CN109453132B - Time-lag controlled-release tablet for treating coronary heart disease and preparation method thereof - Google Patents

Abstract

The invention discloses a controlled release tablet for treating coronary heart disease with time lag and a preparation method thereof. The time-lag controlled-release tablet consists of a tablet core and an enzymolysis type controlled-release coating layer, wherein the tablet core consists of a salvianolic acid B extract, a disintegrating agent, a diluent A, an adhesive and a lubricant A; the enzymolysis type controlled release coating layer consists of a plasticizer, a diluent B, an enzymolysis controlled release polymer material and a lubricant B. The time-lag controlled-release tablet is used for treating cardiovascular diseases, and patients only need to take the tablet once before sleep, so that the risk of sudden diseases in the early morning can be reduced, and the time-lag controlled-release tablet has good patient compliance and safety.

Description

Time-lag controlled-release tablet for treating coronary heart disease and preparation method thereof

Technical Field

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a time-lag controlled-release tablet preparation for treating coronary heart disease and a preparation method thereof.

Background

Because the biological cycle of the organism and the rhythm of the time of drug action determine the drug effect and the periodic rhythm of the metabolism of the drug in the body, for the drug, understanding the time-of-day rhythm further strengthens the knowledge of the drug, can ensure the safety and effectiveness of the drug, and has unpredictable importance. Chronopharmacology originates from China, and the chrono-rhythm is noticed before the Gongyuan to play an important role in the aspects of drug efficacy, physical recovery and the like, and the human body is required to adapt to the change process of yin and yang in the morning and evening: for patients with hundreds of diseases, the physician usually takes the form of Hui-Lu-an, or night. If the trend is oriented, the vital energy of the human beings starts to grow and the pathogenic qi declines, so the people can feel sweet; the middle is that the qi grows longer and the longer is that of the pathogenic factor, so it is safe; in the middle of the day, the qi begins to decline and pathogenic factors begin to grow, so it is also indicated for the night half with qi entering the zang-fu organs and pathogenic factors alone (Lingshu, Shunqi-Qi are divided into four seasons per day). In order to inherit the essence of traditional Chinese medicine, modern medicine is combined, a novel medicine carrying system is adopted to realize chrono-rhythmic administration, and a reasonable administration scheme is made from the rhythmic occurrence of diseases on the basis of chrono-biology and chrono-pharmacology so as to achieve the treatment purpose.

Cardiovascular disease occurs in a circadian rhythm with peak attack times between 6-12 am. For example: blood pressure is mostly "two high and one low", i.e., 9-11am, 3-6pm highest, midnight lowest. 75% of stroke patients develop disease within the time of peak blood pressure; the aggregation of platelets is strongest at 6-8 am; angina pectoris has an increased number of attacks after 6 am; the attack frequency of the myocardial infarction is increased after waking in the morning, and the peak of the attack of the myocardial infarction is 8-10 am. It has been shown that, among cardiovascular drugs, antihypertensive and antiarrhythmic drugs have pharmacokinetic and pharmacodynamic circadian rhythms. The calcium ion antagonist and the beta channel blocker have obvious blood pressure reducing effect in daytime compared with that in nighttime. In the Chinese medicinal preparation, the loranthus parasiticus, the monkshood and the like also have similar curative effect characteristics. Therefore, the proper time for administration can be selected to produce the desired therapeutic effect. However, if the drugs for treating cardiovascular diseases are taken according to the optimal time, the night rest time of patients is affected, and the compliance is poor, so the time-lag controlled-release preparation can overcome the problems, so that the drugs are taken by the patients before sleep and released in vivo after a certain time, and the treatment purpose is achieved in the optimal administration time window. However, conventional enteric coating materials (acrylics) are affected by food, intestinal pH, and affect drug release and absorption. The time-lag controlled release preparation can better exert the curative effect, is convenient to take orally, is administrated according to the needs, ensures the drug effect concentration and has good patient compliance.

Domestic patents on pulse preparations include: the amoxicillin delayed-release preparation CN105796521B, the benzodiazepine drug oral pulsed drug release system CN1188131C, the pulsed CN105796522B containing fluticasone furoate and vilanterol, and the delayed-release preparation CN101496792B of propranolol or its salt, but the preparation adopting enzymolysis colon-specific drug delivery is used for treating coronary heart disease and has not been reported in patent.

Disclosure of Invention

In order to overcome the above-mentioned drawbacks and disadvantages of the prior art, it is an object of the present invention to provide a time-lapse, controlled-release formulation with a rational administration. The preparation is based on the rhythm of cardiovascular disease and the principle of chrono-pharmacology, and is administered at 8-10pm before sleep for 6-8 hr to reach colon position, and release the erosion tablet via specific enzyme in colon to reach maximum drug concentration and control cardiovascular disease.

The second purpose of the invention is to provide a preparation method of a time-lag controlled release preparation for treating coronary heart disease, the preparation process is simple and easy to implement, the time-lag behavior of the drug release is stable and controllable, the reproducibility is good, and the preparation method is suitable for industrial production.

The preparation technology of the time-lag controlled release agent for treating coronary heart disease is realized by the following scheme:

the time-lag controlled-release tablet comprises a tablet core and an enzymolysis type coating layer, wherein the mass ratio of the tablet core to the enzymolysis type coating layer is (1-10): 1; the tablet core is prepared from the following raw materials in parts by mass: 10-80 parts of salvianolic acid B extract, 0.2-2 parts of disintegrating agent, diluent A: 1-5 parts of adhesive: 0.5-5 parts; 0.5-5 parts of a lubricant A; the enzymolysis type coating layer is prepared from the following raw materials in parts by mass: 1-25 parts of plasticizer, 1-5 parts of diluent B, 0.5-5 parts of enzymolysis controlled release type high polymer material and 0.2-5 parts of lubricant B; the enzymolysis controlled-release polymer material is selected from one or a composition of any of the following substances: dextran, cross-linked chitosan, cyclodextrin, and calcium pectin.

Still further, the time-lapse controlled-release tablet is preferably: the mass ratio of the tablet core to the coating layer is 8-10: 1; the tablet core is prepared from the following raw materials in parts by mass: 20-30 parts of salvianolic acid B extract, 0.2-1 part of disintegrating agent, 1-2 parts of diluent A, 1-2 parts of adhesive and 0.1-0.5 part of lubricant A; the enzymolysis type coating layer is prepared from the following raw materials in parts by mass: 0.5-5 parts of plasticizer, 1-4 parts of diluent B, 1-4 parts of enzymolysis controlled release type high polymer material and 0.2-2 parts of lubricant B. Further, preferably, the disintegrating agent is selected from one or a combination of any of the following substances: sodium starch glycolate, sodium croscarmellose, low substituted hydroxypropylcellulose or crospovidone, most preferably crospovidone.

Further, preferably, the diluent A is selected from one or a combination of any several of the following substances: starch, lactose, pregelatinized starch, microcrystalline cellulose or calcium sulfate. Lactose is most preferred.

Further, preferably, the adhesive is selected from one or a combination of any of the following materials: sodium alginate, sodium carboxymethylcellulose, hydroxypropylcellulose, ethylcellulose, povidone or polyethylene glycol, most preferably polyethylene glycol.

Further, preferably, the lubricant A is selected from one or a combination of any of the following substances: magnesium lauryl sulfate, silica gel micropowder, talcum powder or sodium dodecyl sulfate, and most preferably talcum powder.

Further, preferably, the plasticizer is a water-insoluble plasticizer selected from one or a combination of any of the following substances: glycerate, phthalate, acetylated glycerate, dibutyl phthalate, most preferably phthalate.

Further, preferably, the diluent B is selected from one or a combination of any several of the following substances: starch, lactose, pregelatinized starch, microcrystalline cellulose, mannitol, calcium sulfate, ethylcellulose, most preferably pregelatinized starch.

Further, preferably, the lubricant B is selected from one or more of the following compositions: magnesium lauryl sulfate, silica gel micropowder, talc powder or sodium lauryl sulfate, and most preferably magnesium lauryl sulfate.

Further, the time-lapse controlled-release tablet is most preferably: the mass ratio of the tablet core to the coating layer is 10: 1; the tablet core is prepared from the following raw materials in parts by mass: 25 parts of salvianolic acid B extract, 1 part of crospovidone, 1 part of lactose, 1 part of hydroxypropyl cellulose, 0.5 part of polyethylene glycol and 0.25 part of talcum powder; the enzymolysis type coating layer is prepared from the following raw materials in parts by mass: 10 parts of pregelatinized starch, 1 part of calcium sulfate, 25 parts of cyclodextrin, 0.5 part of lauryl alcohol magnesium sulfate and 5 parts of phthalate.

The time-lag controlled-release tablet is prepared according to the following method:

mixing the salvianolic acid B extract with a disintegrating agent and a diluent A according to the formula amount, drying, crushing, sieving with a 100-mesh sieve, adding an adhesive, uniformly mixing to prepare a soft material, granulating, drying to obtain dry granules, adding the lubricant A into the obtained dry granules, uniformly mixing, performing shallow arc circular punching on tablets, drying to prepare tablet cores, and performing dry-method pressing coating outside the tablet cores, wherein the coating process comprises the steps of adding the tablet cores, an enzymolysis type polymer, the diluent B and the lubricant B into a fluidized bed, uniformly stirring, spraying a plasticizer for fusion, and finally pressing the coated tablets to obtain time-lag controlled release tablets; the particle size of the dry particles is 60-90 mm; the drying temperature is 40-70 ℃.

The time-lag controlled-release tablet prepared by the invention releases the medicament after 6-12 hours, preferably 6-8 hours after administration, and the tablet core medicament is completely released within 15 minutes after release.

Compared with the prior art, the invention has the beneficial effects that:

the invention designs and develops an oral time-lag controlled-release tablet for treating coronary heart disease according to the cardiovascular disease time law, wherein the salvianolic acid B is extracted from salvia miltiorrhiza and has strong antioxidation, and in vitro and in vivo experiments prove that the salvianolic acid B can clear oxygen free radicals and inhibit lipid peroxidation, has higher action strength than vitamin C, vitamin E and mannitol, and is one of the currently known natural products with strongest antioxidation. Pharmacological research shows that the salvianolic acid B has obvious antioxidation, platelet aggregation inhibition and thrombosis inhibition effects, and can prolong the survival time of animals under the anoxic condition. Compared with the cardiovascular treatment medicines on the market, the medicine can effectively control the morbidity of the cardiovascular diseases in the time period of high incidence and control the diseases in time; the enzymolysis type controlled release coating only releases the medicine after being dissolved in colon, reduces the stimulation of the medicine to stomach, is safer and more effective than the traditional preparation, has good patient compliance, and improves the bioavailability of the medicine. Meanwhile, the preparation process is simple and mature, and the used materials are FDA approved pharmaceutic adjuvants, so that the industrial production is easy to realize.

Drawings

FIG. 1 is a graph of the release profile of the time-lapse controlled-release tablet of example 7 in a solution simulating the environment of a human body.

Figure 2 is a graph of the release profile of the tablet of comparative example 1 in a solution simulating a human environment.

FIG. 3 is a graph showing the blood concentration of the time-lapse controlled-release tablet of example 8 in experimental animals, and the content of salvianolic acid B is measured.

Detailed Description

The present invention is illustrated in detail by examples. It is to be understood that the following examples are illustrative of the present invention and are not to be construed as limiting the scope of the invention, and that certain insubstantial modifications and adaptations of the invention by those skilled in the art in light of the foregoing description are intended to be included within the scope of the invention. The specific process parameters and the like of the following examples are also only one example of suitable ranges, i.e., those skilled in the art can select the appropriate ranges through the description herein, and are not limited to the specific values exemplified below.

The invention prepares salvianolic acid B into a time-lag controlled-release agent, and a tablet core of the time-lag controlled-release tablet contains a main medicine, a disintegrating agent, a diluent, an adhesive and a lubricant. In the example, each 1000 tablets of the time-lag controlled-release tablet contains 300g of salvianolic acid B extract, 20-50 g of disintegrant, 10-100g of diluent, 10-50g of adhesive and 1-5g of lubricant. The enzymolysis type coating layer comprises the following components: plasticizer, diluent, enzymolysis controlled release type high molecular material and lubricant. In the example, in every 1000 tablets of time-lag controlled-release tablets, 5-50g of plasticizer, 10-100g of diluent, 10-120g of enzymolysis controlled-release polymer material and 2-50g of lubricant.

The preparation method of the salvianolic acid B extract in the embodiment comprises the following steps:

reflux-extracting 5kg of Saviae Miltiorrhizae radix with 70% ethanol with volume fraction 50kg times of the weight of Saviae Miltiorrhizae radix for 3 times, each time for 2 hr, mixing the ethanol extractive solutions, recovering ethanol under reduced pressure, and concentrating to obtain crude drug with mass concentration of 0.25 g/mL; adsorbing with F-type macroporous adsorbent resin, loading sample amount of 3 times column volume, loading sample at flow rate of 1 times column volume/h with 60% ethanol as eluting solvent, eluting, collecting eluate, recovering ethanol under reduced pressure, and drying to obtain salvianolic acid B extract (about 200 g).

Example 1:

250g of salvianolic acid B extract, 10g of croscarmellose sodium, 15g of microcrystalline cellulose, 12.5g of sodium carboxymethylcellulose and 2.5g of superfine silica gel powder are taken, stirred uniformly and sieved by a 100-mesh sieve. Preheating the materials in a fluidized bed, drying at 60 ℃, discharging, sieving by a 40-mesh sieve, grading, transferring to a mixer, adding 2.5g of superfine silica gel powder, uniformly mixing, punching into a shallow arc round tablet, and controlling the weight of the tablet to be 290 +/-5 mg to obtain the tablet core. 6.5g of lactose, 16g of glucan and 0.5g of aerosil are taken and placed in a fluidized bed to be mixed with the tablet core, then 5g of phthalic acid ester is sprayed to be fused, finally the core-spun tablet is pressed, the weight of the tablet core is increased by 10 percent, and the coated tablet is prepared.

Example 2:

250g of salvianolic acid B extract, 10g of crospovidone, 10g of lactose, 10g of hydroxypropyl cellulose, 5g of polyethylene glycol and 2.5g of talcum powder are taken, stirred uniformly and sieved by a 100-mesh sieve. Preheating the materials in a fluidized bed, drying at 60 ℃, discharging, sieving by a 40-mesh sieve, grading, transferring to a mixer, adding micropowder silica gel, uniformly mixing, performing shallow arc circular punching, and controlling the weight of the tablet to be 285 +/-5 mg to obtain the tablet core. 10g of pregelatinized starch, 1g of calcium sulfate, 25g of cyclodextrin and 0.5g of lauryl alcohol magnesium sulfate are uniformly mixed, placed in a fluidized bed to be mixed with the tablet core, then 5g of phthalate is sprayed to be fused, and finally the weight of the tablet core of the pressed core-spun tablet is increased by about 15 percent to prepare the coated tablet.

Example 3:

200g of salvianolic acid B extract, 2g of croscarmellose sodium, 10g of microcrystalline cellulose, 10g of povidone, 5g of calcium sulfate and 2g of talcum powder are taken and stirred uniformly. Preheating the materials in a fluidized bed, drying, adding, discharging after drying, sieving, granulating, transferring to a mixer, adding micropowder silica gel, mixing uniformly, punching into tablets with shallow arc and circle, and controlling the weight of the tablets to be 225 +/-5 mg to obtain the tablet core. Taking 14g of ethyl cellulose, 10g of mannitol, 12g of pectin calcium and 0.5g of talcum powder, uniformly mixing, putting the mixture into a fluidized bed, mixing with a tablet core, spraying 2.5g of glyceric acid acetate for fusion, and finally pressing the core-spun tablet to increase the weight of the tablet core by about 10% to prepare the coated tablet.

Example 4:

300g of salvianolic acid B extract, 3g of low-substituted hydroxypropyl cellulose, 20g of starch, 15g of sodium alginate and 3g of magnesium lauryl sulfate are taken and uniformly stirred. Preheating the materials in a fluidized bed, drying, adding, discharging after drying, sieving, granulating, transferring to a mixer, adding micropowder silica gel, mixing uniformly, punching into tablets with shallow arc and circle, and controlling the weight of the tablets to be 340 +/-5 mg to obtain the tablet core. Taking 5g of starch, 2.5g of mannitol, 20g of cyclodextrin and 0.3g of aerosil, mixing uniformly, placing the mixture in a fluidized bed to mix with a tablet core, spraying 7g of acetylated glycerate for fusion, and finally pressing the weight gain of the tablet core of the core-spun tablet to be about 15% to prepare the coated tablet.

Example 5:

250g of salvianolic acid B extract, 5g of carboxymethyl starch sodium, 15g of pregelatinized starch, 5g of ethyl cellulose and 2.5g of sodium dodecyl sulfate are taken and uniformly stirred. Preheating the materials in a fluidized bed, drying, adding, discharging after drying, sieving, granulating, transferring to a mixer, adding micropowder silica gel, mixing uniformly, punching into tablets with shallow arc circle, and controlling the weight of the tablets to 275 +/-5 mg to obtain the tablet core. 6.5g of ethyl cellulose and 16.5g of cross-linked chitosan are uniformly mixed, placed in a fluidized bed to be mixed with the tablet core, then 0.3g of lauryl sodium sulfate is sprayed to be fused, and finally the weight of the tablet core of the pressed core-spun tablet is increased by about 10 percent to prepare the coated tablet.

Example 6

In-vitro disintegration test of the salvianolic acid B time-lag controlled release tablet core: the tablets were placed in a 10mL water beaker with water temperature controlled at 37 ± 0.5 ℃ and the time required for complete disintegration of the tablets was observed and recorded at rest.

Example 7

In vitro dissolution test of salvianolic acid B time-lag controlled release tablet: 0.1mol/L hydrochloric acid solution was used as release medium, after 2 hours the pH was changed to pH6.8 phosphate buffer solution and after 2 hours the pH was changed to pH8.3 phosphate buffer solution, and the purified enzyme present in the colon was added to this solution. The tablets were put into 1000mL of the solution, the temperature was controlled at 37. + -. 0.5 ℃ and the rotation speed was 50 rpm. 2mL of the liquid was taken out at a specific time node, filtered through a 0.45 μm filter, and subjected to HPLC test (Agilent 1100, Kromasil KR 100-7C18 column) (n ═ 3, Mean. + -. SD) to calculate the dissolution rate.

As can be seen from figure 1, the release profile of example 2 more closely follows the rhythmic release profile.

Comparative example 1

The tablet formulation of example 2 was prepared without adding the enzyme-hydrolyzed polymer, and the other formulation and preparation methods were the same as those of the control tablet. The same in vitro dissolution test as in example 7 was performed. As can be seen from FIG. 2, the drug release curve of the control group did not conform to the rhythmic drug delivery rule.

Example 8

Evaluation of salvianolic acid B in time-lag controlled release tablets: in-vivo drug evaluation was performed using example 2, which is a better in-vitro test evaluation, and 5 healthy male beagle dogs were used for the test, animals were fasted overnight before the test animals were administered, one salvianolic acid B time-lag controlled-release tablet was administered to each beagle dog, and the administration was performed by direct gavage, and then 4mL of blood was taken from the front or hind limb vein of beagle dogs at a specific time node, and the blood was placed in a heparin sodium blood collection tube, centrifuged at 3000 rpm for 10min, and then the supernatant plasma sample was placed in a 2mL centrifuge tube, and blood concentration analysis was performed using high performance liquid chromatography (Agilent 1100, Kromasil KR 100-7C18 column) (n 3, Mean ± SD).

FIG. 3 shows that the blood concentration rises sharply after 6 hours in the beagle dog to achieve the purpose of rhythmic drug release.

Claims (8)

1. A time-lag controlled release tablet characterized by: the time-lag controlled release agent consists of a tablet core and an enzymolysis type coating layer, wherein the mass ratio of the tablet core to the enzymolysis type coating layer is (1-10): 1; the tablet core is prepared from the following raw materials in parts by mass: 10-80 parts of salvianolic acid B extract, 0.2-2 parts of disintegrating agent, diluent A: 1-5 parts of adhesive: 0.5-5 parts; 0.5-5 parts of a lubricant A; the enzymolysis type coating layer is prepared from the following raw materials in parts by mass: 1-25 parts of plasticizer, 1-5 parts of diluent B, 0.5-5 parts of enzymolysis controlled release type high polymer material and 0.2-5 parts of lubricant B; the enzymolysis controlled-release polymer material is selected from one or a composition of any of the following substances: dextran, cross-linked chitosan, cyclodextrin, calcium pectin; the plasticizer is a water-insoluble plasticizer, and is selected from one or a composition of any of the following substances: glycerate, phthalate or acetylated glycerate; the diluent B is selected from one or a combination of any of the following substances: starch, lactose, pregelatinized starch, microcrystalline cellulose, mannitol, calcium sulfate, or ethylcellulose; the lubricant B is selected from one or a combination of any of the following substances: magnesium lauryl sulfate, silica gel micropowder, talcum powder or sodium dodecyl sulfate; the diluent A is selected from one or a combination of any of the following substances: starch, lactose, pregelatinized starch, microcrystalline cellulose or calcium sulfate; the disintegrating agent is selected from one or a combination of any of the following substances: sodium starch glycolate, sodium croscarmellose, low substituted hydroxypropylcellulose or crospovidone; the adhesive is selected from one or a combination of any of the following substances: sodium alginate, sodium carboxymethylcellulose, hydroxypropylcellulose, ethylcellulose, povidone or polyethylene glycol; the lubricant A is selected from one or a combination of any of the following substances: magnesium lauryl sulfate, silica gel micropowder, talcum powder or sodium dodecyl sulfate.

2. The time-lapse, controlled-release tablet according to claim 1, wherein: the time-lapse controlled-release tablet comprises: the mass ratio of the tablet core to the coating layer is 8-10: 1; the tablet core is prepared from the following raw materials in parts by mass: 20-30 parts of salvianolic acid B extract, 0.2-1 part of disintegrating agent, 1-2 parts of diluent A, 1-2 parts of adhesive and 0.1-0.5 part of lubricant A; the enzymolysis type coating layer is prepared from the following raw materials in parts by mass: 0.5-5 parts of plasticizer, 1-4 parts of diluent B, 1-4 parts of enzymolysis controlled release type high polymer material and 0.2-2 parts of lubricant B.

3. The time-lapse, controlled-release tablet according to claim 1, wherein: the salvianolic acid B extract is prepared according to the following steps:

reflux-extracting Saviae Miltiorrhizae radix with 60-80% ethanol for 3-4 times (each for 2 hr), mixing the ethanol extractive solutions, removing ethanol under reduced pressure, and concentrating to obtain Saviae Miltiorrhizae radix concentrated solution with concentration of 0.25-0.5 g/ml; then adsorbing with F-type macroporous adsorbent resin, loading sample amount of 3 times column volume, loading sample with 60% ethanol as eluting solvent at flow rate of 1 time column volume/h, eluting, collecting eluate, removing ethanol under reduced pressure, and drying the obtained product to obtain salvianolic acid B extract.

4. The time-lapse, controlled-release tablet according to claim 1, wherein: the diluent A is lactose; the disintegrant is crosslinked carboxymethyl cellulose sodium; the adhesive is polyethylene glycol; the lubricant A is talcum powder.

5. The time-lapse, controlled-release tablet according to claim 1, wherein: the enzymolysis controlled release type high molecular material is cyclodextrin.

6. The time-lapse, controlled-release tablet according to claim 1, wherein: the plasticizer is phthalate; the diluent B is pregelatinized starch; the lubricant B is magnesium lauryl sulfate.

7. A lag time controlled release tablet according to any one of claims 1 to 6, wherein: the time-lapse controlled-release tablet comprises: the mass ratio of the tablet core to the coating layer is 10: 1; the tablet core is prepared from the following raw materials in parts by mass: 25 parts of salvianolic acid B extract, 1 part of crospovidone, 1 part of lactose, 1 part of hydroxypropyl cellulose, 0.5 part of polyethylene glycol and 0.25 part of talcum powder; the enzymolysis type coating layer is prepared from the following raw materials in parts by mass: 10 parts of pregelatinized starch, 1 part of calcium sulfate, 25 parts of cyclodextrin, 0.5 part of lauryl alcohol magnesium sulfate and 5 parts of phthalate.

8. A method of preparing a time-lapse controlled-release tablet according to claim 1, wherein: the method comprises the following steps:

mixing the salvianolic acid B extract with a disintegrating agent and a diluent A according to the formula amount, drying, crushing, sieving with a 100-mesh sieve, adding an adhesive, uniformly mixing to prepare a soft material, granulating, drying to obtain dry granules, adding the lubricant A into the obtained dry granules, uniformly mixing, performing shallow arc circular punching on tablets, drying to prepare tablet cores, and performing dry-method pressing coating outside the tablet cores, wherein the coating process comprises the steps of adding the tablet cores, an enzymolysis type polymer, the diluent B and the lubricant B into a fluidized bed, uniformly stirring, spraying a plasticizer for fusion, and finally pressing the coated tablets to obtain time-lag controlled release tablets; the particle size of the dry particles is 60-90 mm; the drying temperature is 40-70 ℃.

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