection function.

This product is a new type of calcium antagonist. Its characteristics are:

① Both L-type and T-type calcium channel blockade. Aredipine blocks L-type Ca2 ⁺ channels in a voltage- and frequency-dependent manner, and because of its high affinity to activated and inactivated calcium channels, it has slower kinetics, so it can be long-acting Dilate blood vessels. In addition, it also has a potassium channel opening effect.

②Aredipine can significantly inhibit the pressor response induced by norepinephrine and peripheral sympathetic nerve stimulation, and this effect is closely related to its potent antihypertensive activity.

③Aredipine can also reduce the incidence of stroke, cardiac fibrosis, proliferative fibroarteritis and malignant nephrosclerosis.

Hypertension is a common disease. The incidence rate in my country's 1999 census was 10%. At present, there are about 100 million hypertensive patients. Hypertension is the main cause of coronary heart disease, stroke, and heart and kidney failure. The first survey of causes of death in my country shows that , cardiovascular disease ranks first, and hypertension is its main risk factor. Therefore, the prevention and treatment of hypertension is a research topic of global concern.

At present, Aredipine Granules is a marketed product in Japan. This product was successfully developed by three companies in Japan, Dapeng Pharmaceuticals, Wanzi Pharmaceuticals, and BMS, on dihydropyridine calcium antagonist drugs. The trade name of Dapeng Company is Sapresta Granules. Meatballs and BMS for Bec Granules.

Aredipine has high bioavailability, slow onset, long-lasting effect, is taken once a day, is convenient to use, greatly improves patient compliance, and has a good curative effect for treating hypertension. New drugs for the hypertensive system.

In addition, there is an application date of November 19, 2003, and application number 3120970.X "Application of gastric motility drugs in the preparation of colon-localized pharmaceutical compositions" discloses a composition for oral colon-localized drug delivery, which includes enteric-coated tablets, The tablet is divided into a tablet core and an enteric coating solution. The tablet core contains pharmaceutical ingredients, lactose, microcrystalline cellulose, starch, magnesium stearate, etc., and the enteric coating solution contains Eudragit L (namely: acrylic resin L ), Utechy S (namely: acrylic resin S), etc.

"Journal of the Second Military Medical University" volume 20, issue 7, pages 455-458 discloses nicardipine hydrochloride enteric-coated sustained-release pellets, which use acrylic resin to locate in the intestinal tract, and contain PEG6000, starch, sugar and dextrin and other accessories.

Contents of the invention

The purpose of the invention is to develop aredipine enteric-coated tablets and a preparation method thereof, and provide a new drug for treating hypertension.

In order to achieve the purpose of the present invention, the technical scheme that the present invention takes is as follows: we carry out prescription screening test to select better prescription therefrom with reference to foreign products, see: the research of prescription and technology of aledipine enteric-coated tablet:

Product name: Aredipine enteric-coated tablets

English name: Aranidipine Enteric-coated Tablets

Raw material name: Aredipine

1. Source of raw materials Chemical Pharmaceutical Department of Tianjin Pharmaceutical Research Institute Batch number: 030222

2. Prescription

1) Core (1000 pieces):

Aredipine 5g

Acrylic resin (Eudragit L100) 20g

Acrylic resin (Eudragit S100) 5g

Lactose 80g

Starch 80g

Microcrystalline Cellulose 10g

Hydroxypropyl Methyl Cellulose (HPMC5cps) 10g

Magnesium stearate 1g

Made into 1000 pieces 211g

2) Prescription of enteric coating solution:

Acrylic resin (Eudragit L100) 10g

Macrogol 6000 1g

Talc powder 2g

Titanium Dioxide 2g

85% ethanol 200mL

Pigment Appropriate amount

Coating weight gain 4～6%

3. Preparation process (operation in dark)

1) Tablet preparation process

a. The auxiliary materials are passed through a 100-mesh sieve.

b. Dissolve 5g of Aredipine and 25g of acrylic resin Eudragit L100 in 500ml of 80% ethanol solution to prepare A solution.

c. Dissolve 5g of Aredipine and 25g of acrylic resin Eudragit S100 in 500ml of 80% ethanol solution to prepare solution B.

d. Weigh two portions of mixed auxiliary materials, each containing 80g of lactose, 80g of starch, and 10g of microcrystals, pass through a 40-mesh sieve and mix well.

e. Put one part of the mixed auxiliary materials into the fluidized bed, use A solution as the binder, and granulate by one-step granulation method to obtain granules A.

f. Put another part of mixed auxiliary materials into the fluidized bed, use solution B as binder, and granulate by one-step granulation method to obtain granule B.

g. 24 mesh granules, according to the tablet core prescription, mix the two kinds of granules in proportion (granule A: granule B = 80:20), add hydroxypropyl methylcellulose and magnesium stearate, and fully mix with the mixed granules uniform.

h. Use a φ9 mm shallow concave punch to compress tablets on a single-punch tablet press.

2) Tablet coating process

Acrylic resin Eudragit L100 powder is swelled with an appropriate amount of 85% ethanol, left overnight, fully dissolved by ultrasonication, added polyethylene glycol 6000, stirred well and dissolved, then added 85% ethanol to the full amount, added talcum powder, titanium dioxide and pigment, passed through a colloid mill for 5-6 Again, pass through a 120-mesh sieve, and set aside.

Tablets were coated until the weight of the tablet core increased by 4-6%, and dried at 40°C for 2 hours. Remove from room temperature packaging.

4. Dosage form selection basis

Aredipine was developed by Dapeng Pharmaceutical Co., Ltd. of Japan and was first approved for marketing in Japan in 1996 for the treatment of hypertension. This product has the characteristics of high bioavailability and long-lasting effect. Take it orally, once a day, one bag at a time. The foreign product is granule, and its specification is 5mg/bag. Due to the small dosage, we made it into easy-to-take and portable tablets, and determined the dosage of Aredipine enteric-coated tablets as 5 mg/tablet with reference to foreign products.

5. Prescription screening basis

Referring to the weight and dosage of granules listed in Japan, combined with the situation of pharmaceutical excipients in my country, the formulation was optimized. Based on past experience, we selected lactose, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, starch and Sodium dodecyl sulfate (SDS) has carried out the investigation of prescription and technology, screens prescription with 40 minutes dissolution test results, therefrom selects better prescription, test prescription sees the following table:

The results of the designed prescription trial are as follows:

Prescription I mixes Aredipine and auxiliary materials evenly, makes soft material with ethanol, granulates with 20 mesh sieves, dries, adds magnesium stearate, compresses the tablet core, the tablet is loose, and the hardness is not enough.

Prescription II Mix Aredipine and auxiliary materials evenly, make soft material with 15% PVP (K ₃₀ ) ethanol solution, granulate with 20 mesh sieve, dry, add magnesium stearate, compress tablet core, and disintegrate in 10 minutes.

Prescription III: mix the aredipine raw material with SDS, mix evenly with the rest of the excipients in the prescription, make soft material with 5% PVP (K ₃₀ ) ethanol solution, granulate with 20 mesh sieve, dry, add magnesium stearate, mix After uniformity, press the tablet core with a φ7 mm shallow concave punch on a single-punch tablet press. Dissolution measurement: paddle method, ①100 rpm, 65% dissolved in 0.1mol/L acetic acid solution for 40 minutes, ②100 rpm, 51% dissolved in 0.1mol/L hydrochloric acid solution for 40 minutes, it is considered that this prescription did not meet the design requirements .

Prescription IV Mix Aredipine and SDS, mix evenly with the rest of the excipients in the prescription, make soft material with 5% starch slurry, granulate with 20 mesh sieve, dry, add magnesium stearate, mix well, and press in single punch On the tablet machine, use a φ7mm shallow concave punch to press the tablet core. Measure dissolution rate: paddle method, 50 revs/min, in 0.2% sodium dodecyl sulfate (SDS) 500ml solution, 40 minutes stripping 78%, think that this prescription has the hope to reach design requirement.

Prescription V mixes Aredipine and SDS evenly, mixes evenly with the rest of the excipients in the prescription, makes soft material with 5% PVP ethanol solution, granulates with a 20-mesh sieve, dries, adds magnesium stearate, mixes well, and puts in a single Press the tablet core with a φ7 mm shallow concave punch on the punching tablet machine. Measuring dissolution rate: paddle method, 50 rpm, ①in 500ml solution of 0.2% sodium lauryl sulfate, 77.4% was dissolved in 40 minutes. ② Dissolve 90.3% in 500ml of 0.4% sodium lauryl sulfate solution in 40 minutes. ③In 500ml of 0.6% sodium lauryl sulfate solution, 92.1% was dissolved in 40 minutes. It is considered that this prescription is expected to meet the design requirements.

For prescription VI, mix aredipine, lactose and SDS, and mix well with other excipients in the prescription, use 5% PVP ethanol solution to make soft material, granulate with 20 mesh sieve, dry, add magnesium stearate, mix well, Tablet cores were pressed on a single-punch tablet press with a φ7 mm shallow concave punch. Dissolution measurement: Paddle method, 500ml of 0.4% sodium lauryl sulfate as the dissolution medium, ① 50 rpm, 93.9% dissolved in 40 minutes, ② 75 rpm, 99.2% dissolved in 40 minutes, ③ 100 rpm, 40 minutes Dissolution is 100.3%, and the excipients have no interference to the ultraviolet measurement, and the detection wavelength is determined at 239, so it is considered that the dissolution of this prescription is faster.

For prescription VII, mix aredipine, lactose and SDS, and mix with the rest of the excipients in the prescription evenly, use 5% PVP ethanol solution to make a soft material, granulate with a 20-mesh sieve, dry, add magnesium stearate, and mix well. Tablet cores were pressed on a single-punch tablet press with a φ7 mm shallow concave punch. The prepared tablet cores are film-coated with 15% yellow Opadry coating solution, and then dried at 40° C. for 6 hours to obtain tablets. Measure the dissolution rate: paddle method, 75 rpm, 500ml of 0.4% sodium lauryl sulfate is the dissolution medium, 89.1% is dissolved in 40 minutes, and 96.2% is dissolved in 80 minutes.

Our starting idea is to follow the requirements of the dissolution test in the second part of the Chinese Pharmacopoeia in 2000. The dissolution rate of insoluble drugs can reach more than 70% within 40 minutes. The prescription VII is in good compliance with the requirements of the Chinese Pharmacopoeia. Drugs with long-term release can achieve the effect of one tablet a day. We have investigated the dissolution characteristics of foreign samples in detail in conjunction with the product properties, and according to the requirements of the second part of the Chinese Pharmacopoeia 2000 edition about the release test method of enteric-coated preparations, according to the second method of the release test method in Appendix XD, the dissolution test method ( Appendix X C) The first method device measures foreign products, and the experimental results show that foreign products release 98% after 3 hours in pH6.8 phosphate buffer solution after 0.1mol/L hydrochloric acid solution released for two hours, The release is basically complete, and in pH7.4 phosphate buffer, 97% is released in one hour. Combining with literature and experimental results, we re-screened the prescription of this product, and compared the release of the new prescription with that of foreign products, at pH6. 8 is basically the same in phosphate buffer, and it is 30 minutes slower in pH 7.4 phosphate buffer. Considering that foreign products and this product have been basically dissolved in 3 hours in pH 6.8 phosphate buffer, we think that The difference of the release degree in pH7.4 phosphate buffer solution did not affect the effectiveness of the drug. Finally, a new formulation was selected based on the release of the sample in pH6.8 phosphate buffer solution, and the new formulation was investigated in detail.

Determination of dissolution of foreign samples (granules) 3 minutes 10 minutes 20 minutes 40 minutes 80 minutes 0.4% SDS aqueous solution 4.4% 28% 32.9% 40% 45%

Determination of dissolution rate of foreign samples (granules) in different dissolution media Dissolution medium Dissolution 0.1mol/L Dissolution in 2 hours 0.77% 1.22% 15 minutes 25 minutes 35 minutes 45 minutes PH6.8 buffer 17.5% 30.96% 35.00% 44.31% PH7.4 buffer 38.28% 73.99% 103.78% 117.58%

In our prescription, lactose, starch, and microcrystalline cellulose are selected as the main fillers, and hydroxypropyl methylcellulose is replaced by pH-dependent material acrylic resin as the dispersant. Through experimental screening, different types of acrylic resins (Eudragit L100 and S100) were selected as dispersants, and two kinds of granules with different drug release rates were prepared. By adjusting the different ratios of the two granules, the in vitro release behavior of the product was controlled. The research found that According to the requirements of the Chinese Pharmacopoeia 2000 edition two about the release test method of enteric-coated preparations, according to the second method of the release test method of Appendix X D, the first method of the dissolution test method (Appendix X C) is measured by the device, in the same coating When formulating, when the ratio of granule A to granule B is 80:20, the in vitro release behavior of the prepared tablet is basically the same as that of foreign products. Add HPMC5cps outside as dry binder, select magnesium stearate as lubricant for use, and the pressed tablet has high hardness and smooth surface. The screening process is detailed in the table below.

                Table 1 Prescription Screening Form for Aredipine Enteric-Coated Tablets

Fig. 1 The full release curves of different prescriptions and foreign samples in pH 6.8 phosphate buffer after acid resistance for 2 hours. It can be seen from Table 1 and Figure 1 that the release of prescription 3 is the closest to that of foreign samples, and the new prescription is finally selected as prescription 3.

In previous reports, acrylic resins are only used as acid-resistant materials for enteric coatings because of their pH-dependent tolerance. We use relatively large amounts of acrylic resins (Eudragit L100 and S100) and hydroxypropyl methylcellulose for tablets. In the core, it is to achieve the purpose of sustained release, and the release rate must be consistent with foreign granules. This requirement can only be achieved when the ratio of granule A to granule B is 80:20, and the purpose of once-a-day administration can be achieved.

Investigation of Influencing Factors:

Tablets are made according to prescription 3, each tablet contains 5 mg of the main drug, and the compressibility is good. The appearance is flat and smooth, and the hardness is high, which meets the requirements of the Pharmacopoeia.

After coating the prepared tablet, expose it to high temperature (60°C), high humidity (RH92.5%, room temperature), and light (4500 ± 500Lx) for 10 days to study its performance in high temperature, high humidity, and strong light. Stability under conditions. The results of parameters such as appearance, related substances, and content are shown in Table 2, and the results of related substances are shown in Figures 2a-5b.

Table 2 Coated Tablets Accelerated Stability Investigation Results under High Temperature and High Humidity Conditions acceleration condition Observation indicators Exterior Release(%) content(%) relative substance(%) Acid resistance 2h pH 6.8 buffer for 2 hours before acceleration smooth 0.6 86.7. 99.1 0.24 high temperature smooth 0.8 87.0 97.8 0.28 high humidity smooth 0.8 81.4 99.5 0.32 Light smooth 0.5 80.0 101.0 0.26

It can be seen from the results in the table that high temperature, high humidity and light have basically no effect on the release, content and related substances of aredipine enteric-coated tablets. Compared with uncoated tablets, the photostability of coated tablets is significantly improved. It is recommended that the packaging should be shaded, sealed and stored in a cool place.

Sample amplification preparation and quality inspection results:

According to prescription 3, three batches of amplified samples (5000 tablets per batch), batch numbers 04101001, 04101102, 04101203, five full release curve mean results are compared with foreign samples, see Table 3, as can be seen from the table, the amplified sample is acid-resistant (0.1mol/L hydrochloric acid solution) two hours later, the release rate in pH6.8 phosphate buffer was basically the same as that of foreign samples.

Table 3 Enlarged three batches of the full release curve mean and comparison with foreign samples Foreign samples (n=6) 04101001 batch Batch 04101102 04101203 batch Mean 1 (n=6) Mean 2 (n=6) Mean 3 (n=6) Mean (n=6) Mean (n=6) Acid-resistant 2-hour release rate (%) 0.8 0.78 0.84 0.61 0.59 1.67 time (minutes) Release degree of pH6.8 phosphate buffer solution (%) 30 twenty two 12.3 12.1 9.9 13.6 13.8 60 53 51.5 49.3 46.3 41.5 42.8 90 70 72.0 70.2 67 67.2 66.7 120 82 84.7 86.4 80.6 82.6 86.9 150 88 89.4 95.4 90.5 91.3 93.9 180 98 94.0 98.4 96.7 97.3 99.5 210 99.5 99.3 98.7 99.3 99.9

Fig. 2 enlarges the average value of the full release curves of three batches and the comparison curves of foreign samples. The test results of the content, release rate and related substances of the prescription of this product are shown in Table 4. It is considered that the composition of the prescription is reasonable, the process is feasible, and the quality is reliable.

Table 4 Enlarges three batches of sample content, release rate, related substance test results batch number Exterior content(%) Release(%) relative substance(%) Acid resistance for 2 hours Ph6.8 Phosphate Buffer (2 hours) 04101001 This product is an enteric-coated tablet, which is yellow after removing the coating 99.5 0.78 84.7 0.23 04101102 This product is an enteric-coated tablet, which is yellow after removing the coating 99.0 0.59 82.6 0.20 04101203 This product is an enteric-coated tablet, which is yellow after removing the coating 100.4 1.67 86.9 0.21

Effects of the invention: Enteric-coated tablets for treating hypertension (trade name: Aredipine enteric-coated tablets) have high bioavailability, slow onset of action, and long-lasting effects. They are taken orally once a day, are convenient to use, and greatly improve patient compliance. Dipine is currently one of the antihypertensive drugs with the strongest curative effect and the longest lasting effect among dihydropyridine drugs, which can reduce the economic burden of the general public to a large extent.

Description of drawings

Figure 1 is the full release curve of different formulations and foreign samples in pH 6.8 phosphate buffer after acid resistance for 2 hours.

Fig. 2 is a graph comparing the average value of the full release curves of three batches with foreign samples.

Detailed ways

Embodiment: Treatment of hypertension enteric-coated tablets (trade name: Aledipine enteric-coated tablets) prescription:

1) Core (1000 pieces):

Aredipine 5g

Acrylic resin (Eudragit L100) 20g

Acrylic resin (Eudragit S100) 5g

Lactose 80g

Starch 80g

Microcrystalline Cellulose 10g

Hydroxypropyl Methyl Cellulose (HPMC5cps) 10g

Magnesium stearate 1g

Made into 1000 pieces 211g

2) Prescription of enteric coating solution:

Acrylic resin (L100) 10g

Macrogol 6000 1g

Talc powder 2g

Titanium dioxide 2g

85% ethanol 200mL

Pigment Appropriate amount

Coating weight gain 4～6%

3) Preparation process (operation in dark):

A, tablet preparation process

a. The auxiliary materials are passed through a 100-mesh sieve.

b. Dissolve 5g of Aredipine and 25g of acrylic resin Eudragit L100 in 500ml of 80% ethanol solution to prepare A solution.

c. Dissolve 5g of Aredipine and 25g of acrylic resin Eudragit S100 in 500ml of 80% ethanol solution to prepare solution B.

d. Weigh two portions of mixed auxiliary materials, each containing 80g of lactose, 80g of starch, and 10g of microcrystalline cellulose, pass through a 40-mesh sieve and mix well.

e. Put one part of the mixed auxiliary materials into the fluidized bed, use A solution as the binder, and granulate by one-step granulation method to obtain granules A.

f. Put another part of mixed auxiliary materials into the fluidized bed, use solution B as binder, and granulate by one-step granulation method to obtain granule B.

g. 24 mesh granules, according to the tablet core prescription, mix the two kinds of granules in proportion (granule A: granule B = 80:20), add hydroxypropyl methylcellulose and magnesium stearate, and fully mix with the mixed granules uniform.

h. Use a φ9 mm shallow concave punch to compress tablets on a single-punch tablet press.

B. Tablet coating process

Acrylic resin Eudragit L100 powder is swelled with an appropriate amount of 85% ethanol, left overnight, fully dissolved by ultrasonication, added polyethylene glycol 6000, stirred well and dissolved, then added 85% ethanol to the full amount, added talcum powder, titanium dioxide and pigment, passed through a colloid mill for 5-6 Again, pass through a 120-mesh sieve, and set aside.

Tablets were coated until the weight of the tablet core increased by 4-6%, and dried at 40°C for 2 hours. Remove from room temperature packaging.

Claims (2)

1, a kind of medicine for treating hypertension, the active ingredient of this medicine is Aredipine, it is characterized in that enteric-coated tablet is prepared with the former and adjuvant of following weight ratio: a) The tablet core is prepared with the raw materials and auxiliary materials in the following weight ratio: Aredipine 5g Acrylic resin L100 20g Acrylic resin S100 companion 5g Lactose 80g Starch 80g Microcrystalline Cellulose 10g Hydroxypropyl Methyl Cellulose 10g Magnesium Stearate 1g Made into 1000 pieces 211g b) The enteric coating solution is prepared with the following raw materials in the weight ratio: Acrylic resin L100 10g Macrogol 6000 1g Talc powder 2g Titanium dioxide 2g 85% ethanol 200mL Pigment Appropriate amount Coating weight gain 4-6%. 2. A preparation method for treating hypertension, characterized in that A, tablet core preparation method: a. Excipients pass through a 100-mesh sieve; b. Dissolve 5g of Aredipine and 25g of acrylic resin Eudragit L100 in 500ml of 80% ethanol solution to make solution A; c. Dissolve 5g of Aredipine and 25g of acrylic resin Eudragit S100 in 500ml of 80% ethanol solution to form solution B; d. Weigh two portions of mixed auxiliary materials, each containing 80g of lactose, 80g of starch, and 10g of microcrystalline cellulose, pass through a 40-mesh sieve and mix well; e. Put one part of the mixed auxiliary materials into the fluidized bed, use A solution as the binder, and granulate in one-step granulation method to obtain granules A; f. Put another part of mixed auxiliary materials into the fluidized bed, use solution B as binder, and granulate by one-step granulation method to obtain granules B; g. 24 mesh granules, according to the tablet core prescription, mix the two kinds of granules in proportion (granule A: granule B = 80:20), add hydroxypropyl methylcellulose and magnesium stearate, and fully mix with the mixed granules uniform; h. Use a φ9 mm shallow concave punch to compress tablets on a single-punch tablet press; B. Tablet coating process: Acrylic resin L100 powder is swollen with an appropriate amount of 85% ethanol, left overnight, fully dissolved by ultrasonic, add polyethylene glycol 6000, stir well and dissolve, add 85% ethanol to the full amount, add talcum powder, titanium dioxide and pigment, pass colloid mill 5-6 times , pass through a 120-mesh sieve, and set aside; Tablets are coated until the weight of the tablet core increases by 4-6%, dried at 40°C for 2 hours, taken out and packaged at room temperature.