Indobufen pharmaceutical composition as well as preparation method and application thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to an indobufen-containing pharmaceutical composition and a preparation method thereof.The pharmaceutical composition is prepared from, by weight, 200 parts of indobufen, 175 parts of lactose monohydrate, 93 parts of microcrystalline cellulose, 41.6 parts of sodium carboxymethyl starch, 5.2 parts of lauryl sodium sulfate and 5.2 parts of magnesium stearate. According to the present invention, the purified water is adopted as the adhesive, and the particle size of the indobufen is controlled at D90: 10-20 [mu] m, such that the indobufen tablet has advantages of low production cost, good dissolution rate effect and suitableness for large-scale production.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and in particular relates to an indobufen pharmaceutical composition and a preparation method and use thereof. Background Art

[0002] Indobufen is an isoindolinylphenylbutyric acid derivative, an inhibitor of platelet aggregation, and the only reversible, selective, multi-target antithrombotic drug currently available. It effectively blocks thrombosis by comprehensively inhibiting multiple links and multiple targets in the thrombosis process, thereby achieving rapid, efficient, and safe prevention and treatment of ischemic cardiovascular disease, cerebrovascular disease, venous thrombosis caused by arteriosclerosis, and prevention of thrombosis during hemodialysis. This product mainly exerts its antiplatelet aggregation effect through the following mechanisms:

[0003] (1) Reversibly inhibits platelet cyclooxygenase, reducing the production of thromboxane A2 (a potent activator of platelet aggregation);

[0004] (2) Inhibit platelet aggregation induced by adenosine diphosphate (ADP), epinephrine, platelet activating factor (PAF), collagen, and arachidonic acid;

[0005] (3) Reduce the levels of platelet adenosine triphosphate, serotonin, platelet factor 3, platelet factor 4 and β-thromboglobulin, and reduce platelet adhesion.

[0006] The quality standards of APIs used in preparations usually require the control of the particle size range of APIs, so the concept of particle size distribution is needed to control the particle size of APIs. (Several key indicators that represent particle size characteristics: ①D50: The particle size corresponding to when the cumulative particle size distribution percentage of a sample reaches 50%; ②D90: The particle size corresponding to when the cumulative particle size distribution number of a sample reaches 90%)

[0007] Indobufen is a low-solubility, high-permeability drug. To achieve the same in vivo bioavailability as the reference preparation, in addition to the requirement for the same crystal form of the compound, it is usually necessary to control the particle size of the raw material or prepare a solid dispersion and control its particle size. There are few documents and patents on indobufen-related preparations in the prior art.

[0008] Chinese patent 202011622109.0 discloses an indobufen pharmaceutical composition, which controls the particle size of indobufen to below 100 mesh, preferably not more than 120 mesh. After reverse analysis of the original research, it was found that the particle size of the raw material used in the reference preparation was below 30μm, which is much smaller than 120 mesh. The protection scope of this patent has a major hidden danger that the prepared preparation is not bioequivalent to the reference preparation.

[0009] Chinese patent 202210093749.X discloses a pharmaceutical composition containing indobufen and a preparation method thereof, which improves the in vitro dissolution effect by encapsulating indobufen with polyethylene glycol and xylitol in a certain ratio, thereby achieving in vitro dissolution equivalence with the reference preparation. However, the process is complex, has high requirements for production equipment, and has high difficulty in process implementation, which easily leads to a low product qualification rate.

[0010] Therefore, there is an urgent need in the art to develop new indobufen pharmaceutical compositions that are equivalent to reference preparations. Summary of the invention

[0011] The purpose of the present invention is to overcome the deficiencies of the prior art and provide a pharmaceutical composition containing indobufen which has low production cost, good dissolution effect and is suitable for large-scale production and a preparation method thereof.

[0012] An indobufen pharmaceutical composition is composed of the following raw materials and auxiliary materials in parts by weight:

[0013] Indobufen 200 servings

[0014] 175 parts of lactose monohydrate

[0015] Microcrystalline cellulose 93 parts

[0016] 41.6 parts of sodium carboxymethyl starch

[0017] 5.2 parts of sodium lauryl sulfate

[0018] 5.2 parts of magnesium stearate

[0019] Wherein, the particle size range D90 of the indobufen is 10 to 20 μm.

[0020] The present invention also provides a method for preparing the above-mentioned indobufen pharmaceutical composition, which is characterized by comprising the following steps:

[0021] Step 1, firstly mixing indobufen with lactose monohydrate, microcrystalline cellulose, sodium carboxymethyl starch and sodium lauryl sulfate to obtain a powder mixture;

[0022] Step 2, granulating and tableting the powder mixture to obtain the product.

[0023] Preferably, the granulation method is selected from dry granulation or wet granulation.

[0024] The present invention also provides use of the indobufen pharmaceutical composition in preparing a drug, wherein the drug is used to treat and / or prevent at least one of the following diseases or conditions: arteriosclerotic ischemic cardiovascular disease, ischemic cerebrovascular disease, peripheral arterial disease, dyslipidemia, venous thrombosis, thrombosis caused by diabetes, and thrombosis during extracorporeal circulation surgery.

[0025] The indobufen-containing pharmaceutical composition provided by the present invention can be prepared into tablets whose types of auxiliary materials used and tablet weight are completely consistent with those of domestic and foreign marketed preparation tablets. On the one hand, the present invention achieves in vitro dissolution consistency with the reference preparation by screening and controlling the particle size of the raw material drug; on the other hand, the production process of the indobufen tablets of the present invention can greatly save production costs, thereby reducing product costs and being suitable for large-scale production.

[0026] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0027] The above contents of the present invention are further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 It is a comparison chart of the dissolution curves of Examples 1 to 11 and the reference preparation. DETAILED DESCRIPTION

[0029] In the following examples and experimental examples, reagents and raw materials not specifically described are all commercially available products.

[0030] Example 1: Indobufen pharmaceutical composition

[0031] The pharmaceutical composition of this embodiment is composed as follows:

[0032] materials Dosage Indobufen 200g Lactose Monohydrate 175g Microcrystalline Cellulose 93g Sodium carboxymethyl starch 41.6g Sodium Lauryl Sulfate 5.2g Magnesium Stearate 5.2g

[0033] (1) Premixing: The prescribed amount of indobufen (particle size: D90 is 90-100 μm, manufacturer: Sichuan Inodabo Pharmaceutical Technology Co., Ltd., the same below), lactose monohydrate, microcrystalline cellulose, sodium carboxymethyl starch (internal addition part), and sodium dodecyl sulfate were mixed in a wet granulator for 15 min. The stirring speed of the wet granulator was 200 r / s and the shear speed was 300 r / s.

[0034] (2) Granulation: Add purified water to make soft material, the amount of water is 40%, the stirring speed of the wet granulator is 250r / s, and the shear speed is 1500r / s; the soft material is sieved through a 1.5mm mesh to granulate;

[0035] (3) Drying: Dry the wet granules in an oven (65°C);

[0036] (4) Granulation: The dry granules are sieved through a 1.2 mm sieve;

[0037] (5) Total mixing: adding the prescribed amount of sodium carboxymethyl starch (external portion) and magnesium stearate for total mixing;

[0038] (6) Tablet compression: Tablet weight is about 520 mg, hardness is 14 kg.

[0039] Example 2: Indobufen pharmaceutical composition

[0040] The pharmaceutical composition of this embodiment is composed as follows:

[0041]

[0042]

[0043] (1) Premixing: The prescribed amount of indobufen (particle size: D90 is 80-90 μm, manufacturer: Sichuan Inodabo Pharmaceutical Technology Co., Ltd., the same below), lactose monohydrate, microcrystalline cellulose, sodium carboxymethyl starch (internal addition part), and sodium dodecyl sulfate were mixed in a wet granulator for 15 min. The stirring speed of the wet granulator was 200 r / s and the shear speed was 300 r / s.

[0044] (2) Granulation: Add purified water to make soft material, the amount of water is 40%, the stirring speed of the wet granulator is 250r / s, and the shear speed is 1500r / s; the soft material is sieved through a 1.5mm mesh to granulate;

[0045] (3) Drying: Dry the wet granules in an oven (65°C);

[0046] (4) Granulation: The dry granules are sieved through a 1.2 mm sieve;

[0047] (5) Total mixing: adding the prescribed amount of sodium carboxymethyl starch (external portion) and magnesium stearate for total mixing;

[0048] (6) Tablet compression: Tablet weight is about 520 mg, hardness is 14 kg.

[0049] Example 3: Indobufen pharmaceutical composition

[0050] The pharmaceutical composition of this embodiment is composed as follows:

[0051] materials Dosage Indobufen 200g Lactose Monohydrate 175g Microcrystalline Cellulose 93g Sodium carboxymethyl starch 41.6g Sodium Lauryl Sulfate 5.2g Magnesium Stearate 5.2g

[0052] (1) Premixing: The prescribed amount of indobufen (particle size: D90 is 70-80 μm, manufacturer: Sichuan Inodabo Pharmaceutical Technology Co., Ltd., the same below), lactose monohydrate, microcrystalline cellulose, sodium carboxymethyl starch (internal addition part), and sodium dodecyl sulfate were mixed in a wet granulator for 15 min. The stirring speed of the wet granulator was 200 r / s and the shear speed was 300 r / s.

[0053] (2) Granulation: Add purified water to make soft material, the amount of water is 40%, the stirring speed of the wet granulator is 250r / s, and the shear speed is 1500r / s; the soft material is sieved through a 1.5mm mesh to granulate;

[0054] (3) Drying: Dry the wet granules in an oven (65°C);

[0055] (4) Granulation: The dry granules are sieved through a 1.2 mm sieve;

[0056] (5) Total mixing: adding the prescribed amount of sodium carboxymethyl starch (external portion) and magnesium stearate for total mixing;

[0057] (6) Tablet compression: Tablet weight is about 520 mg, hardness is 14 kg.

[0058] Example 4: Indobufen pharmaceutical composition

[0059] The pharmaceutical composition of this embodiment is composed as follows:

[0060] materials Dosage Indobufen 200g Lactose Monohydrate 175g Microcrystalline Cellulose 93g Sodium carboxymethyl starch 41.6g Sodium Lauryl Sulfate 5.2g Magnesium Stearate 5.2g

[0061] (1) Premixing: The prescribed amount of indobufen (particle size: D90 is 60-70 μm, manufacturer: Sichuan Inodabo Pharmaceutical Technology Co., Ltd., the same below), lactose monohydrate, microcrystalline cellulose, sodium carboxymethyl starch (internal addition part), and sodium dodecyl sulfate were mixed in a wet granulator for 15 min. The stirring speed of the wet granulator was 200 r / s and the shear speed was 300 r / s.

[0062] (2) Granulation: Add purified water to make soft material, the amount of water is 40%, the stirring speed of the wet granulator is 250r / s, and the shear speed is 1500r / s; the soft material is sieved through a 1.5mm mesh to granulate;

[0063] (3) Drying: Dry the wet granules in an oven (65°C);

[0064] (4) Granulation: The dry granules are sieved through a 1.2 mm sieve;

[0065] (5) Total mixing: adding the prescribed amount of sodium carboxymethyl starch (external portion) and magnesium stearate for total mixing;

[0066] (6) Tablet compression: Tablet weight is about 520 mg, hardness is 14 kg.

[0067] Example 5: Indobufen pharmaceutical composition

[0068] The pharmaceutical composition of this embodiment is composed as follows:

[0069] materials Dosage Indobufen 200g Lactose Monohydrate 175g Microcrystalline Cellulose 93g Sodium carboxymethyl starch 41.6g Sodium Lauryl Sulfate 5.2g Magnesium Stearate 5.2g

[0070] (1) Premixing: The prescribed amount of indobufen (particle size: D90 is 50-60 μm, manufacturer: Sichuan Inodabo Pharmaceutical Technology Co., Ltd., the same below), lactose monohydrate, microcrystalline cellulose, sodium carboxymethyl starch (internal addition part), and sodium dodecyl sulfate were mixed in a wet granulator for 15 min. The stirring speed of the wet granulator was 200 r / s and the shear speed was 300 r / s.

[0071] (2) Granulation: Add purified water to make soft material, the amount of water is 40%, the stirring speed of the wet granulator is 250r / s, and the shear speed is 1500r / s; the soft material is sieved through a 1.5mm mesh to granulate;

[0072] (3) Drying: Dry the wet granules in an oven (65°C);

[0073] (4) Granulation: The dry granules are sieved through a 1.2 mm sieve;

[0074] (5) Total mixing: adding the prescribed amount of sodium carboxymethyl starch (external portion) and magnesium stearate for total mixing;

[0075] (6) Tablet compression: Tablet weight is about 520 mg, hardness is 14 kg.

[0076] Example 6: Indobufen pharmaceutical composition

[0077] The pharmaceutical composition of this embodiment is composed as follows:

[0078] materials Dosage Indobufen 200g Lactose Monohydrate 175g Microcrystalline Cellulose 93g Sodium carboxymethyl starch 41.6g Sodium Lauryl Sulfate 5.2g Magnesium Stearate 5.2g

[0079] (1) Premixing: The prescribed amount of indobufen (particle size: D90 is 40-50 μm, manufacturer: Sichuan Inodabo Pharmaceutical Technology Co., Ltd., the same below), lactose monohydrate, microcrystalline cellulose, sodium carboxymethyl starch (internal addition part), and sodium dodecyl sulfate were mixed in a wet granulator for 15 min. The stirring speed of the wet granulator was 200 r / s and the shear speed was 300 r / s.

[0080] (2) Granulation: Add purified water to make soft material, the amount of water is 40%, the stirring speed of the wet granulator is 250r / s, and the shear speed is 1500r / s; the soft material is sieved through a 1.5mm mesh to granulate;

[0081] (3) Drying: Dry the wet granules in an oven (65°C);

[0082] (4) Granulation: The dry granules are sieved through a 1.2 mm sieve;

[0083] (5) Total mixing: adding the prescribed amount of sodium carboxymethyl starch (external portion) and magnesium stearate for total mixing;

[0084] (6) Tablet compression: Tablet weight is about 520 mg, hardness is 14 kg.

[0085] Example 7: Indobufen Pharmaceutical Composition

[0086] The pharmaceutical composition of this embodiment is composed as follows:

[0087]

[0088]

[0089] (1) Premixing: The prescribed amount of indobufen (particle size: D90 is 30-40 μm, manufacturer: Sichuan Inodabo Pharmaceutical Technology Co., Ltd., the same below), lactose monohydrate, microcrystalline cellulose, sodium carboxymethyl starch (internal addition part), and sodium dodecyl sulfate were mixed in a wet granulator for 15 min. The stirring speed of the wet granulator was 200 r / s and the shear speed was 300 r / s.

[0090] (2) Granulation: Add purified water to make soft material, the amount of water is 40%, the stirring speed of the wet granulator is 250r / s, and the shear speed is 1500r / s; the soft material is sieved through a 1.5mm mesh to granulate;

[0091] (3) Drying: Dry the wet granules in an oven (65°C);

[0092] (4) Granulation: The dry granules are sieved through a 1.2 mm sieve;

[0093] (5) Total mixing: adding the prescribed amount of sodium carboxymethyl starch (external portion) and magnesium stearate for total mixing;

[0094] (6) Tablet compression: Tablet weight is about 520 mg, hardness is 14 kg.

[0095] Example 8: Indobufen pharmaceutical composition

[0096] The pharmaceutical composition of this embodiment is composed as follows:

[0097] materials Dosage Indobufen 200g Lactose Monohydrate 175g Microcrystalline Cellulose 93g Sodium carboxymethyl starch 41.6g Sodium Lauryl Sulfate 5.2g Magnesium Stearate 5.2g

[0098] (1) Premixing: The prescribed amount of indobufen (particle size: D90 is 20-30 μm, manufacturer: Sichuan Inodabo Pharmaceutical Technology Co., Ltd., the same below), lactose monohydrate, microcrystalline cellulose, sodium carboxymethyl starch (internal addition part), and sodium dodecyl sulfate were mixed in a wet granulator for 15 min. The stirring speed of the wet granulator was 200 r / s and the shear speed was 300 r / s.

[0099] (2) Granulation: Add purified water to make soft material, the amount of water is 40%, the stirring speed of the wet granulator is 250r / s, and the shear speed is 1500r / s; the soft material is sieved through a 1.5mm mesh to granulate;

[0100] (3) Drying: Dry the wet granules in an oven (65°C);

[0101] (4) Granulation: The dry granules are sieved through a 1.2 mm sieve;

[0102] (5) Total mixing: adding the prescribed amount of sodium carboxymethyl starch (external portion) and magnesium stearate for total mixing;

[0103] (6) Tablet compression: Tablet weight is about 520 mg, hardness is 14 kg.

[0104] Example 9: Indobufen Pharmaceutical Composition

[0105] The pharmaceutical composition of this embodiment is composed as follows:

[0106] materials Dosage Indobufen 200g Lactose Monohydrate 175g Microcrystalline Cellulose 93g Sodium carboxymethyl starch 41.6g Sodium Lauryl Sulfate 5.2g Magnesium Stearate 5.2g

[0107] (1) Premixing: The prescribed amount of indobufen (particle size: D90 is 10-20 μm, manufacturer: Sichuan Inodabo Pharmaceutical Technology Co., Ltd., the same below), lactose monohydrate, microcrystalline cellulose, sodium carboxymethyl starch (internal addition part), and sodium dodecyl sulfate were mixed in a wet granulator for 15 min. The stirring speed of the wet granulator was 200 r / s and the shear speed was 300 r / s.

[0108] (2) Granulation: Add purified water to make soft material, the amount of water is 40%, the stirring speed of the wet granulator is 250r / s, and the shear speed is 1500r / s; the soft material is sieved through a 1.5mm mesh to granulate;

[0109] (3) Drying: Dry the wet granules in an oven (65°C);

[0110] (4) Granulation: The dry granules are sieved through a 1.2 mm sieve;

[0111] (5) Total mixing: adding the prescribed amount of sodium carboxymethyl starch (external portion) and magnesium stearate for total mixing;

[0112] (6) Tablet compression: Tablet weight is about 520 mg and hardness is 14 kg.

[0113] Example 10: Indobufen Pharmaceutical Composition

[0114] The pharmaceutical composition of this embodiment is composed as follows:

[0115] materials Dosage Indobufen 200g Lactose Monohydrate 175g Microcrystalline Cellulose 93g Sodium carboxymethyl starch 41.6g Sodium Lauryl Sulfate 5.2g Magnesium Stearate 5.2g

[0116] (1) Premixing: The prescribed amount of indobufen (particle size: D90 is 5-10 μm, manufacturer: Sichuan Inodabo Pharmaceutical Technology Co., Ltd., the same below), lactose monohydrate, microcrystalline cellulose, sodium carboxymethyl starch (internal addition part), and sodium dodecyl sulfate were mixed in a wet granulator for 15 min. The stirring speed of the wet granulator was 200 r / s and the shear speed was 300 r / s.

[0117] (2) Granulation: Add purified water to make soft material, the amount of water is 40%, the stirring speed of the wet granulator is 250r / s, and the shear speed is 1500r / s; the soft material is sieved through a 1.5mm mesh to granulate;

[0118] (3) Drying: Dry the wet granules in an oven (65°C);

[0119] (4) Granulation: The dry granules are sieved through a 1.2 mm sieve;

[0120] (5) Total mixing: adding the prescribed amount of sodium carboxymethyl starch (external portion) and magnesium stearate for total mixing;

[0121] (6) Tablet compression: Tablet weight is about 520 mg, hardness is 14 kg.

[0122] Example 11: Indobufen Pharmaceutical Composition

[0123] The pharmaceutical composition of this embodiment is composed as follows:

[0124] materials Dosage Indobufen 200g Lactose Monohydrate 175g Microcrystalline Cellulose 93g Sodium carboxymethyl starch 41.6g Sodium Lauryl Sulfate 5.2g Magnesium Stearate 5.2g

[0125] (1) Premixing: The prescribed amount of indobufen (particle size: D90 is 10-20 μm, manufacturer: Sichuan Inodabo Pharmaceutical Technology Co., Ltd., the same below), lactose monohydrate, microcrystalline cellulose, sodium carboxymethyl starch, and sodium lauryl sulfate were mixed in a wet granulator for 15 min. The stirring speed of the wet granulator was 200 r / s and the shear speed was 300 r / s.

[0126] (2) Dry granulation: Control the screw feed speed to 40-95 rpm; the roller speed to 8-30 rpm; the roller oil pressure to 15-20 bar; the roller gap to 0.8-1.8 mm; the crushing speed to 60-100 rpm, and the crushing screen aperture to 3.0 mm; the granulation speed to 100-140 rpm, and the granulation screen aperture to 1.0 mm; add materials from the feed port and start production.

[0127] (3) Total mixing: adding the prescribed amount of magnesium stearate for total mixing;

[0128] (4) Tablet compression: Tablet weight is about 520 mg, hardness is 14 kg.

[0129] Test Example 1: Comparative experimental study of in vitro dissolution curves

[0130] In order to evaluate the solubility of the tablets prepared in Examples 1-11, the tablets prepared in Examples 1-11 were compared with the reference preparation (manufacturer: Pfizer S.r.1 batch number FL0420, trade name: Ibustrin, specification: 0.2g) for in vitro dissolution curve comparison study. The dissolution method is the paddle method of the 2020 edition of the general dissolution method of the Chinese Pharmacopoeia; dissolution instrument manufacturer: Agilent Technology; dissolution conditions: pH 6.2 phosphate buffer (take 250ml of 0.2mol / L potassium dihydrogen phosphate solution, take 40.5ml of 0.2mol / L sodium hydroxide solution, dilute with water to 1000ml, and shake well.) 900ml is the dissolution medium, the rotation speed is 50 revolutions per minute, and the operation is carried out according to the law. The dissolution test results are shown in Table 1, and the dissolution curve is shown in Table 1. Figure 1 .

[0131] Table 1 and Figure 1 The results show that compared with the reference preparation, the f2 values ​​of the dissolution curves of the tablets prepared in Example 9 and Example 11 are both greater than 50, which can be judged to be consistent with the dissolution behavior of the reference preparation.

[0132] Table 1 Dissolution test results of Examples 1-11 and reference preparations in pH 6.2 phosphate buffered saline medium

[0133]

[0134] Note: F2 represents similarity factor, and a value greater than 50 indicates similarity to the reference preparation.

Claims

1. An indobufen pharmaceutical composition, characterized in that: It is composed of the following raw materials in parts by weight: Indobufen 200 servings 175 parts of lactose monohydrate Microcrystalline cellulose 93 parts 41.6 parts of sodium carboxymethyl starch 5.2 parts of sodium lauryl sulfate 5.2 parts of magnesium stearate Wherein, the particle size range D90 of the indobufen is 10 to 20 μm.

2. The method for preparing the indobufen pharmaceutical composition according to claim 1, characterized in that: The steps include: Step 1, firstly mixing indobufen with lactose monohydrate, microcrystalline cellulose, sodium carboxymethyl starch and sodium lauryl sulfate to obtain a powder mixture; Step 2, granulating and tableting the powder mixture to obtain the product.

3. The method for preparing the indobufen pharmaceutical composition according to claim 2, characterized in that: The granulation method is selected from dry granulation or wet granulation.

4. Use of the indobufen pharmaceutical composition according to claim 1 in the preparation of a medicament for treating and / or preventing at least one of the following diseases or conditions: arteriosclerotic ischemic cardiovascular disease, ischemic cerebrovascular disease, peripheral arterial disease, dyslipidemia, venous thrombosis, thrombosis caused by diabetes, and thrombosis during extracorporeal circulation surgery.

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