Indobufen sustained-release formulation, preparation method therefor, and use thereof

Abstract

An indobufen sustained-release formulation, a preparation method therefor, and use thereof. The sustained-release formulation comprises: a main drug, a sustained-release material, a filler, and a binder. The sustained-release formulation achieves slow release of the drug and can continuously and stably release the active ingredient, thereby reducing the peak plasma concentration of the drug, and reducing gastrointestinal irritation. Furthermore, the preparation method is simple and easy to control, and features low cost and good process reproducibility, thus being suitable for large-scale industrial production.

Description

Indobufen sustained-release preparation, preparation method and application thereof

[0001] Priority information

[0002] This application claims priority and benefits of patent application 202311564361.4 filed with the State Intellectual Property Office of China on November 22, 2023, and the entire text of which is incorporated herein by reference. Technical Field

[0003] 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

[0004] Indobufen, Chinese chemical name: (±) 2-[4-(1-oxo-2-isoindolinyl) phenyl] butyric acid, or known as (±) 2-[4-(1-oxo-2-isodihydroindolinyl) 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 NO3, molecular weight: 295.33.

[0005] Indobufen reversibly inhibits platelet cyclooxygenase (COX-1), reducing thromboxane A2 (TXA2) production. It also inhibits platelet aggregation induced by arachidonic acid, adenosine diphosphate (ADP), epinephrine, platelet-activating factor (PAF), and collagen. This compound is also known to reduce platelet ATP, serotonin, platelet factor 3, platelet factor 4, and β-thromboglobulin levels, thereby reducing platelet adhesion. Therefore, indobufen is suitable for the treatment of arterial and venous thromboembolism.

[0006] Indobufen tablets were first launched in Italy in 1984 by Pfizer. The most commonly available product in China is indobufen tablets from Hangzhou Sino-US Huadong Pharmaceutical Co., Ltd., and is taken twice daily, 100-200 mg each time.

[0007] Conventional drug delivery systems require multiple dosings, which is not only inconvenient but also results in significant fluctuations in blood drug concentrations, with peaks and valleys. High blood drug concentrations (peaks) can cause side effects, while low blood drug concentrations (valleys) may be below the therapeutic concentration, preventing optimal therapeutic effects.

[0008] Although there are patents and literatures on indobufen sustained-release preparations, there is still a gap in the preparation product market.

[0009] Korean patent KR1020110005974A discloses, in Example 14, a sustained-release indobufen formulation containing, by weight, 30% indobufen, 10% ethylcellulose (Surelease, Colorcon), 25% lactose, 20% microcrystalline cellulose, 14% low-substituted hydroxypropyl cellulose, and 1% magnesium stearate. 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 micropellets and then applied a sustained-release coating using ethylcellulose and Eudragit®.

[0010] The release of indobufen sustained-release preparations described in existing patents or literature tends to follow a zero-order kinetic curve, and the release rate is significantly affected by the solubility of the drug itself, which is not conducive to the rapid onset of drug efficacy and is difficult to meet the demand for sustained-release preparations that can rapidly exert drug efficacy while maintaining stable drug efficacy (the effective concentration must be reached quickly after administration and maintained for a certain period of time). Furthermore, the preparation process for micropellets is cumbersome and the yield is low, which is not conducive to industrial scale-up. Summary of the Invention

[0011] 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.

[0012] In a first aspect of the present invention, a sustained-release indobufen preparation is provided, 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 the group consisting of: hydropropyl methylcellulose (HPMC) (e.g., HPMC K4M, K15M, K100M), acrylic resin (e.g., Eudragit RL-PO, Eudragit RS-PO, Eudragit NM 30D), or a combination of two thereof.

[0013] 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%.

[0014] Specifically, the content of sustained-release material in the formulation is 1%-40% (e.g., 1%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 15%, 16%, 18%, 20%, 25%, 30%, 35%, 40%).

[0015] In one embodiment of the present invention, the sustained-release material is HPMC, and its content is 1%-30%, for example, 5%-20%, and particularly 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 (for example, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1), particularly 4-6:1, the resulting sustained-release preparation can achieve a better dissolution effect, quickly reach an effective concentration after administration, and maintain an effective concentration for a certain period of time, thereby ensuring rapid and stable drug efficacy.

[0016] In one embodiment of the present invention, the sustained-release material is an acrylic resin, and its content is 1%-40%, for example, 10%-40%, and particularly 20%-35%. In particular, when the sustained-release material is an acrylic resin and the mass ratio of the main drug to the sustained-release material is 1-10:1 (for example, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1), the resulting sustained-release preparation can achieve a better dissolution effect, quickly reach an effective concentration after administration, and maintain an effective concentration for a certain period of time, thereby ensuring rapid and stable drug efficacy.

[0017] Specifically, the sustained-release material is selected from one or more of HPMC K4M, K15M, K100M, Eudragit RL-PO, Eudragit RS-PO and Eudragit NM 30D.

[0018] In one embodiment of the present invention, the sustained-release material is HPMC K4M.

[0019] 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.

[0020] 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.

[0021] In one embodiment of the present invention, the sustained-release material is Eudragit RL-PO.

[0022] In one embodiment of the present invention, the sustained-release materials are Eudragit RL PO and Eudragit RS PO, and the weight ratio of the two can be 1-30:1-30 (e.g., 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.

[0023] In one embodiment of the present invention, the sustained-release material is Eudragit NM 30D.

[0024] 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.

[0025] 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, such as 1:2-5.

[0026] 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.

[0027] 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.

[0028] 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.

[0029] Specifically, the content of filler in the formulation is 0.1%-50% (e.g., 0.1%, 0.5%, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%), for example, 10%-50%, in particular 10%-40% by weight.

[0030] Specifically, the adhesive is selected from one or more of the following: water, ethanol, PVP, HPMC, HPC, MC, CMC-Na or acrylic resin.

[0031] In one embodiment of the present invention, the binder is PVP K30.

[0032] In one embodiment of the present invention, the binder is HPMC E5.

[0033] Specifically, the content of binder in the formulation is 0.1%-20% (e.g., 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 4%, 5%, 10%, 15%, 20%) by weight, for example, 0.1%-10%.

[0034] 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%.

[0035] 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%, particularly 5%-10%.

[0036] 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.

[0037] Specifically, the content of lubricant in the formulation is 0.1%-5% (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% by weight.

[0038] 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.

[0039] Specifically, the content of the glidant in the formulation is 0.1%-5% (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% by weight.

[0040] In one embodiment of the present invention, the preparation comprises: a main drug, MCC, lactose, HPMC E5, HPMC K4M and MS.

[0041] More specifically, the preparation comprises, by weight, 40%-70% of the main drug, 5%-15% of MCC (e.g., 5%, 8%, 10%, 12%, 15%), 5%-35% of lactose (e.g., 5%, 10%, 15%, 20%, 24%, 25%, 26%, 28%, 30%, 35%), 0.1%-10% of HPMC E5, 5%-20% of HPMC K4M (e.g., 5%, 8%, 10%, 12%, 15%, 20%), and 0.1%-5% of MS; as shown in Example 5.

[0042] Furthermore, the preparation comprises, by weight, 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 following.

[0043] In one embodiment of the present invention, the preparation comprises, by weight: 52% of the main drug, 8.8% of MCC, 27.1% of lactose, 1.2% of HPMC E5, 10% of HPMC K4M, and 0.8% of MS.

[0044] In one embodiment of the present invention, the preparation comprises: a main drug, MCC, lactose, HPMC E5, HPMC K4M, HPMC K15M 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 K15M (e.g., 1%, 2%, 3%, 4%, 5%), and 0.1%-5% of MS; for example, the composition shown in Example 6.

[0046] In one embodiment of the present invention, the preparation comprises: a main drug, MCC, lactose, HPMC E5, HPMC K4M, HPMC K100M and MS.

[0047] 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 compositions shown in Examples 7 and 8.

[0048] In one embodiment of the present invention, the formulation comprises: a main drug, lactose, pregelatinized starch, Eudragit RL 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, 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.

[0050] 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.

[0051] More specifically, the formulation 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% of MS; for example, the composition shown in Example 10.

[0052] Specifically, the preparation may further comprise other excipients, for example, one or more of a pH regulator, a buffer, a preservative, a stabilizer, an antioxidant, and a flavor regulator.

[0053] Specifically, the pH adjuster includes, but is not limited to, dilute hydrochloric acid, sodium carbonate, sodium hydroxide, and the like.

[0054] Specifically, the buffer includes, but is not limited to, phosphate buffer, acetate buffer, and the like.

[0055] Specifically, the preservatives include, but are not limited to, sodium benzoate, potassium sorbate, methyl parahydroxybenzoate, propyl parahydroxybenzoate, etc.

[0056] Specifically, the stabilizer and antioxidant include, but are not limited to, calcium sodium edetate, sodium sulfite, vitamin C, E, and the like.

[0057] Specifically, the flavor modifiers include, but are not limited to, maltitol, aspartame, stevia, fructose, sucrose, saccharin sodium, orange flavor, strawberry flavor, and the like.

[0058] Specifically, the indobufen sustained-release preparation is an oral solid preparation, such as tablets, capsules, granules, pellets, etc.

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

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

[0061] In one embodiment of the present invention, the indobufen sustained-release preparation is a granule.

[0062] In one embodiment of the present invention, the indobufen sustained-release preparation is pellets.

[0063] In one embodiment of the invention, when measured using a paddle method (e.g., Chinese Pharmacopoeia 2020 Edition, Part Four, General Chapter 0931, Method 2), pH 6.8 ± 0.05 phosphate buffer, 37° C., 75 rpm, after 0.5 hour, the sustained-release formulation (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.

[0064] In one embodiment of the present invention, when measured using a paddle method (e.g., the second method of Part 0931 of the Chinese Pharmacopoeia 2020 edition), pH 6.8 ± 0.05 phosphate buffer, 37° C., 75 rpm, after 1 hour, the sustained-release formulation (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.

[0065] In one embodiment of the invention, when measured using a paddle method (e.g., Chinese Pharmacopoeia 2020 Edition, Part Four, General Rules 0931, Second Method), pH 6.8 ± 0.05 phosphate buffer, 37°C, 75 rpm, after 4 hours, the sustained-release formulation (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.

[0066] In one embodiment of the present invention, when measured using a paddle method (e.g., Chinese Pharmacopoeia 2020 Edition, Part Four, General Rules 0931, Second Method), pH 6.8 ± 0.05 phosphate buffer, 37°C, 75 rpm, after 5 hours, the sustained-release formulation (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.

[0067] In one embodiment of the present invention, when measured using a paddle method (e.g., Chinese Pharmacopoeia 2020 Edition, Part Four, General Chapter 0931, Method 2), pH 6.8 ± 0.05 phosphate buffer, 37°C, 75 rpm, after 12 hours, the sustained-release formulation (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.

[0068] Preferably, the indobufen sustained-release preparation has an in vitro biodissolution curve with the following dissolution release range at each time point (measured according to the second method of 0931 of the fourth general rule of the Chinese Pharmacopoeia 2020 edition, rotating paddle, using 1000 mL of phosphate buffer with a pH of 6.8±0.05, 37° C., 75 rpm):

[0069] After 0.5 hours, about 10% to 40% (particularly 20% to 35%, 30% to 35%) is released;

[0070] After 4 hours, about 40% to 70% (particularly 55% to 70%, 65% to 70%) is released;

[0071] After 12 hours, not less than about 80% (particularly not less than about 85%, 90%, 92%, 93%, 94%, 95%, 96%, 97%) is released.

[0072] 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.

[0073] 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 1000 mL of phosphate buffer (the measured pH value is 6.8±0.05) as the solvent, the rotation speed is 75 rpm, the temperature is 37°C, taking 5 mL of the solution at the time point to be tested, and at the same time replenishing the phosphate buffer of the same volume at the same temperature, filtering, and using an ultraviolet spectrophotometer to determine the absorbance value of the test solution at 279 nm, and calculating the drug release amount at the test time point.

[0074] Specifically, the indobufen sustained-release preparation is prepared by the method described in the second aspect of the present invention.

[0075] 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, comprising a wet granulation step and, optionally, tableting.

[0076] Specifically, the preparation method includes:

[0077] (1) Mix the main drug and excipient I;

[0078] (2) adding auxiliary material II to the mixture obtained in step (1) to prepare a soft material;

[0079] (3) sieving the soft material obtained in step (2), drying, and granulating;

[0080] (4) adding auxiliary material III to the granules obtained in step (3) and mixing;

[0081] Optionally, (5) preparing the desired dosage form (e.g., tableting or capsule filling, etc.).

[0082] Specifically, the sustained-release material is added in step (1) and / or (4) (ie, contained in excipient I and / or excipient III).

[0083] Specifically, excipient I includes a filler and, optionally, a sustained-release material.

[0084] In one embodiment of the present invention, the excipient I is a filler.

[0085] In one embodiment of the present invention, excipient I is a filler and a sustained-release material.

[0086] Specifically, auxiliary material II includes a binder or an aqueous solution of a binder.

[0087] In one embodiment of the present invention, auxiliary material II is a binder.

[0088] In one embodiment of the present invention, auxiliary material II is an aqueous solution of a binder, wherein the concentration of the binder can be 1%-10% (weight percentage).

[0089] Specifically, excipient III includes a lubricant, optionally, a filler, optionally, a sustained-release material, and optionally, a glidant.

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

[0091] In one embodiment of the present invention, excipient III is a lubricant and a sustained-release material.

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

[0093] In one embodiment of the present invention, excipient III is a lubricant and a filler.

[0094] In one embodiment of the present invention, excipient III is a lubricant, a sustained-release material, and a filler.

[0095] 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.

[0096] In one embodiment of the present invention, the soft material is screened through a 24-mesh sieve in step (3).

[0097] Specifically, the drying temperature in step (3) is 40-60°C (e.g., 40, 45, 50, 55, 60°C).

[0098] In one embodiment of the present invention, the granulation in step (3) is to pass the dried granules through a 1.0 mm sieve.

[0099] In a 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.

[0100] Specifically, the disease is any disease for which indobufen is applicable, such as, but not limited to: ischemic cardiovascular disease, ischemic cerebrovascular disease, venous thrombosis, dyslipidemia, diabetes, and prevention of thrombosis during extracorporeal circulation surgery.

[0101] In one embodiment of the present invention, the disease is arterial / venous thromboembolism.

[0102] Compared with the prior art, the technical solution of the present invention has the following beneficial effects:

[0103] 1. The sustained-release preparation of the present invention achieves slow release of the drug, which reduces the frequency of medication, reduces the risk of missed doses, and improves patient medication compliance;

[0104] 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;

[0105] 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

[0106] The above and / or additional aspects and advantages of the present disclosure will become apparent and readily understood from the description of the embodiments in conjunction with the following drawings, in which:

[0107] FIG1 shows the in vitro release curves of the sustained-release preparations prepared in Examples 5-6 and the reference preparation;

[0108] FIG2 shows the in vitro release curves of the sustained-release preparations prepared in Examples 7-9 and the reference preparation;

[0109] FIG3 shows the in vitro release curves of the sustained-release preparation prepared in Example 10 and the reference preparation.

[0110] Detailed Description of the Invention

[0111] 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.

[0112] The disclosures of various publications, patents, and published patent specifications cited herein are incorporated by reference in their entirety.

[0113] The following will clearly and completely describe the technical solutions of the present invention in conjunction with the embodiments of the present invention. Obviously, the embodiments described 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 making any creative efforts shall fall within the scope of protection of the present invention.

[0114] The release rate of the indobufen sustained-release tablets obtained by the technical solution of the present invention is studied as follows:

[0115] Take this product and follow the dissolution and release determination method (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0931 Second Method), using 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 the solvent, the speed is 75rpm, the temperature is 37°C, and the operation is carried out according to the law. After 0.5, 1, 2, 3, 4, 5, 6, 8, 10, and 12 hours, take 5mL of the solution respectively, and at the same time make up the same volume of phosphate buffer at the same temperature, filter, and use a UV spectrophotometer to measure the absorbance of the test solution at 279nm. Calculate the release amount of indobufen sustained-release tablets at different times.

[0116] Example 1

[0117] Indobufen sustained-release tablets were prepared according to the following ratio:

[0118] Table 1 Tablet composition

[0119] 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% PVP K30 aqueous solution to prepare a soft material, pass the soft material through a 24-mesh sieve to prepare wet granules, dry at 50°C, and granulate through a 1.0mm sieve. Add 2.5g of colloidal silicon dioxide and 2.5g of MS in sequence, mix well, and compress into tablets to obtain indobufen sustained-release tablets.

[0120] Example 2

[0121] Indobufen sustained-release tablets were prepared according to the ratio shown in Table 1 of Example 1.

[0122] Preparation method: Weigh 200g of indobufen, 40g of MCC, and 100g of lactose according to the prescribed amount, mix well, add 5% PVP K30 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 to size the granules, add 150g of HPMC K100M and mix well, then add 2.5g of colloidal silicon dioxide and 2.5g of MS in sequence, mix well, and compress into tablets to obtain indobufen sustained-release tablets.

[0123] Example 3

[0124] Indobufen sustained-release tablets were prepared according to the following ratio:

[0125] Table 2 Tablet composition

[0126] Preparation method: Weigh 200g of indobufen, 34g of MCC, and 104g of lactose according to the prescribed amount, mix well, add 8% HPMC E5 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 to size the granules, add 148.6g of HPMC K4M and mix well, then add 4g of MS, mix well, and press into tablets to obtain indobufen sustained-release tablets.

[0127] Example 4

[0128] Indobufen sustained-release tablets were prepared according to the following ratio:

[0129] Table 3 Tablet composition

[0130] Preparation method: Weigh 200g of indobufen, 34g of MCC, and 104g of lactose according to the prescribed amount, mix well, add 8% HPMC E5 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 to size the granules, add 86.5g of HPMC K4M and mix well, then add 3.5g of MS, mix well, and press into tablets to obtain indobufen sustained-release tablets.

[0131] Example 5

[0132] Indobufen sustained-release tablets were prepared according to the following ratio:

[0133] Table 4 Tablet composition

[0134] Preparation method: Weigh 200g of indobufen, 34g of MCC, and 104g of lactose according to the prescribed amount, mix well, add 8% HPMC E5 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 to size the granules, add 38.4g of HPMC K4M and mix well, then add 3.1g of MS, mix well, and press 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] Preparation method: Weigh 200g of indobufen, 34g of MCC, and 104g of lactose according to the prescribed amount, mix well, add 8% HPMC E5 aqueous solution to prepare a soft material, pass the soft material through a 24-mesh sieve to prepare wet granules, dry at 50°C, and sieve through a 1.0mm sieve to size the granules, add 26.9g of HPMC K4M, 11.5g of HPMC K15M, and 15.7g of MCC, mix well, then add 3.1g of MS, mix well, and press into tablets to obtain indobufen sustained-release tablets.

[0139] Example 7

[0140] Indobufen sustained-release tablets were prepared according to the following ratio:

[0141] Table 6 Tablet composition

[0142] Preparation method: Weigh 200g of indobufen, 34g of MCC, and 104g of lactose according to the prescription amount, mix well, add 8% HPMC E5 aqueous solution to prepare a soft material, pass the soft material through a 24-mesh sieve to prepare wet granules, dry at 50°C, and granulate through a 1.0mm sieve. Add 30.7g of HPMC K4M, 7.7g of HPMC K100M, and 15.7g of MCC, mix well, then add 3.1g of MS, mix well, and compress into tablets to obtain indobufen sustained-release tablets.

[0143] Example 8

[0144] Indobufen sustained-release tablets were prepared according to the following ratio:

[0145] Table 7 Tablet composition

[0146] 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% HPMC E5 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 to size the granules, 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.

[0147] Example 9

[0148] Indobufen sustained-release tablets were prepared according to the following ratio:

[0149] Table 8 Tablet composition

[0150] Preparation method: According to the prescription amount, 200 g of indobufen, 100 g of Eudragit RL PO, 32 g of PVP K30, and 64.8 g of lactose were weighed and mixed to prepare a soft material. The soft material was passed through a 24-mesh sieve to prepare wet granules, dried at 50°C, and granulated with a 1.0 mm sieve. 6.1 g of pregelatinized starch was added and mixed, and then 3.2 g of MS was added, mixed, and tableted to obtain indobufen sustained-release tablets.

[0151] Example 10

[0152] Indobufen sustained-release tablets were prepared according to the following ratio:

[0153] Table 9 Tablet composition

[0154] Preparation method: According to the prescription amount, 200 g of indobufen, 100 g of Eudragit RL PO, 32 g of PVP K30, 48.6 g of lactose, and 16.2 g of pregelatinized starch were weighed and mixed to prepare a soft material. The soft material was passed through a 24-mesh sieve to prepare wet granules, dried at 50°C, and sized with a 1.0 mm sieve. 49.6 g of Eudragit RS PO was added and mixed, and then 3.6 g of MS was added, mixed, and tableted to obtain indobufen sustained-release tablets.

[0155] Example 11

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

[0157] Table 10 Tablet composition

[0158] Preparation method: Weigh 200 g of indobufen and 24 g of CMC-Na according to the prescribed amount, mix well, weigh 110 g of Eudragit NM 30D to prepare a soft material, pass the soft material through a 24-mesh sieve to prepare wet granules, dry at 50°C, and granulate through a 1.0 mm sieve. Add 40.5 g of MCC and mix well. Then add 2.5 g of MS and mix well. After tableting, indobufen sustained-release tablets are obtained.

[0159] Example 12

[0160] Indobufen sustained-release tablets were prepared according to the following ratio:

[0161] Table 11 Tablet composition

[0162] Preparation method: Weigh 200g of indobufen, 34g of MCC, and 104g of lactose according to the prescribed amount, mix well, add 8% HPMC E5 aqueous solution to prepare a soft material, pass the soft material through a 24-mesh sieve to prepare wet granules, dry at 50°C, and sieve through a 1.0mm sieve to size the granules, add 159.4g of HPMC K4M and 26.4g of cross-linked sodium carboxymethyl cellulose, mix well, then add 4.2g of MS, mix well, and compress into tablets to obtain indobufen sustained-release tablets.

[0163] Example 13

[0164] Indobufen sustained-release tablets were prepared according to the following ratio:

[0165] Table 12 Tablet composition

[0166] Preparation: Crush sucrose and pass through an 80-mesh sieve. Weigh 200g of indobufen, 34g of dextrin, and 104g of sucrose according to the prescribed amount, mix thoroughly, and add an 8% HPMC E5 aqueous solution to prepare a soft material. The soft material is passed through a 24-mesh sieve to prepare wet granules. Dry at 50°C, sieve through a 1.0mm sieve, and granulate. Add 38.4g of HPMC K4M and mix thoroughly. Then, add 3.1g of MS, mix thoroughly, and compress into tablets to obtain indobufen sustained-release tablets.

[0167] Example 14

[0168] Indobufen sustained-release tablets were prepared according to the following ratio:

[0169] Table 13 Tablet composition

[0170] Preparation: Crush sucrose and pass through an 80-mesh sieve. Weigh 200g of indobufen, 34g of microcrystalline cellulose, and 104g of sucrose according to the prescribed amount, mix thoroughly, and add an 8% HPMC E5 aqueous solution to prepare a soft material. The soft material is passed through a 24-mesh sieve to prepare wet granules. Dry at 50°C, sieve through a 1.0mm sieve, and granulate. Add 38.4g of HPMC K4M and mix thoroughly. Then, add 3.1g of MS, mix thoroughly, and compress into tablets to obtain indobufen sustained-release tablets.

[0171] Example 15

[0172] Indobufen sustained-release tablets were prepared according to the following ratio:

[0173] Table 14 Tablet composition

[0174] Preparation method: Weigh 200g of indobufen, 34g of dextrin, and 104g of lactose according to the prescribed amount, mix well, add 8% HPMC E5 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 to size the granules, add 38.4g of HPMC K4M and mix well, then add 3.1g of MS, mix well, and press into tablets to obtain indobufen sustained-release tablets.

[0175] Example 16: Dissolution Study

[0176] In order to investigate the sustained-release effect of the indobufen sustained-release tablets prepared in each embodiment, Examples 5 to 10 were subjected to an in vitro dissolution comparative study (using the second method of 0931 of the fourth general rule of the Chinese Pharmacopoeia 2020 edition, Part IV) with the reference preparation (manufacturer: Pfizer Italia Srl, batch number EN9422, trade name: Ibustrin, specification: 0.2 g). Among them, the in vitro dissolution comparative study of Examples 5 and 6 with the reference preparation is shown in Figure 1, the in vitro dissolution comparative study of Examples 7, 8, and 9 with the reference preparation is shown in Figure 2, and the in vitro dissolution comparative study of Example 10 with the reference preparation is shown in 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.

[0177] The dissolution test results of Examples 1-13 in pH 6.8 phosphate buffered saline 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 clinical medication needs.

[0178] Table 15 Dissolution results

[0179] Comparative Example 1: Using ethyl cellulose as sustained-release material

[0180] Indobufen sustained-release tablets were prepared according to the following ratio:

[0181] Table 16 Tablet composition

[0182] The preparation method is as described in Example 2.

[0183] Comparative Example 2: Using ethyl cellulose as sustained-release material

[0184] Indobufen sustained-release tablets were prepared according to the following ratio:

[0185] Table 17 Tablet composition

[0186] The preparation method is as described in Example 2.

[0187] Referring to Example 16, the dissolution of the tablets obtained in Comparative Examples 1 and 2 was investigated. The results are shown in the following table.

[0188] Table 18 Dissolution results

[0189] 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 before 2 hours is small and cannot meet the clinical medication needs.

[0190] Comparative Example 3: No filler

[0191] Indobufen sustained-release tablets were prepared according to the following ratio:

[0192] Table 19 Tablet composition

[0193] The preparation method is as described in Example 2. During the preparation, it was found that the tablets were sticky during tableting, which is not conducive to industrial production.

[0194] Comparative Example 4: Single Filler

[0195] Indobufen sustained-release tablets were prepared according to the following ratio:

[0196] Table 20 Tablet composition

[0197] The preparation method is as described in Example 2.

[0198] The dissolution test was carried out with reference to Example 16. 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.

[0199] Comparative Example 5: Single Filler

[0200] Indobufen sustained-release tablets were prepared according to the following ratio:

[0201] Table 21 Tablet composition

[0202] The preparation method is as described in Example 2.

[0203] 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.

[0204] Table 22 Dissolution results

[0205] It can be seen from the dissolution results in Table 22 that the in vitro dissolution effect is poor when using a single filler, especially the release before 2 hours is small and cannot meet the clinical medication needs.

[0206] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present disclosure. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine different embodiments or examples described in this specification and features of different embodiments or examples, unless they are mutually inconsistent.

[0207] Although the embodiments of the present disclosure have been shown and described above, it is understood that the above embodiments are illustrative and are not to be construed as limitations on the present disclosure. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present disclosure.

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, wherein 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, wherein 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, wherein 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, wherein 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, wherein 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, wherein 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, wherein 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 E5 0.1%-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 E5 0.1%-10%, HPMC K4M 2%-15%, HPMC K15M 1%-5%, MS 0.1%-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%, MS 0.1%-5%.

12. An indobufen sustained-release preparation comprising: a main drug, lactose, pregelatinized starch, Eudragit RL 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, 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 an adhesive or an aqueous solution of an adhesive; 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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