Indobufen sustained release preparation as well as preparation method and application thereof

Abstract

The invention discloses an indobufen sustained release preparation as well as a preparation method and application thereof. The sustained-release preparation comprises a main drug, a sustained-release material, a filler and an adhesive, and realizes the slow release of the drug, the number of times of taking the drug by a patient is reduced, the risk of missing taking is reduced, and the medication compliance of the patient is improved; active ingredients can be continuously and stably released, the peak blood concentration of the medicine is reduced, and the stimulation to gastrointestinal tracts is reduced. The preparation method is simple and easy to control, low in cost, good in process reproducibility and suitable for industrial mass production.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to an indobufen sustained-release preparation and a preparation method and application thereof. Background Art

[0002] Indobufen, Indobufen, Chinese chemical name: (±) 2-[4-(1-oxo-2-isoindolinyl) phenyl] butyric acid, or (±) 2-[4-(1-oxo-2-isoindolinyl) phenyl] butyric acid, English chemical name: (±) 2-[4-(1-oxo-2-isoindolinyl) phenyl] butyric acid, CAS registration number: 63610-08-2, molecular formula: C 18 H 17 NO 3 , molecular weight: 295.33.

[0003] Indobufen can reversibly inhibit platelet cyclooxygenase (COX-1), reduce the production of thromboxane A2 (TXA2), and inhibit platelet aggregation induced by arachidonic acid, adenosine diphosphate (ADP), adrenaline, platelet activating factor (PAF), and collagen. It is also known that the compound can reduce the levels of platelet adenosine triphosphate, serotonin, platelet factor 3, platelet factor 4, and β-thromboglobulin, and reduce platelet adhesion. Therefore, indobufen is suitable for the treatment of arterial / venous thromboembolism.

[0004] Indobufen tablets were launched in Italy in 1984, and the original research company was Pfizer. The product commonly sold in the market in China is the indobufen tablets produced by Hangzhou Sino-US Huadong Pharmaceutical Co., Ltd., which is taken twice a day, 100mg to 200mg each time.

[0005] Conventional drug delivery systems require multiple dosings, which is not only inconvenient to use, but also causes large fluctuations in blood drug concentrations, with peaks and valleys. When the blood drug concentration is high (peak), it may cause side effects; when it is low (valley), it may be below the therapeutic concentration and cannot achieve the desired therapeutic effect.

[0006] Although there are patents and literatures on indobufen sustained-release preparations, there is still a gap in the market for preparation products.

[0007] Korean patent KR1020110005974A discloses an indobufen sustained-release preparation in Example 14, which contains 30% indobufen, 10% ethylcellulose (Surelease, Colorcon), 25% lactose, 20% microcrystalline cellulose, 14% low-substituted hydroxypropyl cellulose and 1% magnesium stearate by weight. R Bianchini et al. (Drug Development and Industrial Pharmacy, Volume 19, 1993-Issue 16) and Sun Shuai et al. (Journal of Shenyang Pharmaceutical University, Issue 3, 2017) both prepared indobufen pellets and then applied sustained-release coating, and the sustained-release coating materials were ethylcellulose and Eudragit.

[0008] The release of indobufen sustained-release preparations described in existing patents or literature tends to be zero-order kinetic curve, and the release rate is greatly affected by the solubility of the drug itself, which is not conducive to the rapid exertion of drug efficacy of the product, and it is difficult to meet the demand for sustained-release preparations that can rapidly exert drug efficacy and stabilize drug efficacy (need to quickly reach the effective concentration after administration and maintain the effective concentration for a certain period of time); furthermore, the preparation process of micro-pellets is cumbersome and the yield of finished products is low, which is not conducive to industrial scale-up. Summary of the invention

[0009] The purpose of the present invention is to overcome the deficiencies of the prior art and provide an indobufen sustained-release preparation and a preparation method and application thereof.

[0010] In a first aspect of the present invention, there is provided an indobufen sustained-release preparation, comprising: a main drug, a sustained-release material, a filler, a binder and a lubricant, wherein the main drug is indobufen or a pharmaceutically acceptable salt thereof, and the sustained-release material is selected from: one or a combination of two of hydroxypropyl methylcellulose (HPMC) (e.g., HPMC K4M, K15M, K100M), and acrylic resin (e.g., Eudragit RL-PO, Eudragit RS-PO, Eudragit NM 30D).

[0011] Specifically, by weight, the content of the main drug in the preparation is 1%-70% (e.g., 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%), for example, 40%-70%.

[0012] Specifically, the content of sustained-release material in the preparation is 1%-40% (e.g., 1%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 15%, 16%, 18%, 20%, 25%, 30%, 35%, 40%).

[0013] In one embodiment of the present invention, the sustained-release material is HPMC, and its content is 1%-30%, such as 5%-20%, especially 5%-15%. In particular, when the sustained-release material is HPMC and the mass ratio of the main drug to the sustained-release material is 3-10:1 (such as 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1), especially 4-6:1, the obtained sustained-release preparation can obtain a better dissolution effect, can quickly reach the effective concentration after administration, and maintain the effective concentration for a certain period of time, ensuring rapid exertion of the drug effect while stabilizing the drug effect.

[0014] In one embodiment of the present invention, the sustained-release material is acrylic resin, and its content is 1%-40%, such as 10%-40%, and particularly 20%-35%. In particular, when the sustained-release material is acrylic resin and the mass ratio of the main drug to the sustained-release material is 1-10:1 (e.g., 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1), the obtained sustained-release preparation can obtain a better dissolution effect, can quickly reach the effective concentration after administration, and maintain the effective concentration for a certain period of time, ensuring that the drug effect is quickly exerted while stabilizing the drug effect.

[0015] Specifically, the sustained-release material is selected from one or more of HPMC K4M, K15M, K100M, Eudragit RL-PO, Eudragit RS-PO or Eudragit NM 30D.

[0016] In one embodiment of the present invention, the sustained-release material is HPMC K4M.

[0017] In one embodiment of the present invention, the sustained-release materials are HPMC K4M and HPMC K15M, and the weight ratio of the two can be 1-15:1-15 (e.g., 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 10:1, 12:1, 15:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:10, 1:12, 1:15), in particular 1-15:1, for example 2-5:1.

[0018] In one embodiment of the present invention, the sustained-release materials are HPMC K4M and HPMC K100M, and the weight ratio of the two can be 1-15:1-15 (e.g., 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 10:1, 12:1, 15:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:10, 1:12, 1:15), in particular 1-15:1, for example 2-5:1.

[0019] In one embodiment of the present invention, the sustained-release material is Eudragit RL-PO.

[0020] In one embodiment of the present invention, the sustained-release material is Eudragit RL PO and Eudragit RSPO, and the weight ratio of the two can be 1-30:1-30 (for example 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 10:1, 15:1, 20:1, 25:1, 30:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:10, 1:15, 1:20, 1:25, 1:30), in particular 1-15:1, for example 2-5:1.

[0021] In one embodiment of the present invention, the sustained-release material is Eudragit NM 30D.

[0022] Specifically, the filler is selected from two or more of the following: microcrystalline cellulose (MCC), pregelatinized starch, lactose, sodium carboxymethylcellulose (CMC-Na), starch, dextrin, calcium carbonate or sucrose.

[0023] In one embodiment of the present invention, the fillers are MCC and lactose, and the weight ratio of the two can be 1-15:1-15 (e.g., 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 10:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:10), in particular 1:1-15, for example 1:2-5.

[0024] In one embodiment of the present invention, the filler is pregelatinized starch and lactose, and the weight ratio of the two can be 1-15:1-15 (e.g., 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 10:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:10), in particular 1:1-15, for example 1:2-12.

[0025] In one embodiment of the present invention, the fillers are MCC and sucrose, and the weight ratio of the two can be 1-15:1-15 (e.g., 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 10:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:10), in particular 1:1-15, such as 1:2-5.

[0026] In one embodiment of the present invention, the filler is dextrin and lactose, and the weight ratio of the two can be 1-15:1-15 (for example 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 10:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:10), in particular 1:1-15, for example 1:2-5.

[0027] Specifically, the content of filler in the formulation is 0.1%-50% by weight (e.g., 0.1%, 0.5%, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%), for example, 10%-50%, especially 10%-40%.

[0028] Specifically, the adhesive is selected from one or more of the following: water, ethanol, PVP, HPMC, HPC, MC, CMC-Na or acrylic resin.

[0029] In one embodiment of the present invention, the binder is PVP K30.

[0030] In one embodiment of the present invention, the binder is HPMC E5.

[0031] Specifically, the content of binder in the formulation is 0.1%-20% by weight (e.g., 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 4%, 5%, 10%, 15%, 20%), for example, 0.1%-10%.

[0032] In one embodiment of the present invention, the sustained-release material is HPMC, and the content of the binder in the preparation is 0.1%-10%, particularly 0.5%-5%.

[0033] In one embodiment of the present invention, the sustained-release material is acrylic resin, and the content of the binder in the preparation is 0.1%-10%, especially 5%-10%.

[0034] Specifically, the lubricant is selected from one or more of the following: talc, magnesium stearate (MS), colloidal silicon dioxide, polyethylene glycol or magnesium lauryl sulfate.

[0035] Specifically, the content of lubricant in the formulation is 0.1%-5% by weight (e.g., 0.1%, 0.2%, 0.4%, 0.5%, 0.8%, 1%, 1.5%, 2%, 3%, 4%, 5%), for example, 0.1%-5%, especially 0.1%-3%.

[0036] In one embodiment of the present invention, the preparation further comprises a glidant; specifically, the glidant is selected from one or more of the following: colloidal silicon dioxide, micronized silica gel or talc.

[0037] Specifically, the content of the glidant in the preparation is 0.1%-5% (e.g., 0.1%, 0.2%, 0.4%, 0.5%, 0.8%, 1%, 1.5%, 2%, 3%, 4%, 5%) by weight, for example, 0.1%-5%, especially 0.1%-3%.

[0038] In one embodiment of the present invention, the preparation comprises: a main drug, MCC, lactose, HPMC E5, HPMC K4M and MS.

[0039] More specifically, the preparation comprises, by weight, 40%-70% of the main drug, 5%-15% (e.g., 5%, 8%, 10%, 12%, 15%) of MCC, 5%-35% (e.g., 5%, 10%, 15%, 20%, 24%, 25%, 26%, 28%, 30%, 35%) of lactose, 0.1%-10% of HPMC E5, 5%-20% (e.g., 5%, 8%, 10%, 12%, 15%, 20%) of HPMC K4M, and 0.1%-5% of MS; as shown in Example 5.

[0040] Furthermore, by weight, the preparation comprises: 45%-55% of the main drug, 5%-10% of MCC, 25%-30% of lactose, 0.1%-3% of HPMC E5, 8%-12% of HPMC K4M, and 0.1%-3% of MS, or consists of the above.

[0041] In one embodiment of the present invention, the preparation comprises, by weight: main drug 52%, MCC 8.8%, lactose 27.1%, HPMC E 51.2%, HPMC K4M 10%, and MS 0.8%.

[0042] In one embodiment of the present invention, the preparation comprises: a main drug, MCC, lactose, HPMC E5, HPMC K4M, HPMC K15M and MS.

[0043] More specifically, the preparation comprises, by weight, 40%-70% of the main drug, 5%-15% (e.g., 5%, 8%, 10%, 12%, 14%, 15%) of MCC, 5%-35% (e.g., 5%, 10%, 15%, 20%, 24%, 25%, 26%, 28%, 30%, 35%) of lactose, 0.1%-10% of HPMC E5, 2%-15% (e.g., 2%, 4%, 5%, 6%, 8%, 10%, 12%, 15%) of HPMC K15M, 1%-5% (e.g., 1%, 2%, 3%, 4%, 5%) of MS, and the composition shown in Example 6.

[0044] In one embodiment of the present invention, the preparation comprises: a main drug, MCC, lactose, HPMC E5, HPMC K4M, HPMC K100M and MS.

[0045] More specifically, the preparation comprises, by weight, 40%-70% of the main drug, 5%-15% of MCC (e.g., 5%, 8%, 10%, 12%, 14%, 15%), 5%-35% of lactose (e.g., 5%, 10%, 15%, 20%, 24%, 25%, 26%, 28%, 30%, 35%), 0.1%-10% of HPMC E5, 2%-15% of HPMC K4M (e.g., 2%, 4%, 5%, 6%, 8%, 10%, 12%, 15%), 1%-5% of HPMC K100M (e.g., 1%, 1.5%, 2%, 2.5%, 3%, 4%, 5%), and 0.1%-5% of MS; for example, the composition shown in Examples 7 and 8.

[0046] In one embodiment of the present invention, the preparation comprises: a main drug, lactose, pregelatinized starch, EudragitRL PO, PVP K30 and MS.

[0047] More specifically, the preparation comprises, by weight, 40%-70% of the main drug, 5%-30% (e.g., 5%, 10%, 15%, 20%, 24%, 25%, 26%, 28%, 30%) of lactose, 1%-10% (e.g., 1%, 2%, 3%, 4%, 5%, 6%, 8%, 10%) of pregelatinized starch, 20%-35% (e.g., 20%, 22%, 24%, 25%, 26%, 30%, 35%) of Eudragit RL PO, 0.1%-10% of PVP K30, and 0.1%-5% of MS; for example, the composition shown in Example 9.

[0048] In one embodiment of the present invention, the formulation comprises: a main drug, lactose, pregelatinized starch, Eudragit RL PO, Eudragit RS PO, PVP K30 and MS.

[0049] More specifically, the preparation comprises, by weight, 40%-70% of the main drug, 5%-30% (e.g., 5%, 10%, 15%, 20%, 24%, 25%, 26%, 28%, 30%) of lactose, 1%-10% (e.g., 1%, 2%, 3%, 4%, 5%, 6%, 8%, 10%) of pregelatinized starch, 15%-25% (e.g., 15%, 20%, 22%, 24%, 25%, 26%, 30%) of Eudragit RL PO, 5%-15% (e.g., 5%, 6%, 8%, 10%, 12%, 14%, 15%) of Eudragit RS PO, 0.1%-10% (e.g., 5%) of PVP K30, and 0.1%-5% (e.g., the composition shown in Example 10).

[0050] Specifically, the preparation may further include other auxiliary materials, for example, one or more of a pH adjuster, a buffer, a preservative, a stabilizer, an antioxidant, and a flavor adjuster.

[0051] Specifically, the pH adjuster includes, but is not limited to, dilute hydrochloric acid, sodium carbonate, sodium hydroxide, and the like.

[0052] Specifically, the buffer includes, but is not limited to, phosphate buffer, acetate buffer, and the like.

[0053] Specifically, the preservatives include, but are not limited to, sodium benzoate, potassium sorbate, methyl paraben, propyl paraben, etc.

[0054] Specifically, the stabilizer and antioxidant include, but are not limited to, calcium sodium edetate, sodium sulfite, vitamin C, E, and the like.

[0055] Specifically, the taste modifiers include, but are not limited to, maltitol, aspartame, stevioside, fructose, sucrose, saccharin sodium, orange flavor, strawberry flavor, and the like.

[0056] Specifically, the indobufen sustained-release preparation is an oral solid preparation, such as tablets, capsules, granules, pellets, etc.

[0057] In a preferred embodiment of the present invention, the indobufen sustained-release preparation is a tablet.

[0058] In one embodiment of the present invention, the indobufen sustained-release preparation is a capsule.

[0059] In one embodiment of the present invention, the indobufen sustained-release preparation is a granule.

[0060] In one embodiment of the present invention, the indobufen sustained-release preparation is pellets.

[0061] In one embodiment of the invention, when measured using the paddle method (e.g., the second method of 0931 of the fourth general rule of the Chinese Pharmacopoeia 2020 edition), pH 6.8±0.05 phosphate buffer, 37°C, 75rpm, after 0.5 hours, the sustained-release preparation (e.g., tablet) releases not less than about 10% (especially not less than about 15%, 20%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%) of indobufen, especially not less than about 30% of indobufen.

[0062] In one embodiment of the present invention, when measured using the paddle method (e.g., the second method of 0931 of the fourth general rule of the Chinese Pharmacopoeia 2020 edition), pH 6.8±0.05 phosphate buffer, 37°C, 75rpm, after 1 hour, the sustained-release preparation (e.g., tablet) releases not less than about 35% (especially not less than about 36%, 37%, 38%, 39%, 40%, 41%) of indobufen, especially not less than about 40% of indobufen.

[0063] In one embodiment of the invention, when measured using the paddle method (e.g., the second method of 0931 of the fourth general rule of the Chinese Pharmacopoeia 2020 edition), pH 6.8±0.05 phosphate buffer, 37°C, 75rpm, after 4 hours, the sustained-release preparation (e.g., tablet) releases about 40% to 70% (e.g., about 45%, 50%, 55%, 56%, 58%, 60%, 62%, 64%, 65%, 66%, 68%) of indobufen, in particular about 65% to 70% of indobufen.

[0064] In one embodiment of the present invention, when measured using the paddle method (e.g., the second method of 0931 of the fourth general rule of the Chinese Pharmacopoeia 2020 edition), pH 6.8±0.05 phosphate buffer, 37°C, 75rpm, after 5 hours, the sustained-release preparation (e.g., tablet) releases about 60% to 80% (e.g., about 60%, 65%, 70%, 72%, 74%, 75%, 76%, 80%) of indobufen, in particular about 70% to 75% of indobufen.

[0065] In one embodiment of the present invention, when measured using the paddle method (e.g., the second method of 0931 of the fourth general rule of the Chinese Pharmacopoeia 2020 edition), pH 6.8±0.05 phosphate buffer, 37°C, 75rpm, after 12 hours, the sustained-release preparation (e.g., tablet) releases not less than about 80% (especially not less than about 85%, 90%, 92%, 93%, 94%, 95%, 96%, 97%) of indobufen, especially not less than about 95% of indobufen.

[0066] Preferably, the indobufen sustained-release preparation has an in vitro biodissolution curve with the following dissolution release range at each time point (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules, 0931, Method 2, rotating paddle, using 1000 mL of phosphate buffer with a pH of 6.8±0.05, 37° C., 75 rpm, measured):

[0067] After 0.5 hours, about 10% to 40% (particularly 20% to 35%, 30% to 35%) is released;

[0068] After 4 hours, about 40% to 70% (particularly 55% to 70%, 65% to 70%) is released;

[0069] After 12 hours, the release is not less than about 80% (particularly not less than about 85%, 90%, 92%, 93%, 94%, 95%, 96%, 97%).

[0070] The dissolution characteristics described above are conducive to the sustained-release preparation quickly reaching the effective concentration after administration and maintaining the effective concentration for a certain period of time, ensuring rapid drug efficacy while stabilizing the drug efficacy, which is conducive to maintaining the treatment time and reducing the number of administrations.

[0071] Specifically, the solubility and release rate are measured according to the second method of 0931 of the fourth part of the general rules of the Chinese Pharmacopoeia 2020 edition, including the following steps: taking the sample to be tested, using 1000mL of phosphate buffer (the measured pH value is 6.8±0.05) as the solvent, the rotation speed is 75rpm, the temperature is 37°C, 5mL of the solution is taken at the time point to be tested, and at the same time, the phosphate buffer of the same volume and temperature is supplemented, filtered, and the absorbance value of the test solution at 279nm is determined by ultraviolet spectrophotometer, and the drug release at the test time point is calculated.

[0072] Specifically, the indobufen sustained-release preparation is prepared by the method described in the second aspect of the present invention.

[0073] In a second aspect of the present invention, there is provided a method for preparing the indobufen sustained-release preparation according to the first aspect, which comprises a wet granulation step and, optionally, tableting.

[0074] Specifically, the preparation method comprises:

[0075] (1) Mix the main drug and excipient I;

[0076] (2) adding auxiliary material II to the mixture obtained in step (1) to prepare a soft material;

[0077] (3) sieving, drying and granulating the soft material obtained in step (2);

[0078] (4) adding auxiliary material III to the granules obtained in step (3) and mixing;

[0079] Optionally, (5) preparing the desired dosage form (e.g., tableting or capsule filling, etc.).

[0080] Specifically, the sustained-release material is added in step (1) and / or (4) (ie, contained in excipient I and / or excipient III).

[0081] Specifically, excipient I includes a filler and, optionally, a sustained-release material.

[0082] In one embodiment of the present invention, the auxiliary material I is a filler.

[0083] In one embodiment of the present invention, excipient I is a filler and a sustained-release material.

[0084] Specifically, auxiliary material II includes a binder or an aqueous solution of a binder.

[0085] In one embodiment of the present invention, auxiliary material II is a binder.

[0086] In one embodiment of the present invention, auxiliary material II is an aqueous solution of a binder, wherein the concentration of the binder may be 1%-10% (weight percentage).

[0087] Specifically, auxiliary material III includes a lubricant, optionally, a filler, optionally, a sustained-release material, and optionally, a glidant.

[0088] In one embodiment of the present invention, excipient III is a lubricant and a glidant.

[0089] In one embodiment of the present invention, excipient III is a lubricant and a sustained-release material.

[0090] In one embodiment of the present invention, excipient III is a lubricant, a glidant and a sustained-release material.

[0091] In one embodiment of the present invention, auxiliary material III is a lubricant and a filler.

[0092] In one embodiment of the present invention, excipient III is a lubricant, a sustained-release material and a filler.

[0093] Specifically, the preparation method may further include the step of adding other auxiliary materials after step (4). Specifically, the other auxiliary materials are as described in the first aspect of the present invention.

[0094] In one embodiment of the present invention, the soft material is screened through a 24-mesh sieve in step (3).

[0095] Specifically, the drying temperature in step (3) is 40-60°C (e.g., 40, 45, 50, 55, 60°C).

[0096] In one embodiment of the present invention, the granulation in step (3) is to pass the dried granules through a 1.0 mm sieve.

[0097] In the third aspect of the present invention, there is provided use of the indobufen sustained-release preparation described in the first aspect in the preparation of a medicament for preventing and / or treating a disease.

[0098] Specifically, the disease is any disease for which indobufen can be used, such as, but not limited to: ischemic cardiovascular disease, ischemic cerebrovascular disease, venous thrombosis, dyslipidemia, diabetes, and prevention of thrombosis during extracorporeal circulation surgery.

[0099] In one embodiment of the invention, the disease is arterial / venous thromboembolism.

[0100] Compared with the prior art, the technical solution of the present invention has the following beneficial effects:

[0101] 1. The sustained-release preparation of the present invention realizes the slow release of drugs, reduces the number of times patients take medicine, reduces the risk of missed doses, and improves the compliance of patients in taking medicine;

[0102] 2. The sustained-release preparation of the present invention can continuously and stably release the active ingredient, reduce the peak blood concentration of the drug, and reduce gastrointestinal irritation;

[0103] 3. The preparation method of the present invention is simple and easy to control, has low cost, good process reproducibility, and is suitable for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0104] Figure 1 Shown are the in vitro release curves of the sustained-release preparations prepared in Examples 5-6 and the reference preparation.

[0105] Figure 2 Shown are the in vitro release curves of the sustained-release preparations prepared in Examples 7-9 and the reference preparation.

[0106] Figure 3 Shown are the in vitro release curves of the sustained-release preparation prepared in Example 10 and the reference preparation. DETAILED DESCRIPTION

[0107] Unless otherwise defined, all scientific and technical terms used in the present invention have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention relates.

[0108]

[00136] Various publications, patents, and published patent specifications are cited herein, the disclosures of which are incorporated by reference in their entireties.

[0109] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0110] The release rate research method of the indobufen sustained-release tablets obtained by the technical solution of the present invention is as follows:

[0111] Take this product, according to the dissolution and release determination method (Chinese Pharmacopoeia 2020 Edition Four General Rules 0931 Second Method), use phosphate buffer [take 250mL of 0.2mol / L potassium dihydrogen phosphate, add 112mL of 0.2mol / L sodium hydroxide, shake well, dilute with water to 1000mL, and the pH value should be 6.8±0.05] 1000mL as solvent, the speed is 75rpm, the temperature is 37℃, operate according to the law, after 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12 hours, take 5mL of solution each, and at the same time make up the same volume of phosphate buffer at the same temperature, filter, and use ultraviolet spectrophotometer to determine the absorbance of the test solution at 279nm. Calculate the release amount of indobufen sustained-release tablets at different times.

[0112] Example 1

[0113] Indobufen sustained-release tablets were prepared according to the following ratio:

[0114] Table 1 Tablet composition

[0115] Element Weight(g) Weight percentage (%) Indobufen 200 40 HPMCK100M 150 30 MCCPH101 40 8 lactose 100 20 PVPK30 5 1 MS 2.5 0.5 Colloidal Silica 2.5 0.5

[0116] Preparation method: Weigh 200g of indobufen, 40g of MCC, 100g of lactose, and 150g of HPMC K100M according to the prescription amount, mix well, add 5% PVPK30 aqueous solution to prepare soft material, pass the soft material through a 24-mesh sieve to prepare wet granules, dry at 50°C, sieve through a 1.0mm sieve to size the granules, add 2.5g of colloidal silicon dioxide and 2.5g of MS in sequence, mix well, and press into tablets to obtain indobufen sustained-release tablets.

[0117] Example 2

[0118] Indobufen sustained-release tablets were prepared according to the ratio shown in Table 1 of Example 1.

[0119] Preparation method: Weigh 200g of indobufen, 40g of MCC, and 100g of lactose according to the prescription amount, mix them, add 5% PVPK30 aqueous solution to prepare a soft material, pass the soft material through a 24-mesh sieve to prepare wet granules, dry at 50°C, sieve the granules with a 1.0mm sieve, add 150g of HPMCK100M and mix them, then add 2.5g of colloidal silicon dioxide and 2.5g of MS in sequence, mix them, and press them into tablets to obtain indobufen sustained-release tablets.

[0120] Example 3

[0121] Indobufen sustained-release tablets were prepared according to the following ratio:

[0122] Table 2 Tablet composition

[0123] Element Weight(g) Weight percentage (%) Indobufen 200 40.4 HPMCK4M 148.6 30 MCCPH101 34 6.9 lactose 104 21 HPMCE5 4.8 1 MS 4 0.8

[0124] Preparation method: Weigh 200g of indobufen, 34g of MCC, and 104g of lactose according to the prescription amount, mix them, add 8% HPMCE5 aqueous solution to prepare a soft material, pass the soft material through a 24-mesh sieve to prepare wet granules, dry at 50°C, sieve the granules with a 1.0mm sieve, add 148.6g of HPMCK4M and mix them, then add 4g of MS, mix them, and press them into tablets to obtain indobufen sustained-release tablets.

[0125] Example 4

[0126] Indobufen sustained-release tablets were prepared according to the following ratio:

[0127] Table 3 Tablet composition

[0128] Element Weight(g) Weight percentage (%) Indobufen 200 46.2 HPMCK4M 86.5 20 MCCPH101 34 7.9 lactose 104 24 HPMCE5 4.8 1.1 MS 3.5 0.8

[0129] Preparation method: Weigh 200g of indobufen, 34g of MCC, and 104g of lactose according to the prescription amount, mix them, add 8% HPMCE5 aqueous solution to prepare a soft material, pass the soft material through a 24-mesh sieve to prepare wet granules, dry at 50°C, sieve the granules with a 1.0mm sieve, add 6.5g of HPMCK4M8, mix them, then add 3.5g of MS, mix them, and press them into tablets to obtain indobufen sustained-release tablets.

[0130] Example 5

[0131] Indobufen sustained-release tablets were prepared according to the following ratio:

[0132] Table 4 Tablet composition

[0133] Element Weight(g) Weight percentage (%) Indobufen 200 52 HPMCK4M 38.4 10 MCCPH101 34 8.8 lactose 104 27.1 HPMCE5 4.8 1.2 MS 3.1 0.8

[0134] Preparation method: Weigh 200g of indobufen, 34g of MCC, and 104g of lactose according to the prescription amount, mix them, add 8% HPMCE5 aqueous solution to prepare a soft material, pass the soft material through a 24-mesh sieve to prepare wet granules, dry at 50°C, sieve the granules with a 1.0mm sieve, add 38.4g of HPMCK4M and mix them, then add 3.1g of MS, mix them, and press them into tablets to obtain indobufen sustained-release tablets.

[0135] Example 6

[0136] Indobufen sustained-release tablets were prepared according to the following ratio:

[0137] Table 5 Tablet composition

[0138] Element Weight(g) Weight percentage (%) Indobufen 200 50.0 HPMCK4M 26.9 6.7 HPMCK15M 11.5 2.9 MCCPH101 49.7 12.4 lactose 104 26.0 HPMCE5 4.8 1.2 MS 3.1 0.8

[0139] Preparation method: Weigh 200g of indobufen, 34g of MCC, and 104g of lactose according to the prescription amount, mix them, add 8% HPMCE5 aqueous solution to prepare a soft material, pass the soft material through a 24-mesh sieve to prepare wet granules, dry at 50°C, sieve through a 1.0mm sieve, add 26.9g HPMCK4M, 11.5g HPMCK15M and 15.7g MCC, mix them, then add 3.1g MS, mix them, and press them into tablets to obtain indobufen sustained-release tablets.

[0140] Example 7

[0141] Indobufen sustained-release tablets were prepared according to the following ratio:

[0142] Table 6 Tablet composition

[0143] Element Weight(g) Weight percentage (%) Indobufen 200 50.0 HPMCK4M 30.7 7.7 HPMCK100M 7.7 1.9 MCCPH101 49.7 12.4 lactose 104 26.0 HPMCE5 4.8 1.2 MS 3.1 0.8

[0144] Preparation method: Weigh 200g of indobufen, 34g of MCC, and 104g of lactose according to the prescription amount, mix them, add 8% HPMCE5 aqueous solution to prepare a soft material, pass the soft material through a 24-mesh sieve to prepare wet granules, dry at 50°C, sieve the granules with a 1.0mm sieve, add 30.7g HPMCK4M, 7.7g HPMCK100M and 15.7g MCC, mix them, then add 3.1g MS, mix them, and press them into tablets to obtain indobufen sustained-release tablets.

[0145] Example 8

[0146] Indobufen sustained-release tablets were prepared according to the following ratio:

[0147] Table 7 Tablet composition

[0148] Element Weight(g) Weight percentage (%) Indobufen 200 54.2 HPMCK4M 15.4 4.2 HPMCK100M 7.4 2.0 MCCPH101 34.1 9.2 lactose 104.5 28.3 HPMCE5 4.8 1.3 MS 3 0.8

[0149] Preparation method: Weigh 200g of indobufen, 34.1g of MCC, 104.5g of lactose, and 15.4g of HPMC K4M according to the prescription amount, mix well, add 8% HPMCE5 aqueous solution to prepare soft material, pass the soft material through a 24-mesh sieve to prepare wet granules, dry at 50°C, sieve through a 1.0mm sieve to granulate, add 7.4g of HPMC K100M and mix well, then add 3g of MS, mix well, and press into tablets to obtain indobufen sustained-release tablets.

[0150] Example 9

[0151] Indobufen sustained-release tablets were prepared according to the following ratio:

[0152] Table 8 Tablet composition

[0153] Element Weight(g) Weight percentage (%) Indobufen 200 49.2 EudragitRLPO 100 24.6 Pregelatinized starch 6.1 1.5 lactose 64.8 16.0 PVPK30 32 7.9 MS 3.2 0.8

[0154] Preparation method: Weigh 200 g of indobufen, 100 g of Eudragit RLPO, 32 g of PVPK30, and 64.8 g of lactose according to the prescription amount, mix well to prepare a soft material, pass the soft material through a 24-mesh sieve to prepare wet granules, dry at 50°C, sieve through a 1.0 mm sieve, add 6.1 g of pregelatinized starch, mix well, then add 3.2 g of MS, mix well, and tablet to obtain indobufen sustained-release tablets.

[0155] Example 10

[0156] Indobufen sustained-release tablets were prepared according to the following ratio:

[0157] Table 9 Tablet composition

[0158] Element Weight(g) Weight percentage (%) Indobufen 200 44.4 EudragitRLPO 100 22.2 EudragitRSPO 49.6 11.0 Pregelatinized starch 16.2 3.6 lactose 48.6 10.8 PVPK30 32 7.1 MS 3.6 0.8

[0159] Preparation method: Weigh 200 g of indobufen, 100 g of Eudragit RLPO, 32 g of PVPK30, 48.6 g of lactose, and 16.2 g of pregelatinized starch according to the prescription amount, mix well to prepare a soft material, pass the soft material through a 24-mesh sieve to prepare wet granules, dry at 50°C, sieve through a 1.0 mm sieve, add 49.6 g of Eudragit RSPO, mix well, then add 3.6 g of MS, mix well, and tablet to obtain indobufen sustained-release tablets.

[0160] Embodiment 11

[0161] Indobufen sustained-release tablets were prepared according to the following ratio:

[0162] Table 10 Tablet composition

[0163] Element Weight(g) Weight percentage (%) Indobufen 200 66.7 EudragitNM30D 110 11 MCCPH101 40.5 13.5 CMC-Na 24 8 MS 2.5 0.8

[0164] Preparation method: Weigh 200g of indobufen and 24g of CMC-Na according to the prescription amount, mix them evenly, weigh 110g of Eudragit NM30D to prepare soft material, pass the soft material through a 24-mesh sieve to prepare wet granules, dry at 50°C, sieve through a 1.0mm sieve, add 40.5g of MCC and mix evenly, then add 2.5g of MS and mix evenly, then press into tablets to obtain indobufen sustained-release tablets.

[0165] Embodiment 12:

[0166] Indobufen sustained-release tablets were prepared according to the following ratio:

[0167] Table 11 Tablet composition

[0168] Element Weight(g) Weight percentage (%) Indobufen 200 37.6 HPMCK4M 159.4 30 Microcrystalline Cellulose 34 6.4 lactose 104 19.6 HPMCE5 3 0.6 Magnesium Stearate 4.2 0.8 Croscarmellose Sodium 26.4 5

[0169] Preparation method: Weigh 200g of indobufen, 34g of MCC, and 104g of lactose according to the prescription amount, mix them, add 8% HPMCE5 aqueous solution to prepare a soft material, pass the soft material through a 24-mesh sieve to prepare wet granules, dry at 50°C, sieve through a 1.0mm sieve, add 159.4g of HPMCK4M and 26.4g of cross-linked sodium carboxymethyl cellulose, mix them, then add 4.2g of MS, mix them, and press them into tablets to obtain indobufen sustained-release tablets.

[0170] Embodiment 13:

[0171] Indobufen sustained-release tablets were prepared according to the following ratio:

[0172] Table 12 Tablet composition

[0173] Element Weight(g) Weight percentage (%) Indobufen 200 52.3 HPMCK4M 38.2 10 dextrin 34 8.9 sucrose 104 27.2 HPMCE5 3 0.8 Magnesium Stearate 3.1 0.8

[0174] Preparation method: crush sucrose and pass through 80 mesh sieve. Weigh 200g of indobufen, 34g of dextrin and 104g of sucrose according to the prescription, mix well, add 8% HPMCE5 aqueous solution to make soft material, pass the soft material through 24 mesh sieve to make wet granules, dry at 50℃, sieve with 1.0mm mesh to make granules, add 38.4g of HPMCK4M and mix well, then add 3.1g of MS, mix well, and press into tablets to obtain indobufen sustained-release tablets.

[0175] Embodiment 14:

[0176] Indobufen sustained-release tablets were prepared according to the following ratio:

[0177] Table 13 Tablet composition

[0178]

[0179]

[0180] Preparation method: crush sucrose and pass through 80 mesh sieve. Weigh 200g of indobufen, 34g of microcrystalline cellulose and 104g of sucrose according to the prescription, mix well, add 8% HPMCE5 aqueous solution to prepare soft material, pass the soft material through 24 mesh sieve to prepare wet granules, dry at 50℃, sieve with 1.0mm mesh to size, add 38.4g of HPMCK4M and mix well, then add 3.1g of MS, mix well, and press into tablets to obtain indobufen sustained-release tablets.

[0181] Embodiment 15:

[0182] Indobufen sustained-release tablets were prepared according to the following ratio:

[0183] Table 14 Tablet composition

[0184] Element Weight(g) Weight percentage (%) Indobufen 200 52.3 HPMCK4M 38.2 10 dextrin 34 8.9 lactose 104 27.2 HPMCE5 3 0.8 Magnesium Stearate 3.1 0.8

[0185] Preparation method: Weigh 200g of indobufen, 34g of dextrin, and 104g of lactose according to the prescription amount, mix them, add 8% HPMCE5 aqueous solution to prepare a soft material, pass the soft material through a 24-mesh sieve to prepare wet granules, dry at 50°C, sieve through a 1.0mm sieve, add 38.4g of HPMCK4M and mix them, then add 3.1g of MS, mix them, and press them into tablets to obtain indobufen sustained-release tablets.

[0186] Example 16: Dissolution Study

[0187] In order to investigate the sustained-release effect of the indobufen sustained-release tablets prepared in each example, Examples 5 to 10 were subjected to an in vitro dissolution comparative study with the reference preparation (manufacturer: Pfizer Italia S.rl, batch number EN9422, trade name: Ibustrin, specification: 0.2 g) (using the second method of 0931 of the fourth general rule of the Chinese Pharmacopoeia 2020 edition), wherein the in vitro dissolution comparative study of Examples 5 and 6 with the reference preparation is shown in Table 1. Figure 1 , Examples 7, 8, 9 and the reference preparation in vitro dissolution comparison study see Figure 2 , Example 10 and the reference preparation in vitro dissolution comparison study see Figure 3 It can be seen that the sustained-release effect of the indobufen sustained-release tablets provided by the present invention is good and can meet the clinical medication needs.

[0188] The dissolution test results of Examples 1-13 in pH 6.8 phosphate buffer medium are shown in the table below. As can be seen from Table 15, Examples 1, 2, 3, 4 and 11 all released less before 2 hours and could not meet the clinical medication needs.

[0189] Table 15 Dissolution results

[0190]

[0191] Comparative Example 1: Using ethyl cellulose as sustained-release material

[0192] Indobufen sustained-release tablets were prepared according to the following ratio:

[0193] Table 16 Tablet composition

[0194] Element Weight(g) Weight percentage (%) Indobufen 200 45.9 Microcrystalline Cellulose 40 9.2 lactose 100 23 PVPK30 5 1.1 EC20cp 87.1 20 Magnesium Stearate 3.5 0.8

[0195] The preparation method is described in Example 2.

[0196] Comparative Example 2: Using ethyl cellulose as sustained-release material

[0197] Indobufen sustained-release tablets were prepared according to the following ratio:

[0198] Table 17 Tablet composition

[0199] Element Weight(g) Weight percentage (%) Indobufen 200 51.7 Microcrystalline Cellulose 40 10.3 lactose 100 25.9 PVPK30 5 1.3 EC20cp 38.7 10 Magnesium Stearate 3.1 0.8

[0200] The preparation method is described in Example 2.

[0201] Referring to Example 16, the dissolution test was conducted on the tablets obtained in Comparative Examples 1 and 2. The results are shown in the following table.

[0202] Table 18 Dissolution results

[0203]

[0204] It can be seen from the dissolution results in Table 18 that the in vitro dissolution effect of ethyl cellulose as a sustained-release material is poor, especially the release is low before 2 hours and cannot meet the clinical medication needs.

[0205] Comparative Example 3: No filler

[0206] Indobufen sustained-release tablets were prepared according to the following ratio:

[0207] Table 19 Tablet composition

[0208] Element Weight(g) Weight percentage (%) Indobufen 200 59.4 CMC-Na 24 7.1 EudragitNM30D 110 32.7 Magnesium Stearate 2.7 0.8

[0209] The preparation method is described in Example 2. During the preparation, it was found that sticking occurred during tableting, which is not conducive to industrial production.

[0210] Comparative Example 4: Single Filler

[0211] Indobufen sustained-release tablets were prepared according to the following ratio:

[0212] Table 20 Tablet composition

[0213] Element Weight(g) Weight percentage (%) Indobufen 200 50 EudragitRLPO 100 25 PVPK30 32 8 lactose / / Pregelatinized starch 64.8 16.2 Magnesium Stearate 3.2 0.8

[0214] The preparation method is described in Example 2.

[0215] The dissolution test was carried out with reference to Example 16, and it was found that the tablets prepared in this comparative example were completely released within 2 hours, and the sustained-release effect was not obvious.

[0216] Comparative Example 5: Single Filler

[0217] Indobufen sustained-release tablets were prepared according to the following ratio:

[0218] Table 21 Tablet composition

[0219] Element Weight(g) Weight percentage (%) Indobufen 200 50 EudragitRLPO 100 25 PVPK30 32 8 lactose 64.8 16.2 Pregelatinized starch / / Magnesium Stearate 3.2 0.8

[0220] The preparation method is described in Example 2.

[0221] The dissolution test was carried out in accordance with the description in Example 16. It was found that the sustained release effect of the tablets prepared in this example was poor, with only 3.74% released in 0.5 h. The specific results are shown in the following table.

[0222] Table 22 Dissolution results

[0223]

[0224] It can be seen from the dissolution results in Table 22 that the in vitro dissolution effect is not good when a single filler is used, especially the release before 2 hours is too low to meet clinical medication needs.

[0225] The above descriptions are only some typical embodiments of the present invention and do not limit the present invention in any way. Any equivalent implementation or modification that does not deviate from the present invention shall fall within the protection scope of the technical solution of the present invention.

Claims

1. An indobufen sustained-release preparation, comprising: a main drug, a sustained-release material, a filler, a binder and a lubricant, wherein: The main drug is indobufen or a pharmaceutically acceptable salt thereof, and the sustained-release material is selected from: one or a combination of two of hydroxypropyl methylcellulose and acrylic resin.

2. The preparation according to claim 1, characterized in that The content of the sustained-release material in the preparation is 1%-40%; Preferably, the hydroxypropyl methylcellulose is selected from one or more of HPMC K4M, HPMC K15M or HPMC K100M, and the acrylic resin is selected from one or more of Eudragit RL-PO, Eudragit RS-PO or Eudragit NM 30D; More preferably, the sustained-release material is HPMC K4M; or The sustained-release material is HPMC K4M and HPMC K15M, and the weight ratio of the two is 1-15:1-15, preferably 1-15:1; or, The sustained-release material is HPMC K4M and HPMC K100M, and the weight ratio of the two is 1-15:1-15, preferably 1-15:1; or, The sustained-release material is Eudragit RL-PO; or The sustained-release material is Eudragit RL PO and Eudragit RS PO, and the weight ratio of the two is 1-30:1-30, preferably 1-15:1; or, The sustained-release material is Eudragit NM 30D.

3. The preparation according to claim 1, characterized in that The content of filler in the preparation is 0.1%-50%, preferably 10%-40%; Preferably, the filler is selected from two or more of the following: microcrystalline cellulose MCC, pregelatinized starch, lactose, sodium carboxymethyl cellulose CMC-Na, starch, dextrin and calcium carbonate; More preferably, the filler is MCC and lactose, and the weight ratio of the two is 1-15:1-15; or, The filler is pregelatinized starch and lactose, and the weight ratio of the pregelatinized starch and lactose is 1-15:1-15; or, The filler is MCC and sucrose, and the weight ratio of the two is 1-15:1-15; or, The fillers are dextrin and lactose, and the weight ratio of the two is 1-15:1-15.

4. The preparation according to claim 1, characterized in that The content of the binder in the preparation is 0.1%-20%, preferably 0.1%-10%; Preferably, the binder is selected from one or more of the following: water, ethanol, polyvinylpyrrolidone PVP, hydroxypropylmethylcellulose HPMC, hydroxypropylcellulose HPC, methylcellulose MC, microcrystalline cellulose sodium CMC-Na or acrylic resin; More preferably, the adhesive is PVP K30 or HPMC E5.

5. The preparation according to claim 1, characterized in that The content of lubricant in the preparation is 0.1%-5%, preferably 0.1%-3%; Preferably, the lubricant is selected from one or more of the following: talc, magnesium stearate MS, colloidal silicon dioxide, polyethylene glycol or magnesium lauryl sulfate.

6. The preparation according to claim 1, characterized in that The formulation further comprises a glidant; Preferably, the content of the glidant in the preparation is 0.1%-5%, preferably 0.1%-3%.

7. The preparation according to claim 1, characterized in that The preparation may further comprise other auxiliary materials, preferably one or more selected from the group consisting of a pH regulator, a buffer, a preservative, a stabilizer, an antioxidant, and a flavor regulator.

8. The preparation according to any one of claims 1 to 7, characterized in that The indobufen sustained-release preparation is an oral solid preparation, preferably selected from the group consisting of tablets, capsules, granules or pellets.

9. An indobufen sustained-release preparation comprising: a main drug, MCC, lactose, HPMC E5, HPMC K4M and MS, wherein: The main drug is indobufen or a pharmaceutically acceptable salt thereof; Preferably, the preparation comprises: main drug 40%-70%, MCC 5%-15%, lactose 5%-35%, HPMC E50.1%-10%, HPMC K4M 5%-20%, MS 0.1%-5%.

10. An indobufen sustained-release preparation, comprising: a main drug, MCC, lactose, HPMC E5, HPMC K4M, HPMC K15M and MS, wherein: The main drug is indobufen or a pharmaceutically acceptable salt thereof; Preferably, the preparation comprises: main drug 40%-70%, MCC 5%-15%, lactose 5%-35%, HPMC E50.1%-10%, HPMC K4M 2%-15%, HPMC K15M 1%-5%, MS0.1%-5%.

11. An indobufen sustained-release preparation comprising: a main drug, MCC, lactose, HPMC E5, HPMC K4M, HPMC K100M and MS, wherein: The main drug is indobufen or a pharmaceutically acceptable salt thereof; Preferably, the preparation comprises: main drug 40%-70%, MCC 5%-15%, lactose 5%-35%, HPMC E5 0.1%-10%, HPMC K4M 2%-15%, HPMC K100M 1%-5%, and MS 0.1%-5%.

12. An indobufen sustained-release preparation, comprising: a main drug, lactose, pregelatinized starch, Eudragit RL PO, PVPK30 and MS, wherein: The main drug is indobufen or a pharmaceutically acceptable salt thereof; Preferably, the preparation comprises: 40%-70% of the main drug, 5%-30% of lactose, 1%-10% of pregelatinized starch, 20%-35% of Eudragit RL PO, 0.1%-10% of PVP K30, and 0.1%-5% of MS.

13. An indobufen sustained-release preparation, comprising: a main drug, lactose, pregelatinized starch, Eudragit RL PO, Eudragit RS PO, PVP K30 and MS, wherein: The main drug is indobufen or a pharmaceutically acceptable salt thereof; Preferably, the preparation comprises: 40%-70% of the main drug, 5%-30% of lactose, 1%-10% of pregelatinized starch, 15%-25% of Eudragit RL PO, 5%-15% of Eudragit RS PO, 0.1%-10% of PVP K30, and 0.1%-5% of MS.

14. A method for preparing the indobufen sustained-release preparation according to any one of claims 1 to 8, comprising the following steps: (1) Mix the main drug and excipient I; (2) adding auxiliary material II to the mixture obtained in step (1) to prepare a soft material; (3) sieving, drying and granulating the soft material obtained in step (2); (4) adding auxiliary material III to the granules obtained in step (3) and mixing; in, The auxiliary material I includes a filler; The auxiliary material II includes a binder or an aqueous solution of a binder; The auxiliary material III includes a lubricant; The sustained-release material is added in step (1) and / or (4).

15. Use of the indobufen sustained-release preparation according to any one of claims 1 to 13 in the preparation of a medicament for preventing and / or treating a disease; Preferably, the disease is selected from: ischemic cardiovascular disease, ischemic cerebrovascular disease, venous thrombosis, dyslipidemia, and diabetes; More preferably, the disease is arterial / venous thromboembolism.

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