Anti-platelet aggregation active pharmaceutical composition and preparation method thereof

Abstract

The invention provides an anti-platelet aggregation active pharmaceutical composition and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. The anti-platelet aggregation active pharmaceutical composition disclosed by the invention is prepared from the following components in parts by weight: 200 parts of indobufen, 40 to 60 parts of microcrystalline cellulose, 180 to 230 parts of lactose, 20 to 40 parts of carboxymethyl starch sodium, 10 to 20 parts of povidone, 1 to 10 parts of lauryl sodium sulfate and 1 to 10 parts of magnesium stearate. By adopting a micronization process, the solubility of the indobufen raw material medicine can be remarkably improved, the bioavailability is improved, the in-vivo bioequivalence of the medicine and a reference preparation is improved, meanwhile, a high-shear wet granulation process is adopted, the adhesive povidone is increased, the dosage of the adhesive povidone is optimized, the defects caused by micronization are reduced, the process robustness is improved, and the bioavailability of the indobufen raw material medicine is improved. The obtained product is uniform and controllable in quality, and is suitable for large-scale production, the production cost is greatly reduced, and the production benefit is greatly improved.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an antiplatelet aggregation active pharmaceutical composition and a preparation method thereof. Background Art

[0002] In recent years, due to the accelerating aging of the population, unhealthy diets, the widespread prevalence of unhealthy lifestyles such as lack of physical activity and smoking, cardiovascular diseases have accounted for a relatively high proportion of the causes of death among residents and have become a major public health problem. Research shows that the formation of thrombus is a key factor leading to cardiovascular diseases. A thrombus refers to a small piece formed by the coagulation of blood in a blood vessel. When a thrombus forms in the coronary artery, it will block the coronary artery, leading to myocardial hypoxia and necrosis, and triggering diseases such as angina pectoris and myocardial infarction; when a thrombus forms in the cerebral blood vessel, it will cause diseases such as stroke and cerebral embolism. Cardiovascular diseases and lower extremity arterial thrombosis often have some of the same risk factors, such as hypertension, hyperlipidemia, diabetes, smoking, obesity, advanced age, etc. These factors can cause vascular endothelial damage, increased blood viscosity, and hemodynamic changes, thereby increasing the risk of thrombus formation, and the formation of thrombus will further exacerbate blood vessel blockage and damage, forming a vicious cycle. Lower extremity arterial thrombosis can sometimes be a manifestation or complication of cardiovascular diseases. Once lower extremity arterial thrombosis occurs, it indicates that the patient has a relatively high risk of developing cardiovascular diseases, and the probability of future occurrence of cardiovascular adverse events such as myocardial infarction and stroke may increase.

[0003] At present, the treatment of thrombus in the treatment field is generally divided into three categories, namely antiplatelet drugs, anticoagulant drugs, and thrombolytic drugs. Among them, antiplatelet aggregation drugs have the highest market share and are widely used. Representative drugs include aspirin, clopidogrel, and warfarin. However, the above drugs each have their drawbacks. For example, taking aspirin is often accompanied by severe gastrointestinal reactions and increases the risk of intraoperative bleeding; taking clopidogrel may cause bleeding complications in some patients, such as nosebleeds, gum bleeding, skin ecchymosis, etc.; when using warfarin, it is necessary to closely monitor the coagulation function to ensure the safety and effectiveness of the drug, and its anticoagulant effect is easily affected by food and drugs.

[0004] Indobufen is a new type of anticoagulant drug. By inhibiting platelet aggregation and release reactions, as well as inhibiting the formation of thromboxane A2, it achieves the anticoagulant effect without affecting the activity of coagulation factors. Traditional antithrombotic drugs such as warfarin mainly play an anticoagulant role by inhibiting the synthesis or activity of coagulation factors, while antiplatelet drugs such as aspirin mainly play a role by inhibiting platelet aggregation. Compared with traditional antithrombotic drugs, indobufen has a relatively lower bleeding risk because it does not affect the activity of coagulation factors and has a relatively small impact on the coagulation system. Therefore, when preventing and treating thrombotic diseases, it can effectively reduce the risk of adverse reactions such as bleeding while effectively anticoagulating. Indobufen compounds are more suitable for patients at risk of bleeding, such as those undergoing cardiac stent surgery, cerebrovascular diseases, peptic ulcers, etc. The use of traditional antithrombotic drugs in these patients may be restricted to a certain extent, and the bleeding risk needs to be evaluated more carefully.

[0005] In the field of clinical treatment, indobufen is mainly sold in the market as immediate-release tablets. It was included in the national essential medicine list in 2018 and has become the first choice for antiplatelet aggregation drugs. Since indobufen raw material belongs to BCS class II drugs and has pH dependence, its solubility is relatively low under acidic conditions, resulting in a longer blood entry time and lower dissolution rate of conventional indobufen tablets. There are many research reports on this situation in the existing technology.

[0006] Chinese Patent CN116251072A discloses an indobufen tablet and its preparation method and uses. This patent uses the inclusion technology to produce indobufen tablets, aiming to improve the drug loading and encapsulation efficiency of indobufen inclusion compounds. However, in the actual production process, this preparation method exposes many difficult problems. On the one hand, the operation convenience is poor, the control of the encapsulation efficiency is very difficult, and the control of the intermediate process is extremely complicated, requiring high ability and large difficulty coefficient for technical personnel. The unstable encapsulation efficiency may interfere with the drug solubility, resulting in significant differences between different batches of products, making it difficult to control the product quality. On the other hand, the complex preparation process and strict control requirements will undoubtedly increase the production cost, which forms a serious obstacle to the large-scale commercial production of the product, greatly weakening the competitiveness and commercial value of the product in the market.

[0007] Chinese Patent CN114225042A discloses a pharmaceutical composition containing indobufen and its preparation method. In this patent, indobufen is included with polyethylene glycol and xylitol, and then pre-gelatinized starch is added to improve the bioavailability. This patent innovatively introduces the concept of co-entrapping agent, which can improve the encapsulation efficiency and in vitro dissolution. The prepared tablets and capsules can reduce the weight of the preparation without changing the specifications. The preparation process mainly involves mixing polyethylene glycol and xylitol, heating to 80 - 90 °C, adding indobufen, stirring, cooling, pulverizing, and uniformly mixing with pre-gelatinized starch. This preparation method is not suitable for operation in large-scale production, requires high production equipment, has strict process requirements, and is difficult for industrial production.

[0008] The main problems exposed by the above-mentioned related patents are that they do not consider the industry production level, cannot achieve adaptability, are not suitable for industrial production, thus increasing production costs and reducing competitiveness and commercial value in the market. Summary of the Invention

[0009] In view of this, the purpose of the present invention is to provide an antiplatelet aggregation active pharmaceutical composition and its preparation method to solve the problems of low dissolution rate, low bioavailability, poor stability, and unsuitability for large-scale production of existing drugs.

[0010] To achieve the above-mentioned invention purpose, the present invention provides the following technical solutions:

[0011] The present invention provides an antiplatelet aggregation active pharmaceutical composition, including the following components in parts by weight:

[0012] Indobufen 200 parts;

[0013] Microcrystalline cellulose 40 - 60 parts;

[0014] Lactose 180 - 230 parts;

[0015] Sodium carboxymethyl starch 20 - 40 parts;

[0016] Povidone 10 - 20 parts;

[0017] Sodium dodecyl sulfate 1 - 10 parts;

[0018] Magnesium stearate 1 - 10 parts.

[0019] Preferably, the particle size of the indobufen is < 10 μm.

[0020] The present invention also provides a preparation method of the antiplatelet aggregation active pharmaceutical composition, including the following steps:

[0021] 1) Mix povidone and water to obtain a povidone solution;

[0022] 2) Pre-mix microcrystalline cellulose, indobufen, sodium lauryl sulfate, sodium carboxymethyl starch, and lactose, and use povidone solution as a binder to perform wet granulation to obtain wet granules;

[0023] 3) After drying the wet granules, add sodium carboxymethyl starch and magnesium stearate for total mixing to obtain total mixed granules;

[0024] 4) Compress the total mixed granules to obtain an antiplatelet aggregation active pharmaceutical composition.

[0025] Preferably, the mass ratio of povidone to water in step 1) is 1:5 - 9.

[0026] Preferably, the stirring speed of the pre-mixing in step 2) is 160 - 200 rpm, the shear speed of the pre-mixing is 1000 - 1400 rpm, and the time of the pre-mixing is 3 - 7 min.

[0027] Preferably, the stirring speed of the wet granulation in step 2) is 160 - 200 rpm, the shear speed of the wet granulation is 1000 - 1400 rpm, the atomization pressure of the wet granulation is 0.05 - 0.15 Mpa, and the liquid addition time of the wet granulation is 100 - 140 s.

[0028] Preferably, the drying temperature in step 3) is 55 - 65 °C, and the final moisture content after drying is ≤ 3.0%.

[0029] Preferably, the rotation speed of the total mixing in step 3) is 5 - 10 rpm, and the time of the total mixing is 3 - 7 min.

[0030] Preferably, the tablet weight of the tableting in step 4) is 520 ± 15 mg, and the hardness of the tableting is 80 - 120 N.

[0031] Compared with the prior art, the present invention has the following beneficial effects:

[0032] The present invention adopts a micronization process, which can significantly improve the solubility of indobufen raw material medicine, improve the bioavailability, and is beneficial to improving the in vivo bioequivalence of the drug and the reference preparation. At the same time, a high-shear wet granulation process is adopted, the binder povidone is increased and its dosage is optimized, the disadvantages brought by micronization are reduced, the process robustness is improved, the product quality obtained is uniform and controllable, and it is suitable for large-scale production, greatly reducing the production cost and significantly improving the production efficiency.

[0033] Micronization is likely to cause poor fluidity of the API, increased hygroscopicity, and the risk of spontaneous agglomeration due to static electricity. Polyvinylpyrrolidone has strong interfacial binding force, hydrophilicity, and film-forming property. At appropriate dosages, through the wet granulation process, it reduces the static electricity effect caused by micronization and improves the mixing uniformity; the capillary action of its solution promotes the close packing of fine powder particles to form granules with appropriate voids, and the swelling effect of polyvinylpyrrolidone molecular chains can accelerate drug release, which not only improves fluidity but also prevents fluctuations in dissolution behavior caused by agglomeration of micronized particles and overly hard particles, maximizing the improvement of dissolution by micronization; polyvinylpyrrolidone can form a protective film to reduce moisture absorption and will not hinder the penetration of moisture into the interior of the particles due to an overly thick film layer, ensuring the dissolution rate.

[0034] Aiming at the disadvantages of micronized APIs such as "strong surface activity, weak fluidity, and high hygroscopicity", polyvinylpyrrolidone converts micronized particles into particles with appropriate particle size, controllable strength, and good fluidity through its adhesiveness, hydrophilicity, and film-forming property, while inhibiting moisture absorption, agglomeration, and static electricity problems, ensuring the content uniformity, dissolution rate, and production robustness of the preparation. It not only gives full play to the advantage of micronization in improving the dissolution rate but also systematically reduces the technical risks brought by micronization through the synergistic optimization of polyvinylpyrrolidone characteristics and process parameters. Description of the Drawings

[0035] Figure 1 is the chemical structural formula of indobufen. Detailed Embodiments

[0036] The present invention provides an antiplatelet aggregation active pharmaceutical composition, comprising the following components in parts by weight:

[0037] 200 parts of indobufen;

[0038] 40 - 60 parts of microcrystalline cellulose;

[0039] 180 - 230 parts of lactose;

[0040] 20 - 40 parts of sodium carboxymethyl starch;

[0041] 10 - 20 parts of polyvinylpyrrolidone;

[0042] 1 - 10 parts of sodium lauryl sulfate;

[0043] 1 - 10 parts of magnesium stearate.

[0044] In the present invention, the particle size of the indobufen is preferably <10 μm, and the chemical structural formula of the indobufen is as Figure 1As shown; the dosage of the microcrystalline cellulose is preferably 45 to 55 parts; the dosage of the lactose is preferably 190 to 220 parts; the dosage of the sodium carboxymethyl starch is preferably 25 to 35 parts; the dosage of the polyvinylpyrrolidone is preferably 12 to 18 parts; the dosage of the sodium lauryl sulfate is preferably 2 to 8 parts; the dosage of the magnesium stearate is preferably 2 to 8 parts.

[0045] The present invention also provides a preparation method of the antiplatelet aggregation active pharmaceutical composition, comprising the following steps:

[0046] 1) Mix polyvinylpyrrolidone and water to obtain a polyvinylpyrrolidone solution;

[0047] 2) Premix microcrystalline cellulose, indobufen, sodium lauryl sulfate, sodium carboxymethyl starch, and lactose, and use the polyvinylpyrrolidone solution as a binder to perform wet granulation to obtain wet granules;

[0048] 3) After drying the wet granules, add sodium carboxymethyl starch and magnesium stearate for total mixing to obtain total mixed granules;

[0049] 4) Press the total mixed granules to obtain the antiplatelet aggregation active pharmaceutical composition.

[0050] In the present invention, polyvinylpyrrolidone and water are mixed to obtain a polyvinylpyrrolidone solution. The mass ratio of the polyvinylpyrrolidone to the water is 1:5 to 9.

[0051] In the present invention, microcrystalline cellulose, indobufen, sodium lauryl sulfate, sodium carboxymethyl starch, and lactose are premixed, and the polyvinylpyrrolidone solution is used as a binder to perform wet granulation to obtain wet granules. The stirring speed of the premixing is preferably 160 to 200 rpm, more preferably 170 to 190 rpm; the shear speed of the premixing is preferably 1000 to 1400 rpm, more preferably 1100 to 1300 rpm; the premixing time is preferably 3 to 7 min, more preferably 4 to 6 min; the stirring speed of the wet granulation is preferably 160 to 200 rpm, more preferably 170 to 190 rpm; the shear speed of the wet granulation is preferably 1000 to 1400 rpm, more preferably 1100 to 1300 rpm; the atomization pressure of the wet granulation is preferably 0.05 to 0.15 Mpa, more preferably 0.1 Mpa; the liquid addition time of the wet granulation is preferably 100 to 140 s, more preferably 110 to 130 s.

[0052] In the present invention, after the wet granules are dried, sodium carboxymethyl starch and magnesium stearate are added for total mixing to obtain total mixed granules. The drying temperature is preferably 55-65°C, more preferably 58-62°C; the drying is carried out until the end point moisture content ≤ 3.0%; after drying, sieving is performed, and the diameter of the sieve used for sieving is preferably 1-2 mm, more preferably 1.5 mm; the rotation speed for total mixing is preferably 5-10 rpm, more preferably 6-9 rpm; the total mixing time is preferably 3-7 min, more preferably 4-6 min.

[0053] In the present invention, the total mixed granules are tableted to obtain an antiplatelet aggregation active pharmaceutical composition. The diameter of the tablet is preferably 10-14 mm, more preferably 11-13 mm; the tablet weight of the tablet is preferably 520 ± 15 mg, more preferably 520 ± 10 mg; the hardness of the tablet is preferably 80-120 N, more preferably 90-110 N.

[0054] The technical solutions provided by the present invention are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0055] Example 1

[0056] The composition of the antiplatelet aggregation active pharmaceutical composition is shown in Table 1, with the unit of mg.

[0057] Table 1 Composition of the antiplatelet aggregation active pharmaceutical composition in Example 1

[0058] Raw and auxiliary materials Unit dosage (mg) Indobufen 200 Microcrystalline cellulose 53.08 Lactose 209.72 Sodium carboxymethyl starch 15.6 Povidone 15.6 Sodium lauryl sulfate 5.2 Sodium carboxymethyl starch (added externally to granules) 15.6 Magnesium stearate (added externally to granules) 5.2

[0059] The preparation method is as follows:

[0060] S1. The indobufen raw material drug is pulverized by an air flow pulverizer, and the particle size D90 of the output material is controlled to be less than 10 μm;

[0061] S2. Polyvinylpyrrolidone and water are stirred and dissolved in a mass ratio of 1:7 to prepare an aqueous polyvinylpyrrolidone solution as the granulation solution;

[0062] S3. Microcrystalline cellulose, indobufen raw material drug, sodium dodecyl sulfate, sodium carboxymethyl starch and lactose are sequentially added to a wet granulator, and the stirring speed is set to 180 rpm, the shearing speed is 1200 rpm, and pre-mixing is carried out for 5 min;

[0063] S4. The wet granulator is set with a stirring speed of 180 rpm, a shearing speed of 1200 rpm, an atomization pressure of 0.1 Mpa, the granulation solution is added, and the liquid addition time is controlled to be 120 s;

[0064] S5. Turn on the fluidized bed and dry until the final moisture content is ≤ 3.0% at an inlet air temperature of 60°C;

[0065] S6. Pass the dried material through a 1.5 mm round sieve, and add it to a laboratory hopper mixer together with sodium carboxymethyl starch (externally added to the granules) and magnesium stearate (externally added to the granules). Set the rotation speed to 8 rpm and the mixing time to 5 min;

[0066] S7. Use a 12 mm round shallow concave single-sided through-notch, and press tablets according to a tablet weight of 520 ± 15 mg and a hardness of 80 - 120 N to obtain the antiplatelet aggregation active pharmaceutical composition.

[0067] Example 2

[0068] The composition of the antiplatelet aggregation active pharmaceutical composition is shown in Table 2, with the unit of mg.

[0069] Table 2 Composition of the antiplatelet aggregation active pharmaceutical composition in Example 2

[0070] Raw and auxiliary materials Unit dosage (mg) Indobufen 200 Microcrystalline cellulose 40 Lactose 180 Sodium carboxymethyl starch 10 Povidone 10 Sodium lauryl sulfate 1 Sodium carboxymethyl starch (added externally to granules) 10 Magnesium stearate (added externally to granules) 1

[0071] The preparation method is as follows:

[0072] S1. Crush the indobufen API with an air jet mill, and control the particle size D90 of the output material to be less than 10 μm;

[0073] S2. Stir and dissolve povidone and water in a mass ratio of 1:5 to prepare a povidone aqueous solution as the granulation solution;

[0074] S3. Add microcrystalline cellulose, indobufen API, sodium lauryl sulfate, sodium carboxymethyl starch, and lactose to a wet granulator in sequence. Set the stirring speed to 160 rpm, the shear speed to 1000 rpm, and premix for 3 min;

[0075] S4. Set the stirring speed of the wet granulator to 160 rpm, the shear speed to 1000 rpm, the atomization pressure to 0.05 Mpa, add the granulation solution, and control the liquid addition time to 100 s;

[0076] S5. Turn on the fluidized bed and dry until the final moisture content is ≤ 3.0% at an inlet air temperature of 55°C;

[0077] S6. Pass the dried material through a 1 mm round sieve, and add it to a laboratory hopper mixer together with sodium carboxymethyl starch (externally added to the granules) and magnesium stearate (externally added to the granules). Set the rotation speed to 5 rpm and the mixing time to 3 min;

[0078] S7. Use a 10 mm round shallow concave single-sided through-notch, and press tablets according to a tablet weight of 520 ± 15 mg and a hardness of 80 - 120 N to obtain the antiplatelet aggregation active pharmaceutical composition.

[0079] Example 3

[0080] The composition of the antiplatelet aggregation active pharmaceutical composition is shown in Table 3, with the unit being mg.

[0081] Table 3 Composition of the antiplatelet aggregation active pharmaceutical composition in Example 3

[0082] Raw and auxiliary materials Unit dosage (mg) Indobufen 200 Microcrystalline cellulose 60 Lactose 230 Sodium carboxymethyl starch 20 Povidone 20 Sodium lauryl sulfate 10 Sodium carboxymethyl starch (added externally to granules) 20 Magnesium stearate (added externally to granules) 10

[0083] The preparation method is as follows:

[0084] S1. Pulverize the indobufen raw material drug with an air jet mill, and control the particle size D90 of the output material to be less than 10 μm;

[0085] S2. Stir and dissolve povidone and water according to a mass ratio of 1:9 to prepare a povidone aqueous solution as the granulation solution;

[0086] S3. Add microcrystalline cellulose, indobufen raw material drug, sodium lauryl sulfate, sodium carboxymethyl starch, and lactose into a wet granulator in sequence, set the stirring speed at 200 rpm, the shear speed at 1400 rpm, and premix for 7 min;

[0087] S4. Set the stirring speed at 200 rpm, the shear speed at 1400 rpm, and the atomization pressure at 0.15 Mpa in the wet granulator, add the granulation solution, and control the liquid addition time to be 140 s;

[0088] S5. Turn on the fluidized bed and dry at an inlet air temperature of 65 °C until the final moisture content ≤ 3.0%;

[0089] S6. Pass the dried material through a 2-mm round sieve mesh, add sodium carboxymethyl starch (externally added to the granules) and magnesium stearate (externally added to the granules) into a laboratory hopper mixer, set the rotation speed at 10 rpm, and mix for 7 min;

[0090] S7. Use a 14-mm round shallow concave unilateral through-scribed mark to press tablets according to a tablet weight of 520 ± 15 mg and a hardness of 80 - 120 N to obtain the antiplatelet aggregation active pharmaceutical composition.

[0091] Comparative Example 1

[0092] The difference from Example 1 is that the particle size D90 of the output material is controlled to be 10 - 35 μm after pulverizing the raw material drug.

[0093] Comparative Example 2

[0094] The difference from Example 1 is that the dosage of povidone is 26 mg.

[0095] Comparative Example 3

[0096] It is different from Example 1 in that water is used as the granulation solvent, and the preparation method is as follows:

[0097] S1. The indobufen raw material drug is crushed by a jet mill, and the particle size D90 of the output material is controlled not to exceed 10 μm;

[0098] S2. Microcrystalline cellulose, the raw material drug, sodium lauryl sulfate, sodium carboxymethyl starch, polyvinylpyrrolidone K30 and lactose are sequentially added to a wet granulator, and the stirring speed is set at 180 rpm, the shear speed is 1200 rpm, and the mixture is stirred for 5 min;

[0099] S3. The wet granulator is set with a stirring speed of 180 rpm, a shear speed of 1200 rpm, and an atomization pressure of 0.1 Mpa, and the granulation solution is added, and the liquid addition time is controlled for 120 s;

[0100] S4. The fluidized bed is started, and it is dried at an inlet air temperature of 60 °C until the final moisture content ≤ 3.0%;

[0101] S5. The dried material is passed through a 1.5 mm round sieve, and sodium carboxymethyl starch (externally added to the granules) and magnesium stearate (externally added to the granules) are added to a laboratory hopper mixer, and the rotation speed is set at 8 rpm, and the mixing time is 5 min;

[0102] S6. Using a 12 mm round shallow concave unilateral through-scar, tablets are pressed according to a tablet weight of 520 ± 15 mg and a hardness of 80 - 120 N to obtain an antiplatelet aggregation active pharmaceutical composition.

[0103] Comparative Example 4

[0104] It is different from Example 1 in that the amount of polyvinylpyrrolidone is 5.2 mg.

[0105] Experimental Example 1

[0106] 1. The drugs prepared in Example 1, Comparative Example 1, Comparative Example 2, Comparative Example 3, and Comparative Example 4 and the reference preparation are respectively taken for dissolution curve testing.

[0107] Reference preparation: The manufacturer is Pfizer Italia S.r.l, the trade name is Ibustrin, and the specification is 0.2 g.

[0108] Testing method: Refer to Method 1 (basket method) of "0931 Determination of Dissolution and Release" in the fourth part of the Chinese Pharmacopoeia 2020 edition, with a rotation speed of 75 rpm.

[0109] Detection instrument: Ultraviolet spectrophotometer and dissolution tester.

[0110] Dissolution medium: pH 6.4 phosphate buffer solution.

[0111] Sampling time: 5 min, 10 min, 15 min, 20 min, 30 min.

[0112] Result determination: The similarity factor (f2) method in the non-model-dependent method is adopted. If f2 > 50, the dissolution behaviors are similar.

[0113] Experimental results: As shown in Table 4.

[0114] Table 4 Dissolution curve data

[0115]

[0116] It can be seen from Table 4 that the dissolution trend and the final dissolution amount of Example 1 are similar to those of the reference preparation. However, for Comparative Examples 1, 2, and 4, the final dissolution amount at 30 min did not reach 90% close to that of the reference preparation, and there may be a risk of "low bioavailability". The similarity degrees of Comparative Examples 3 and 4 are also relatively low, which is not conducive to the in vivo bioequivalence of the product and the reference preparation.

[0117] For Comparative Example 1, the particle size of the active pharmaceutical ingredient is relatively high, with D90 being 10 - 35 μm and the particle size being relatively large. The solubility of the active pharmaceutical ingredient decreases, resulting in a slower dissolution behavior of the preparation compared to the reference preparation, belonging to slow similarity, which is not conducive to the in vivo bioequivalence of the product and the reference preparation. For Comparative Example 2, the amount of povidone is increased to 26 mg. With the increase in the amount of povidone, the porosity of the granules obtained by granulation decreases, and the balance between adhesiveness and water solubility is not optimal, resulting in a slower dissolution behavior of the preparation compared to the reference preparation, belonging to slow similarity, which is not conducive to the in vivo bioequivalence of the product and the reference preparation. For Comparative Example 3, povidone is changed to dry powder for addition, and water is used for granulation. During this process, the local povidone concentration is uneven or there are residues of undissolved powder, resulting in a faster dissolution behavior of the preparation compared to the reference preparation. For Comparative Example 4, the amount of povidone is reduced to 5.2 mg. During the granulation process, the povidone concentration is insufficient, and the resulting granules are reduced, resulting in a faster dissolution behavior of the preparation compared to the reference preparation.

[0118] 2. Take the drugs prepared in Example 1, Comparative Example 1, Comparative Example 2, Comparative Example 3, and Comparative Example 4 and the reference preparation respectively for friability testing.

[0119] Reference preparation: The manufacturer is Pfizer Italia S.r.l, the trade name is Ibustrin, and the specification is 0.2 g.

[0120] Testing method: Refer to the "Friability Test for Tablets" in General Chapter 0923 of the Fourth Part of the Chinese Pharmacopoeia 2020 Edition.

[0121] Experimental results: As shown in Table 5.

[0122] Table 5 Friability results

[0123]

[0124] Example 1 uses povidone solution as a binder for granulation (solution method): The particle size distribution of the granules is relatively narrow, the structure is dense, and the internal binding force is strong, which is especially suitable for granulation of micronized APIs or hydrophobic drugs. Comparative Example 3 is obtained by replacing the "povidone solution granulation (solution method)" in Example 1 with "adding povidone powder and then granulating with water (dry powder method)". Its friability is relatively high because the formation of granules by the dry powder method is slower, relying on moisture diffusion and mixing time, and there may be uneven local povidone concentration or residual powder that is not fully dissolved. If the water addition speed is too fast or the mixing is insufficient, "dry powder lumps" are easily formed, resulting in too strong or too weak local adhesion and uneven granule strength. In Comparative Example 4, the amount of povidone used is reduced, the granule strength is insufficient, and there are many fines, which cannot achieve the purpose of agglomerating micronized APIs and fine powders of excipients into granules with a certain particle size and strength, that is, an appropriate granule-to-powder ratio and granule porosity, through the povidone solution in the high-shear wet granulation process, resulting in a decrease in the compressibility of the product, characterized by a relatively high friability. It can be seen that the process of Comparative Example 3 has poor robustness and is not conducive to large-scale production.

[0125] From the above examples, comparative examples and experimental examples, it can be seen that the dissolution trend and friability results of Example 1 are both similar to those of the reference preparation, indicating that the micronization process of the API can significantly improve the solubility of the API, enhance the bioavailability, and is beneficial to the in vivo bioequivalence of the product and the reference preparation. At the same time, the high-shear wet granulation process and appropriate formulation composition are adopted to reduce the disadvantages brought by micronization, improve the process robustness, and the product quality is uniform and controllable, which is suitable for large-scale production.

[0126] The above description is only a preferred embodiment of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.​

Claims

1. An antiplatelet aggregation active pharmaceutical composition, characterized in that, Comprising the following components in parts by weight: Indobufen 200 parts; Microcrystalline cellulose 40 - 60 parts; Lactose 180 - 230 parts; Sodium carboxymethyl starch 20 - 40 parts; Povidone 10 - 20 parts; Sodium lauryl sulfate 1 - 10 parts; Magnesium stearate 1 - 10 parts.

2. The antiplatelet aggregation active pharmaceutical composition according to claim 1, wherein The particle size of the indobufen is < 10 μm.

3. The preparation method of the antiplatelet aggregation active pharmaceutical composition according to claim 1 or 2, characterized in that, Comprising the following steps: 1) Mix povidone and water to obtain a povidone solution; 2) Pre - mix microcrystalline cellulose, indobufen, sodium lauryl sulfate, sodium carboxymethyl starch, and lactose, and use the povidone solution as a binder to perform wet granulation to obtain wet granules; 3) After drying the wet granules, add sodium carboxymethyl starch and magnesium stearate for total mixing to obtain total - mixed granules; 4) Compress the total - mixed granules by tableting to obtain an anti - platelet aggregation active pharmaceutical composition.

4. The preparation method according to claim 3, wherein, In step 1), the mass ratio of the povidone to water is 1:5 - 9.

5. The preparation method according to claim 3, characterized in that, In step 2), the stirring speed of the pre - mixing is 160 - 200 rpm, the shear speed of the pre - mixing is 1000 - 1400 rpm, and the time of the pre - mixing is 3 - 7 min.

6. The preparation method according to claim 3, wherein In step 2), the stirring speed of the wet granulation is 160 - 200 rpm, the shear speed of the wet granulation is 1000 - 1400 rpm, the atomization pressure of the wet granulation is 0.05 - 0.15 Mpa, and the liquid - adding time of the wet granulation is 100 - 140 s.

7. The preparation method according to claim 3, characterized in that, In step 3), the drying temperature is 55 - 65 °C, and the moisture content at the end of drying is ≤ 3.0%.

8. The preparation method according to claim 3, characterized in that, In step 3), the rotation speed of the total mixing is 5 - 10 rpm, and the time of the total mixing is 3 - 7 min.

9. The preparation method according to claim 3, characterized in that, In step 4), the tablet weight of the tableting is 520 ± 15 mg, and the hardness of the tableting is 80 - 120 N.

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