Topiroxostat osmotic pump controlled-release tablet and preparation method therefor

Abstract

Disclosed in the present invention are a topiroxostat osmotic pump tablet and a preparation method therefor. The topiroxostat osmotic pump tablet comprises: a tablet core consisting of a drug layer and a push layer; a semipermeable membrane coating outside the tablet core; a single drug-release orifice on the controlled-release tablet surface on the side of the drug layer; and an isolation film coating. Compared with topiroxostat tablets currently on the market, the topiroxostat osmotic pump controlled-release tablet prepared in the present invention achieves sustained and stable constant-rate drug release. The drug in a drug-release layer is not released immediately after a patient takes the drug; within the ten or more hours thereafter, the tablet can release the drug rhythmically under the action of the push layer, maintaining a steady-state plasma concentration, delaying the time at which the peak is reached, and prolonging the half-life of the drug, thereby improving bioavailability and achieving a sustained release effect of 12 h or more. Because a dual-layer osmotic pump controlled-release technology is used, the drug has stronger controllability, a more complete release, and higher bioavailability in comparison with single-layer tablets.

Description

Tolperisone osmotic pump controlled release tablets and preparation method thereof TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical preparations, in particular, the present application relates to a kind of tolperisone osmotic pump controlled release tablets and preparation method thereof. BACKGROUND

[0002] The prevalence of hyperuricemia and gout in China is increasing year by year, according to the research results published in "Guidelines for the Diagnosis and Treatment of Gout and Hyperuricemia at the Grassroots Level 2019": hyperuricemia patients have accounted for 13.3% of the total population, and the prevalence of gout is 1% to 3%. In the past few decades, the research and development of gout drugs has been seriously neglected, and only a small number of drugs have been approved for marketing. The drugs currently used to inhibit uric acid production are allopurinol and febuxostat tablets, but both have certain defects. Allopurinol has an allergic risk and serious side effects; febuxostat tablets have potential risks to the cardiovascular system.

[0003] Tolperisone tablets are another non-purine xanthine oxidase inhibitor after febuxostat. It reaches the peak blood concentration faster than febuxostat, so it has a faster onset of action; there is no in vivo accumulation; it is not affected by food; it is safe for the cardiovascular system and has low side effects, improving the safety and compliance of patients taking the drug. The instructions for the tolperisone tablets marketed in Japan show that the drug is taken twice a day, regardless of the dosage of 20mg, 40mg or 60mg. However, for elderly patients, taking gout medication once a day usually improves patient compliance. Forming a sustained-release preparation can greatly reduce the number of times patients take medication, reduce blood concentration fluctuations, reduce discomfort caused by peak and valley phenomena, and reduce side effects, but there are still individual differences, unstable release rate and other shortcomings.

[0004] The osmotic pump drug delivery system is a high-end drug controlled release technology based on the principle of osmotic pressure. Its core advantage is to achieve precise and stable release of drugs through a physical mechanism, which is not affected by pH, digestive enzymes, food or intestinal peristalsis, ensuring the stability and predictability of drug release, reducing individual differences and absorption differences between different patients, especially for groups with large metabolic differences, which can achieve once-daily dosing (QD dosing method) and reduce the number of doses. Developing tolperisone into an osmotic pump drug delivery system or an important research direction for improved tolperisone formulations. SUMMARY

[0005] The purpose of the present application is to provide a kind of tolperisone osmotic pump controlled release tablets and preparation method thereof, which can control the release rate of tolperisone osmotic pump controlled release tablets, has the advantages of convenient administration, long-acting, stable release and small side effects.

[0006] Technical scheme: The technical problem to be solved by the present application is solved by the following technical scheme.

[0007] A toptipride osmotic pump controlled release tablet, comprising a tablet core composed of a drug layer and a push layer, a semi-permeable membrane coating outside the tablet core, and a single drug release orifice on the surface of the controlled release tablet on the side of the drug layer and a separating coating film;

[0008] The drug layer is composed of the following ingredients, calculated as a percentage of the weight of the drug layer:

[0009] 20.0-50% of toptipride raw material;

[0010] 40-70% of entraining polymer;

[0011] 2.0-5.0% of binding agent;

[0012] 1.5-5% of osmotic pressure promoter;

[0013] 1.0-2.0% of lubricant;

[0014] The push layer is composed of the following ingredients, calculated as a percentage of the weight of the push layer:

[0015] 60-70% of swelling agent;

[0016] 25-35% of osmotic pressure promoter;

[0017] 1.0-3.0% of lake;

[0018] 1.0-3.0% of lubricant.

[0019] Preferably, the weight of the drug layer is 240-480 mg, and the weight of the push layer is 120-240 mg.

[0020] The entraining polymer is the core component of the osmotic pump preparation design. On the one hand, it forms a gel layer by swelling after absorbing water, providing osmotic pressure driving force. On the other hand, it makes the formation of the gel layer more stable due to its high molecular weight characteristics, thereby delaying drug release. In addition, the high viscosity and thickening effect of the entraining polymer can also stabilize the drug particles in the drug-containing layer, prevent sedimentation, and ensure the uniformity of the release of the poorly soluble drug toptipride. This requires the entraining polymer to have moderate swelling capacity, and the formed gel layer needs to have sufficient mechanical strength to resist the physical stress of the gastrointestinal tract, and has corresponding tabletting and coating process adaptability. Preferably, the entraining polymer is selected from one of polyoxyethylene 200000, polyethylene glycol 6000, lactose monohydrate or HPMC K750.

[0021] In the osmotic pump controlled release tablet, the binder is the key auxiliary material to ensure the tablet structure integrity and the controlled release requirements, which can maintain the mechanical strength of the tablet, ensure that it does not break in the tabletting, coating and gastrointestinal environment, and has good compatibility with the controlled release material without affecting the osmotic pressure driving mechanism, and also provides certain feasibility for the optimization of the preparation process. This requires the binder to have corresponding physical and chemical properties on the one hand, that is, controllable hydrophilicity, low swelling, no osmotic activity, and excellent process stability on the other hand, that is, uniform granules can be quickly formed in wet granulation, compatible with coating process, etc. Preferably, the binder is selected from one of hydroxypropyl methyl cellulose E5, hydroxypropyl methyl cellulose K4M, hydroxypropyl methyl cellulose K15M or PVP K90.

[0022] In the osmotic pump controlled release tablet, the swelling agent is the key to the physical swelling and drug release kinetics. The swelling agent can generate volume expansion force by rapid water absorption and swelling, push the drug in the drug-containing layer to release through the release hole on the semi-permeable membrane, and cooperate with the osmotic pressure promoter to maintain the osmotic pressure gradient. This requires the swelling agent to have high water absorption and swelling capacity, and the gel formed after swelling has certain mechanical stability and will not break and collapse in the gastrointestinal peristalsis. Preferably, the swelling agent is selected from one of polyoxyethylene 5000000, polyoxyethylene 7000000 or sodium alginate.

[0023] Preferably, the osmotic pressure promoter is sodium chloride, the lubricant is magnesium stearate, and the lake is iron oxide red. The osmotic pressure promoter can increase the osmotic pressure, promote the release of tobradex, and improve the absorption of tobradex by the human body. The lubricant can also be calcium stearate, sodium stearate, etc., which can prevent sticking during tabletting and increase the flowability of the granules.

[0024] Preferably, the semi-permeable membrane coating material is cellulose acetate, and the ratio of semi-permeable membrane coating weight to total weight of the double-layer tablet core is 7.5-15.0%,

[0025] Preferably, the isolation film coating material is Opadry gastroresistant film coating premix, and the ratio of isolation film coating weight to total weight of the tablet core after semi-permeable membrane coating is 2.0-5.0%.

[0026] The application also provides a preparation method of the tobradex osmotic pump controlled release tablet, which comprises the following steps:

[0027] 1) Preparation of the drug layer: wet granulation of the entraining polymer, the binder, the osmotic pressure promoter and the tobradex raw material, then dry granulation, and then adding and uniformly mixing the lubricant;

[0028] 2) Preparation of the push layer: wet granulation of the swelling agent, the osmotic pressure promoter and the lake, then dry granulation, and then adding and uniformly mixing the lubricant.

[0029] 3) Double-layer tablet compression: using a tablet press to pre-press the drug layer, and then fill and push the layer to compress into a double-layer tablet core;

[0030] 4) After the double-layer tablet core is coated with a semi-permeable membrane, a hole is punched on the drug layer side of the semi-permeable membrane to obtain a osmotic pump tablet, and then a separation coating film is coated, thereby obtaining a toripastat osmotic pump controlled-release tablet.

[0031] In the osmotic pump controlled-release tablet, the size of the drug release aperture is a key parameter for determining the drug release rate and the stability of the preparation. If the aperture is too large, the mechanical strength of the semi-permeable membrane can be weakened, resulting in rupture under the influence of gastrointestinal peristalsis. If the aperture is too small (<200 μm), it can be blocked by high-viscosity drug suspensions or gastrointestinal contents. Preferably, the hole punching in step 4) is performed by laser punching, and the aperture is preferably 0.4-0.6 mm to achieve zero-order release of the drug.

[0032] Advantages:

[0033] The toripastat osmotic pump tablet provided by the application comprises a tablet core composed of a drug layer and a push layer, a semi-permeable membrane coating outside the tablet core, and a single drug release aperture on the surface of the drug layer side of the controlled-release tablet and a separation coating film. Due to the use of the double-layer osmotic pump controlled-release technology, water molecules in the digestive tract enter the tablet core through the semi-permeable membrane, the drug layer and the push layer absorb water, and the osmotic pressure promoter in the drug layer and the swelling agent in the push layer generate a sustained osmotic pressure and a pushing force, so that the drug layer containing toripastat is released through the drug release aperture on the semi-permeable membrane. The release rate of the drug is not affected by gastric juice and food, and toripastat can be completely discharged within a predetermined time. Compared with a single-layer tablet, the drug has stronger controllability, more complete release, and higher utilization.

[0034] Compared with the currently marketed toripastat tablet, the toripastat osmotic pump controlled-release tablet prepared by the application can achieve sustained and stable constant-speed release of the drug. After the patient takes the medicine, the drug in the drug release layer will not be released immediately, and within the next ten or more hours, the tablet can rhythmically release the drug under the action of the push layer, maintain a steady-state blood drug concentration, delay the peak time, and prolong the drug half-life, thereby improving the bioavailability and achieving a 12h or more sustained-release effect. BRIEF DESCRIPTION OF DRAWINGS

[0035] Figure 1 is a dissolution curve diagram of Examples 1, 2 and 3 using 0.1M hydrochloric acid solution as the dissolution medium.

[0036] Figure 2 is a dissolution curve diagram of Examples 1, 2 and 3 using pH 6.8 phosphate buffer + 1.0% SDS solution as the dissolution medium.

[0037] Figure 3 is a dissolution curve diagram of Example 4 using 0.1M hydrochloric acid solution as the dissolution medium.

[0038] Figure 4 is a dissolution profile of Example 7 of the present application.

[0039] Figure 5 is a dissolution profile of Example 8 of the present application.

[0040] Figure 6 is a dissolution profile of Example 9 of the present application.

[0041] Figure 7 is a dissolution profile of Example 10 of the present application. DETAILED DESCRIPTION

[0042] In order to further understand the present application, the present application will be further described in detail below in conjunction with the examples and the accompanying drawings, which are only used to explain the present application and do not constitute a limitation to the protection scope of the present application.

[0043] Table 1 is the source information of some of the raw and auxiliary materials used in the examples. The other raw and auxiliary materials are commercially available.

[0044] Table 1 Source information of raw and auxiliary materials

[0045]

[0046] Example 1 Composition of toptipirate osmotic pump controlled release tablet

[0047] Table 2 Composition of tablet of Example 1

[0048]

[0049] Example 2 Composition of toptipirate osmotic pump controlled release tablet

[0050] The composition of the drug layer of the tablet core and the coating of Example 2 is the same as that of Example 1, except that the total weight of the push layer is 160 mg.

[0051] Table 3 Composition of tablet of Example 2

[0052]

[0053] Example 3 Composition of toptipirate osmotic pump controlled release tablet

[0054] The composition of the drug layer of the tablet core and the coating of prescription 3 is the same as that of prescription 1, except that the total weight of the push layer is 200 mg.

[0055] Table 4 Composition of tablet of prescription 3

[0056]

[0057] Example 4 Composition of toptipirate osmotic pump controlled release tablet

[0058] The core weight and components of Example 4 and the components of the coating film are the same as those of Example 1, and the percentage content of some of the auxiliary materials is adjusted on this basis.

[0059] Table 5 Tablet composition of Formulation 4

[0060]

[0061] Example 5 Preparation of a topticip osmotic pump controlled release tablet

[0062] The preparation method of the topticip osmotic pump controlled release tablet of Examples 1, 2, 3 and 4 is the same, and is as follows:

[0063] (1) Preparation of drug-containing layer granules

[0064] ① Pretreatment: PEO 200000, hydroxypropyl methyl cellulose E5, sodium chloride, API were respectively passed through a 40-mesh sieve.

[0065] ②Premixing: The auxiliary materials were mixed by shaking.

[0066] ③ Wet granulation: A 90% ethanol aqueous solution (V / V) was used as a wetting agent to prepare a soft material, and the amount of liquid added was about 10% (W / W).

[0067] ④ Wet granulation: Wet granulation was performed through a 14-mesh sieve.

[0068] ⑤ Drying: The wet granules were placed in a 40°C oven for 1 hour to remove the organic solvent, and then dry granulation was performed through a 14-mesh sieve.

[0069] ⑥ Total mixing: The above dry granules were mixed with the prescribed amount of magnesium stearate by shaking, and the drug-containing layer granules were obtained.

[0070] (2) Preparation of push layer granules

[0071] ① Pretreatment: PEO 5000000, sodium chloride, and red iron oxide were respectively passed through a 40-mesh sieve.

[0072] ②Premixing: All the auxiliary materials were mixed by shaking.

[0073] ③ Wet granulation: A 95% ethanol aqueous solution (V / V) was used as a wetting agent to prepare a soft material, and the amount of liquid added was about 10% (W / W).

[0074] ④ Wet granulation: Wet granulation was performed through a 14-mesh sieve.

[0075] ⑤ Drying: The wet granules were placed in a 40°C oven for 1 hour, and then dry granulation was performed through a 14-mesh sieve.

[0076] ⑥ Total mixing: The above dry granules were mixed with the prescribed amount of magnesium stearate by shaking, and the push layer granules were obtained.

[0077] (3) Double-layer tablet compression:

[0078] The tablet of Example 1 and 4 filled with drug layer 240 mg and push layer 120 mg (total weight of tablet core 360 mg) was compressed using 9.0 mm round punch, and the hardness of the double-layer tablet core was controlled at 10-12 kg;

[0079] The tablet of Example 2 filled with drug layer 240 mg and push layer 160 mg (total weight of tablet core 400 mg) was compressed using 10.0 mm round punch, and the hardness of the double-layer tablet core was controlled at 10-12 kg;

[0080] The tablet of Example 3 filled with drug layer 240 mg and push layer 200 mg (total weight of tablet core 440 mg) was compressed using 11.0 mm round punch, and the hardness of the double-layer tablet core was controlled at 10-12 kg.

[0081] (4) Semi-permeable membrane coating: The coating liquid was a 5% solid content acetocellulose acetate solution in acetone-water mixture, acetone: water = 94:6 (W / W); the average coating weight gain was about 15%; after the coating weight gain reached the requirement, it was placed in a 40°C oven for 12 h for drying, for the purpose of aging.

[0082] (5) Perforation: laser perforation on the drug-containing layer side, with a hole diameter of about 0.6 mm.

[0083] (6) Isolation film coating: the coating liquid was a 10% solid content Opadry aqueous solution; the coating weight gain was about 3%.

[0084] Example 6 In-vitro dissolution test

[0085] The tablets prepared in Examples 1, 2 and 3 were respectively taken, and the dissolution curves were drawn according to the second method of Chinese Pharmacopoeia 2020 Edition Vol. IV General Test 0931, using 0.1M hydrochloric acid solution and pH 6.8 phosphate buffer + 1.0% SDS solution as the dissolution medium, as shown in Figures 1 and 2. The dissolution results showed that the drugs in Examples 1, 2 and 3 were all completely released in 0.1M hydrochloric acid solution medium after 14 h, reaching the plateau, and the dissolution rates were all close to 100%, and the rising trend of the drug dissolution curve was relatively smooth within 14 h, showing zero-order kinetic release; in pH 6.8 phosphate buffer + 1.0% SDS medium, the drug reached the plateau after about 12 h, and the dissolution rate was about 60%, and the rising trend of the drug dissolution curve was relatively smooth within 12 h.

[0086] The dissolution results show that the gastric dissolution layer of each of Examples 1-3 begins to dissolve at 2 min in a 0.1M hydrochloric acid solution medium, and the gastric dissolution coating layer is completely dissolved at 1 h; at 3 h, the push layer of the semi-permeable membrane coating of Example 2 has a slight crack, the push layer of the semi-permeable membrane coating of Example 3 is obviously cracked, and Example 1 has no obvious change. In a pH 6.8 phosphate buffer + 1.0% SDS medium, the push layer of the semi-permeable membrane coating of Example 2 and Example 3 is cracked at 4 h, and Example 1 has no obvious change. Therefore, the tosuenzole osmotic pump tablets prepared by the prescription components of the push layer within the scope of the present application have a more optimal drug release effect.

[0087] As shown in FIG. 3, the tosuenzole osmotic pump tablets prepared in Example 4 and the tosuenzole osmotic pump tablets prepared in Example 1 are dissolved in a 0.1M hydrochloric acid solution as a dissolution medium, and the dissolution curves are drawn. The dissolution results show that the dissolution curve trends of the tablets prepared in the two examples are basically consistent.

[0088] Example 7: Tosuenzole osmotic pump tablets with different drug layers entraining polymers

[0089] The entraining polymer PEO200000 in the drug layer of Example 1 is replaced by the same weight of polyethylene glycol 6000 (PEG6000), lactose monohydrate and HPMC K750, respectively, and other conditions are the same. The dissolution is determined according to the method of Example 6, and the dissolution curve is shown in FIG. 4.

[0090] The study shows that PEG6000 can accelerate drug dissolution through its pore-forming effect. The dissolution results show that the use of PEG6000 instead of the entraining polymer PEO200000 significantly accelerates drug release, shortens the zero-order release phase, and basically reaches the plateau period at 8 h of dissolution. In addition, polyethylene glycol 6000 has a certain hygroscopicity and is easy to absorb moisture and form lumps in a relatively humid environment, resulting in a decrease in powder flowability. The rest angle of the drug-containing layer powder prepared by using polyethylene glycol 6000 increases from 38% to 50% under the condition of a relative humidity of 75%.

[0091] After absorbing water, HPMC K750 forms a viscous gel layer, which may slow down the penetration of water and the diffusion of the drug, resulting in a decrease in the dissolution rate. The dissolution results show that the prescription prepared by using HPMC K750 has almost no drug release within 2 h in 0.1M hydrochloric acid, and the dissolution of the drug reaches only 48.88% at 12 h.

[0092] Lactose monohydrate cannot form a gel layer or a suspension system, has a faster dissolution rate, and may not be able to maintain the osmotic pressure gradient, resulting in uneven drug release and a risk of burst release. The dissolution results show that the use of lactose monohydrate instead of the entraining polymer PEO200000 causes a burst release at the initial stage of drug release, and the dissolution RSD value of the parallel group is large.

[0093] Therefore, the tolfenpirit osmotic pump tablets prepared by using PEG6000, HPMC K750 or lactose monohydrate as the entraining polymer cannot achieve the ideal sustained-release effect.

[0094] Example 8 Tolfenpirit osmotic pump tablets with different drug layer binders

[0095] The hydroxypropyl methyl cellulose E5 in the drug layer tablet core of Example 1 was replaced with the same weight of hydroxypropyl methyl cellulose K4M, hydroxypropyl methyl cellulose K15M and PVP K90 respectively, and other conditions were the same. The dissolution rate was determined according to the method of Example 6, and the dissolution curve was plotted as shown in Figure 5.

[0096] The dissolution results show that the drug release rate is significantly delayed when HPMC K4M and HPMC K15M are used as binders, and the dissolution rates at 12h are 54.62% and 20.36% respectively; the drug release rate is significantly accelerated when PVP K90 is used as the binder, and it is basically completely released at 8h. Therefore, the tolfenpirit osmotic pump tablets prepared by using HPMC K4M, HPMC K15M and PVP K90 as the binder cannot achieve the ideal sustained-release effect. In comparison, the HPMC E5 binder prescription has a moderate in vitro dissolution rate, which meets the expected sustained-release effect.

[0097] Example 9 Tolfenpirit osmotic pump tablets with different push layer swelling agents

[0098] The swelling agent PEO 5000000 in the push layer tablet core of Example 1 was replaced with the same weight of PEO 7000000 and sodium alginate respectively, and other conditions were the same. The dissolution rate was determined according to the method of Example 6, and the dissolution curve was plotted as shown in Figure 6. The results of the study show that sodium alginate as a swelling agent has low swelling rate and driving force, which is not enough to support the high osmotic pressure requirement of tolfenpirit osmotic pump tablets alone, and the swelling capacity of sodium alginate is reduced under acidic conditions, which may affect the drug release stability, and the dissolution rate at 12h is only 17.02%; using PEO 5000000 or PEO 7000000 as the swelling agent, the drug dissolution curves are similar, but PEO 7000000 has greater viscosity, and the wet granulation process is more difficult than the PEO 5000000 prescription, and the use of PEO 5000000 is more conducive to industrial production.

[0099] Example 10 Tolfenpirit osmotic pump tablets with different semi-permeable membrane coating weights

[0100] The semi-permeable membrane of step (4) in Example 5 was coated to increase the weight by 7.5%, 10.0%, 12.5%, and 15.0% of the weight of the double-layer tablet core, respectively, and the release pore size was 0.6 mm. The dissolution rate was determined according to the method of Example 6, and the dissolution curve is shown in Figure 7. The dissolution curve results show that the release of the prescription drug with a coating weight of 15.0% is relatively smooth, and the sustained-release effect is significantly better than that of other smaller coating weights within 8 h.

[0101] The above description is merely preferred embodiments of the present application, but not to limit the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A toiprant permeation pump controlled release tablet, characterized by, The osmotic pump tablet comprises a tablet core composed of a drug layer and a push layer, a semi-permeable membrane coating outside the tablet core, and a single drug release hole and a separation film coating on the surface of the drug layer side of the tablet; The drug layer is composed of the following ingredients, calculated by percentage of the weight of the drug layer: Torpisert raw material 20.0-50%; Carried polymer 40-70%; Binding agent 2.0-5.0%; Osmotic pressure promoter 1.5-5%; Lubricant 1.0-2.0%; The push layer is composed of the following ingredients, calculated by percentage of the weight of the push layer: Expanding agent 60-70%; Osmotic pressure promoter 25-35%; Lake 1.0-3.0%; Lubricant 1.0-3.0%.

2. The toposide osmotic pump controlled release tablet according to claim 1, wherein The weight of the drug layer is 240 mg-480 mg, and the weight of the push layer is 120 mg-240 mg.

3. The toposide osmotic pump controlled release tablet according to claim 1, wherein The carried polymer is selected from one of polyoxyethylene 200000, polyethylene glycol 6000, lactose monohydrate or HPMC K750.

4. The toposide osmotic pump controlled release tablet according to claim 1, wherein The binding agent is selected from one of hypromellose E5, hypromellose K4M, hypromellose K15M or PVP K90.

5. The toposide osmotic pump controlled release tablet according to claim 1, wherein The expanding agent is selected from one of polyoxyethylene 5000000, polyoxyethylene 7000000 or sodium alginate.

6. The tolfenpyrat osmotic pump controlled release tablet according to claim 1, wherein The osmotic pressure promoter is sodium chloride, the lubricant is magnesium stearate, and the lake is iron oxide red.

7. The tolfenpyrat osmotic pump controlled release tablet according to claim 1, wherein The semi-permeable membrane coating material is cellulose acetate, and the semi-permeable membrane coating weight accounts for 7.5-15.0% of the total weight of the double-layer tablet core.

8. The tolfenpyrat osmotic pump controlled release tablet according to claim 1, wherein The separation film coating material is Opadry gastroresistant film coating premix, and the separation film coating weight accounts for 2.0-5.0% of the total weight of the tablet core after semi-permeable membrane coating.

9. The process for preparing the topropide osmotic pump controlled release tablet according to any one of claims 1 to 8, wherein, The method comprises the following steps: 1) Preparation of the drug layer: the carried polymer, the binding agent, the osmotic pressure promoter and the torpisert raw material are granulated by wet method, then dry granulation is performed, and then the lubricant is added and mixed uniformly; 2) Preparation of the push layer: the expanding agent, the osmotic pressure promoter and the lake are granulated by wet method, then dry granulation is performed, and then the lubricant is added and mixed uniformly; 3) Double-layer tablet compression: the drug layer is pre-pressed using a tablet press, and then the push layer is filled and compressed to form a double-layer tablet core; 4) After the double-layer tablet core is coated with a semi-permeable membrane, a hole is punched on the semi-permeable membrane on the drug layer side to obtain an osmotic pump tablet, and then a separation film coating is performed to obtain a torpisert osmotic pump controlled-release tablet.

10. The method of claim 9, wherein, The hole punching in step 4) can be performed by mechanical or laser punching, and the hole diameter is 0.4-0.6 mm.

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