Topiromilast osmotic pump controlled release tablet and preparation method thereof

Abstract

The invention discloses a topiromilast osmotic pump tablet and a preparation method thereof. The topiromilast osmotic pump tablet comprises a tablet core composed of a drug layer and a pushing layer, a semipermeable membrane coating outside the tablet core, and a single drug release small hole and an isolation coating on the surface of a controlled release tablet on one side of the drug layer. Compared with topiromilast tablets on the market at present, the topiromilast osmotic pump controlled release tablet prepared by the invention can realize continuous and stable constant-speed release of drugs. After a patient takes the medicine, the medicine in the medicine release layer cannot be released immediately, and the tablet can rhythmically release the medicine, maintain the steady-state blood concentration, delay the peak time and prolong the half-life period of the medicine within more than ten subsequent hours under the action of the pushing layer, so that the bioavailability is improved, and the slow release effect of more than 12 hours is achieved. Due to the adoption of a double-layer osmotic pump controlled release technology, compared with a single-layer tablet, the double-layer osmotic pump controlled release tablet has the advantages of stronger controllability, more complete release and higher availability.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations. Specifically, the present invention relates to a tolterodine osmotic pump controlled-release tablet and a preparation method thereof. Background Art

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

[0003] Tolterodine tablet is another non-purine xanthine oxidase inhibitor after febuxostat. It reaches the peak blood drug concentration faster than febuxostat, so it takes effect faster; there is no phenomenon of in vivo accumulation; it is not affected by diet, has high safety for the cardiovascular system and low side effects, improving the safety and compliance of patients taking medicine. The instructions of the tolterodine tablets marketed in Japan show that regardless of whether the dosage is 20 mg, 40 mg or 60 mg, the drug is taken twice a day. However, for elderly patients, taking gout medicine once a day can usually improve the compliance of patients. Making a sustained-release or controlled-release preparation can greatly reduce the number of times patients take medicine, reduce the fluctuation of blood drug concentration, reduce the discomfort caused by the peak-valley phenomenon, and reduce the toxic and side effects. However, there are still disadvantages such as large individual differences and unstable drug release rate.

[0004] The osmotic pump drug delivery system is a high-end drug controlled-release technology designed based on the principle of osmotic pressure. Its core advantage lies in achieving precise and stable drug release through a physical mechanism, being unaffected by pH value, digestive enzymes, food or intestinal peristalsis, ensuring the stability and predictability of drug release, with small individual differences and reduced absorption differences among different patients. It is especially suitable for groups with large metabolic differences and can achieve once-daily dosing (QD dosing method), reducing the number of times of taking medicine. Developing tolterodine into an osmotic pump drug delivery system may become an important research direction for modified tolterodine preparations. Summary of the Invention

[0005] Object of the Invention: The object of the present invention is to provide a tolterodine osmotic pump controlled-release tablet and a preparation method thereof, which can control the release rate of the tolterodine osmotic pump controlled-release tablet, and has the advantages of convenient administration, long-lasting effect, stable release and small side effects.

[0006] Technical Solution: The technical problems to be solved by the present invention are achieved by adopting the following technical solutions.

[0007] A tolterodine osmotic pump controlled-release tablet, comprising a tablet core composed of a drug layer and a pushing layer, a semipermeable membrane coating outside the tablet core, and a single drug release hole and an isolating film coating on the surface of the controlled-release tablet on the side of the drug layer;

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

[0009] Tolterodine API 20.0 - 50%;

[0010] Entraining polymer 40 - 70%;

[0011] Binder 2.0 - 5.0%;

[0012] Osmotic pressure promoter 1.5 - 5%;

[0013] Lubricant 1.0 - 2.0%;

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

[0015] Swelling agent 60 - 70%;

[0016] Osmotic pressure promoter 25 - 35%;

[0017] Lake 1.0 - 3.0%;

[0018] Lubricant 1.0 - 3.0%.

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

[0020] As the core component of the osmotic pump preparation design, the entraining polymer, on the one hand, forms a gel layer through water absorption and swelling to provide an osmotic pressure driving force, and on the other hand, makes the formation of the gel layer more stable by virtue of 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 tolterodine. This requires that the entraining polymer has appropriate swelling ability, the formed gel layer has sufficient mechanical strength to resist the physical stress of the gastrointestinal tract, and has corresponding compatibility with the tableting and coating processes. Preferably, the entraining polymer is selected from one of polyethylene oxide 200000, polyethylene glycol 6000, lactose monohydrate, or HPMC K750.

[0021] In an osmotic pump controlled-release tablet, the binder is a key excipient to ensure the structural integrity of the tablet and the controlled-release requirements. It can not only maintain the mechanical strength of the tablet to ensure that it does not break during tabletting, coating, and the gastrointestinal environment, but also have good compatibility with the controlled-release material while not affecting the osmotic pressure-driven mechanism. In addition, it provides certain feasibility for the optimization of the preparation process. This requires the binder to have corresponding physicochemical properties on the one hand, that is, controllable hydrophilicity, low swelling property, and no osmotic activity, and on the other hand, excellent process stability, that is, it can quickly form uniform granules in wet granulation and be compatible with the coating process. Preferably, the binder is selected from one of hypromellose E5, hypromellose K4M, hypromellose K15M, or PVP K90.

[0022] In an osmotic pump controlled-release tablet, the swelling agent is a key hub connecting physical swelling and drug release kinetics. The swelling agent can generate a volume expansion force through rapid water absorption and swelling, pushing the drug in the drug-containing layer to be released through the drug release holes on the semipermeable membrane, and acting synergistically with the osmotic pressure promoter to maintain the osmotic pressure gradient. This requires the swelling agent to have high water absorption performance and swelling ability, and at the same time, the gel formed after swelling has certain mechanical stability and will not break and collapse during gastrointestinal peristalsis. Preferably, the swelling agent is selected from one of polyethylene oxide 5000000, polyethylene oxide 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 tolebrutinib, and enhance the absorption of tolebrutinib by the human body. The lubricant can also be calcium stearate, sodium stearate, etc., and its function is to prevent sticking during tabletting and at the same time increase the fluidity of the granules.

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

[0025] Preferably, the coating material of the isolating film is Opadry gastro-resistant film coating premix, and the ratio of the weight gain of the isolating film coating to the total weight of the tablet core after semipermeable membrane coating is 2.0 - 5.0%.

[0026] The present invention also provides a preparation method of the tolebrutinib osmotic pump controlled-release tablet, comprising the following steps:

[0027] 1) Preparation of the drug layer: The entrained polymer, binder, osmotic pressure promoter, and tolebrutinib raw material are wet granulated and then dry-sized, and then the lubricant is added and mixed evenly.

[0028] 2) Preparation of the pushing layer: The swelling agent, osmotic pressure promoter, and lake are wet granulated and then dry-sized, and then the lubricant is added and mixed evenly.

[0029] 3) Double-layer tablet pressing: Use a tableting machine to pre-press the drug layer, and then fill the pushing layer to press into a double-layer tablet core;

[0030] 4) After coating the double-layer tablet core with a semi-permeable membrane, punch holes on one side of the drug-containing layer on the semi-permeable membrane to obtain an osmotic pump element tablet, and then coat it with an isolating film to obtain the tolterodine osmotic pump controlled-release tablet.

[0031] In the osmotic pump controlled-release tablet, the size of the drug release pore diameter is a key parameter determining the drug release rate and the preparation stability. An overly large pore diameter may weaken the mechanical strength of the semi-permeable membrane, resulting in its rupture under the influence of gastrointestinal peristalsis; an overly small pore diameter (<200 μm) may be blocked by a highly viscous drug suspension or gastrointestinal contents. Preferably, laser drilling is used for the drilling in step 4), and the pore diameter is preferably 0.4 - 0.6 mm to achieve zero-order release of the drug.

[0032] Beneficial effects:

[0033] The tolterodine osmotic pump tablet provided by the present invention comprises a tablet core composed of a drug layer and a pushing layer, a semi-permeable membrane coating outside the tablet core, as well as a single drug release small hole and an isolating film coating on the surface of the controlled-release tablet on one side of the drug layer. Due to the adoption of the double-layer osmotic pump controlled-release technology, water molecules in the digestive tract penetrate through the semi-permeable membrane into the tablet core. The drug layer and the pushing layer absorb water, and the osmotic pressure promoter in the drug layer and the swelling agent in the pushing layer generate continuous osmotic pressure and driving force, so that the drug layer containing tolterodine is released through the drug release holes on the semi-permeable membrane. The drug release rate is not affected by gastric juice and food, and tolterodine can be completely excreted within a predetermined time. Compared with a single-layer tablet, the controllability of the drug is stronger, the release is more complete, and the utilization rate is higher.

[0034] Compared with the currently marketed tolterodine tablets, the tolterodine osmotic pump controlled-release tablets prepared by the present invention can achieve continuous and stable constant-rate release of the drug. After the patient takes the medicine, the drug in the drug release layer will not be immediately released. In the subsequent more than ten hours, under the action of the pushing layer, the tablet can rhythmically release the drug, maintain a steady-state blood drug concentration, delay the peak time, and prolong the drug half-life, thereby improving the bioavailability and achieving a sustained-release effect of more than 12 h. Description of the drawings

[0035] Figure 1 It is the dissolution curve graph of Examples 1, 2 and 3 with 0.1 M hydrochloric acid solution as the dissolution medium.

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

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

[0038] Figure 4 It is the dissolution curve of Example 7 of the present invention.

[0039] Figure 5 It is the dissolution curve of Example 8 of the present invention.

[0040] Figure 6 It is the dissolution curve of Example 9 of the present invention.

[0041] Figure 7 It is the dissolution curve of Example 10 of the present invention. Detailed implementation manners

[0042] To deepen the understanding of the present invention, the present invention will be further described in detail below in combination with examples and drawings. These examples are only used to explain the present invention and do not constitute a limitation on the protection scope of the present invention.

[0043] Table 1 shows the source information of some of the raw and auxiliary materials used in the examples. Other raw and auxiliary materials can be obtained commercially.

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

[0045]

[0046] Composition of the toprimate osmotic pump controlled release tablets in Example 1

[0047] Table 2 Composition of the tablets in Example 1

[0048]

[0049]

[0050] Composition of the toprimate osmotic pump controlled release tablets in Example 2

[0051] The drug layer and coating composition of the tablet core in Example 2 are the same as those in Example 1, except that the total weight of the pushing layer is 160 mg.

[0052] Table 3 Composition of the tablets in Example 2

[0053]

[0054] Composition of the toprimate osmotic pump controlled release tablets in Example 3

[0055] The drug layer and coating composition of the tablet core in Prescription 3 are the same as those in Prescription 1, except that the total weight of the pushing layer is 200 mg.

[0056] Table 4 Composition of the tablets in Prescription 3

[0057]

[0058]

[0059] Example 4 Composition of Toripristone Osmotic Pump Controlled Release Tablets

[0060] The core weight, components of Example 4 and each component of the coating film are the same as those of Example 1. On this basis, the percentage contents of some excipients are adjusted.

[0061] Table 5 Composition of Prescription 4 Tablets

[0062]

[0063] Preparation of Toripristone Osmotic Pump Controlled Release Tablets in Example 5

[0064] The preparation methods of the toripristone osmotic pump controlled release tablets in Examples 1, 2, 3 and 4 are the same, and are specifically as follows:

[0065] (1) Preparation of drug-containing layer granules

[0066] ① Pretreatment: Pass PEO 200000, hypromellose E5, sodium chloride, and API through a 40-mesh sieve respectively.

[0067] ② Premixing: Vigorously shake and mix the excipients.

[0068] ③ Wet granulation: Use 90% ethanol aqueous solution (V / V) as the wetting agent to prepare soft materials, and the liquid addition amount is about 10% (W / W). ④ Wet screening: Screen wet through a 14-mesh sieve.

[0069] ⑤ Drying: Place the wet granules in an oven at 40°C for 1 hour to remove organic solvents, and screen dry through a 14-mesh sieve.

[0070] ⑥ Total mixing: Add the prescribed amount of magnesium stearate to the above dry granules, shake and mix to obtain the drug-containing layer granules.

[0071] (2) Preparation of the pushing layer granules

[0072] ① Pretreatment: Pass PEO 5000000, sodium chloride, and iron oxide red through a 40-mesh sieve respectively.

[0073] ② Premixing: Vigorously shake and mix all excipients.

[0074] ③ Wet granulation: Use 95% ethanol aqueous solution (V / V) as the wetting agent to prepare soft materials, and the liquid addition amount is about 10% (W / W). ④ Wet screening: Screen wet through a 14-mesh sieve.

[0075] ⑤ Drying: Place the wet granules in an oven at 40°C for 1 hour, and screen dry through a 14-mesh sieve.

[0076] ⑥Total mixing: Add the prescribed amount of magnesium stearate to the above dry granules, shake and mix to obtain the pushing layer granules.

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

[0078] For the tablets of Examples 1 and 4, fill the drug layer with 240 mg and the pushing layer with 120 mg (total core weight 360 mg), use a 9.0 mm round punch for tablet pressing, and control the hardness of the double-layer tablet core to be 10 - 12 kg;

[0079] For the tablets of Example 2, fill the drug layer with 240 mg and the pushing layer with 160 mg (total core weight 400 mg), use a 10.0 mm round punch for tablet pressing, and control the hardness of the double-layer tablet core to be 10 - 12 kg;

[0080] For the tablets of Example 3, fill the drug layer with 240 mg and the pushing layer with 200 mg (total core weight 440 mg), use a 11.0 mm round punch for tablet pressing, and control the hardness of the double-layer tablet core to be 10 - 12 kg.

[0081] (4) Semi-permeable membrane coating: The coating solution is an acetone-water mixed solution of cellulose acetate with a solid content of 5%, acetone: water = 94:6 (W / W); the average coating weight gain is about 15%; after the coating weight gain reaches the requirement, place it in an oven at 40 °C and dry for 12 h for the purpose of aging.

[0082] (5) Punching: Laser punch on the side of the drug-containing layer, and the pore diameter is about 0.6 mm.

[0083] (6) Isolation film coating: The coating solution is an aqueous solution of Opadry with a solid content of 10%; the coating weight gain is about 3%.

[0084] In vitro dissolution test of Example 6

[0085] Respectively take the tablets prepared in Examples 1, 2 and 3, and determine according to the second method of General Principles 0931 in the Fourth Part of Chinese Pharmacopoeia 2020 Edition. Respectively use 0.1M hydrochloric acid solution and pH6.8 phosphate buffer solution + 1.0% SDS solution as the dissolution media, draw the dissolution curves, as Figure 1 and Figure 2 shown. The dissolution results show that for Examples 1, 2, and 3, the drugs are basically completely released after 14 h in the 0.1M hydrochloric acid solution medium, reaching the plateau phase, the dissolution degrees are all close to 100%, and the rising trends of the drug dissolution curves within 14 h are all relatively stable, showing zero-order kinetic release; in the pH6.8 phosphate buffer solution + 1.0% SDS medium, the drug release reaches the plateau phase after about 12 h, and the dissolution degrees are all about 60%, and the rising trends of the drug dissolution curves within 12 h are all relatively stable.

[0086] The dissolution phenomenon shows that in a 0.1M hydrochloric acid solution medium, the gastric-soluble layer of Examples 1 to 3 began to dissolve at 2 minutes, and the gastric-soluble coating layer was completely dissolved in 1 hour; at 3 hours, slight cracks occurred in the semi-permeable membrane coating of the pushing layer in Example 2, and the semi-permeable membrane coating of the pushing layer in Example 3 was significantly cracked, while there was no obvious change in Example 1. In a pH 6.8 phosphate buffer solution + 1.0% SDS medium, at 4 hours, the semi-permeable membrane coating of the pushing layer in Example 2 and Example 3 cracked, and there was no obvious change in Example 1. Therefore, the tolterodine osmotic pump tablets prepared with the prescription components in which the dosage of the pushing layer of Example 1 is within the scope of the present invention have a better drug release effect.

[0087] As Figure 3 shown, for the tolterodine osmotic pump tablets prepared in Example 4 and the tolterodine osmotic pump tablets prepared in Example 1, with 0.1M hydrochloric acid solution as the dissolution medium, dissolution curves were plotted. The dissolution results show that the trends of the dissolution curves of the tablets prepared in the two examples are basically the same.

[0088] Tolterodine osmotic pump tablets with different drug layers entrapping polymers in Example 7

[0089] The polymer PEO200000 entrapped in the drug layer of Example 1 was respectively replaced with the same weight of polyethylene glycol 6000 (PEG6000), lactose monohydrate, and HPMC K750, and other conditions were the same. The dissolution degree was measured according to the method of Example 6, and the dissolution curve was plotted as Figure 4 shown.

[0090] Research shows that PEG6000 can accelerate drug dissolution through its pore-forming effect. The dissolution results show that when PEG6000 is used to replace the entrapped polymer PEO200000, the drug release is significantly accelerated, the zero-order release stage is shortened, and the dissolution has basically reached the plateau at 8 hours. In addition, polyethylene glycol 6000 has a certain hygroscopicity and is prone to moisture absorption and caking in a relatively humid environment, resulting in a decrease in the powder fluidity. The angle of repose of the drug-containing layer powder prepared with polyethylene glycol 6000 increased from the initial 38% to 50% under the condition of a relative humidity of 75%.

[0091] HPMC K750 forms a viscous gel layer after absorbing water, which may delay water penetration and drug diffusion, resulting in a slower dissolution rate. The dissolution results show that for the prescription prepared with HPMC K750 in 0.1M hydrochloric acid, the drug hardly releases within 2 hours, and the drug dissolution degree at 12 hours only reaches 48.88%.

[0092] However, lactose monohydrate cannot form a gel layer or suspension system, and its dissolution speed is relatively fast. It may not be able to maintain the osmotic pressure gradient, resulting in uneven drug release and a risk of sudden release. The dissolution results show that when lactose monohydrate is used to replace the entrapped polymer PEO200000, sudden release occurs at the initial stage of drug release, and the RSD value of the dissolution degree of the parallel groups is relatively large.

[0093] Therefore, for the topiramate osmotic pump tablets prepared using PEG6000, HPMC K750 or lactose monohydrate as entraining polymers, the ideal sustained-release effect cannot be achieved.

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

[0095] Replace the hypromellose E5 in the drug layer tablet core of Example 1 with hypromellose K4M, hypromellose K15M, and PVP K90 of the same weight respectively, and keep other conditions the same. Determine the dissolution rate according to the method of Example 6, and draw the dissolution curve as Figure 5 shown.

[0096] The dissolution results show that when using HPMC K4M and HPMC K15M as binders, the drug release rate is significantly delayed, and the dissolution rates at 12 h are 54.62% and 20.36% respectively; when using PVP K90 as the binder, the drug release rate is significantly accelerated, and it is basically completely released at 8 h. Therefore, for the topiramate osmotic pump tablets prepared using HPMC K4M, HPMC K15M and PVP K90 as binders, the ideal sustained-release effect cannot be achieved. In comparison, the in vitro dissolution rate of the HPMC E5 binder formulation is moderate, meeting the expected sustained-release effect.

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

[0098] Replace the swelling agent PEO 5000000 in the push layer tablet core of Example 1 with PEO7000000 and sodium alginate of the same weight respectively, and keep other conditions the same. Determine the dissolution rate according to the method of Example 6, and draw the dissolution curve as Figure 6 shown. The research results show that as a swelling agent, sodium alginate has a low swelling rate and driving force, which is not sufficient to support the high osmotic pressure requirement of the topiramate osmotic pump tablets alone, and the swelling ability of sodium alginate decreases under acidic conditions, which may affect the drug release stability, and the dissolution rate at 12 h is only 17.02%; when using PEO 5000000 or PEO 7000000 as the swelling agent, the drug dissolution curves are relatively similar, but PEO 7000000 has greater viscosity, and the wet granulation process is more difficult than the PEO 5000000 formulation. Using PEO5000000 is more conducive to industrial production.

[0099] Topiramate osmotic pump tablets with different semipermeable membrane coating weight gains in Example 10

[0100] Prepare the semipermeable membrane coating weight gains in step (4) of Example 5 to be 7.5%, 10.0%, 12.5%, and 15% of the weight of the double-layer tablet core respectively, and the drug release pore diameter is 0.6 mm. Determine the dissolution rate according to the method of Example 6, and draw the dissolution curve asFigure 7 As shown. The dissolution curve results show that the drug release of the formulation with a coating weight gain of 15.0% is relatively gentle, and the sustained-release effect within 8 hours is significantly better than that of other formulations with smaller coating weight gains.

[0101] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the protection scope of the present invention.

Claims

1. A topiramate osmotic pump controlled-release tablet, characterized in that: The tablet comprises a core composed of a drug layer and a push layer, a semipermeable membrane coating on the outside of the core, and a single drug release hole and a separation film coating on the surface of the controlled-release tablet on one side of the drug layer; The drug layer is composed of the following ingredients, calculated as a percentage of the weight of the drug layer: Topiramate API 20.0-50%; Entrained polymer 40-70%; Adhesive 2.0-5.0%; Osmotic pressure enhancer 1.5-5%; Lubricant 1.0-2.0%; The push layer is composed of the following components, calculated as a percentage of the push layer weight: Expansion agent 60-70%; Osmotic pressure enhancer 25-35%; Lake 1.0~3.0%; Lubricant 1.0~3.0%.

2. The topiramate osmotic pump controlled-release tablet according to claim 1, characterized in that: The weight of the drug layer is 240mg to 480mg, and the weight of the push layer is 120mg to 240mg.

3. The topiramate osmotic pump controlled-release tablet according to claim 1, characterized in that: The entraining polymer is selected from one of polyoxyethylene 200000, polyethylene glycol 6000, lactose monohydrate or HPMC K750.

4. The topiramate osmotic pump controlled-release tablet according to claim 1, characterized in that: The binder is selected from one of hydroxypropyl methylcellulose E5, hydroxypropyl methylcellulose K4M, hydroxypropyl methylcellulose K15M or PVP K90.

5. The topiramate osmotic pump controlled-release tablet according to claim 1, characterized in that: The swelling agent is selected from one of polyoxyethylene 5000000, polyoxyethylene 7000000 or sodium alginate.

6. The topiramate osmotic pump controlled-release tablet according to claim 1, characterized in that: The osmotic pressure enhancer is sodium chloride, the lubricant is magnesium stearate, and the color lake is red iron oxide.

7. The topiramate osmotic pump controlled-release tablet according to claim 1, characterized in that: The semipermeable membrane coating material is cellulose acetate, and the weight gain ratio of the semipermeable membrane coating to the total weight of the double-layer tablet core is 7.5-15.0%.

8. The topiramate osmotic pump controlled-release tablet according to claim 1, characterized in that: The isolation coating film coating material is Opadry gastric soluble film coating premix, and the ratio of the isolation coating film coating weight gain to the total weight of the tablet core after the semipermeable membrane coating is 2.0-5.0%.

9. The method for preparing the topiramate osmotic pump controlled-release tablets according to any one of claims 1 to 8, characterized in that: The steps include: 1) Preparation of the drug layer: wet granulating the entrained polymer, the binder, the osmotic pressure enhancer and the topiramate API, performing dry granulation, and then adding a lubricant and mixing evenly; 2) Preparation of the push layer: dry granulation of the expander, osmotic pressure enhancer and lake after wet granulation, and then adding a lubricant and mixing evenly; 3) Double-layer tablet compression: Use a tablet press to pre-compress the drug layer, then fill and push the layer to form a double-layer tablet core; 4) After the double-layer tablet core is coated with a semipermeable membrane, a hole is punched on one side of the drug-containing layer of the semipermeable membrane to obtain an osmotic pump tablet, which is then coated with a spacer film to obtain a topiralast osmotic pump controlled-release tablet.

10. The preparation method according to claim 9, characterized in that: The punching in step 4) can be performed mechanically or by laser, and the hole diameter is 0.4-0.6 mm.

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