CN101766577B - Solid preparation of clopidogrel free alkali and preparation process thereof - Google Patents

Abstract

The invention relates to a solid preparation of clopidogrel free base and a preparation method thereof. The solid preparation uses clopidogrel free base as the main drug, with anhydrous lactose, microcrystalline cellulose, mannitol, hydroxypropyl cellulose, partially pregelatinized starch, fumed silicon dioxide, and magnesium stearate as auxiliary materials . The method is prepared by wet granulation. The solid preparation of the invention solves the problem of clopidogrel hydrolyzate in the production of the solid preparation of clopidogrel free base, improves the safety and stability of the solid preparation of clopidogrel free base, and makes it play a therapeutic role more effectively.

Description

A kind of solid preparation of clopidogrel free base and its preparation process

technical field

The invention relates to a solid preparation of clopidogrel free base and a preparation method thereof.

Background technique

Clopidogrel is an inducible platelet aggregation inhibitor, which can selectively inhibit the binding of ADP to platelet receptors, and then inhibit the activation of ADP and glycoprotein GP IIb/IIIa complex, thereby inhibiting the aggregation of platelets. This product can also inhibit platelet aggregation caused by non-ADP without affecting the activity of phosphodiesterase. This product affects the lifespan of platelets by irreversibly changing platelet ADP receptors. Clopidogrel reduces the chance of arterial blockage by inhibiting platelet aggregation, achieves the effect of preventing stroke and heart attack, and can effectively treat and prevent atherosclerosis.

Clopidogrel is an inactive prodrug that is metabolized into active metabolites by hepatic cytochrome P450. Its structure is as follows:

Clopidogrel is a free base, usually administered in the form of its sulfate, but there are many defects in the commercially available clopidogrel sulfate tablets, which are mainly reflected in two aspects: on the one hand, clopidogrel meets some commonly used Lubricants are easily degraded into clopidogrel acid, which affects product stability; on the other hand, the dextroisomer of clopidogrel in clopidogrel sulfate tablets is converted into the clopidogrel levoisomer, reported in the prior art The L-isomer of clopidogrel has almost no anti-platelet aggregation effect, and the results of animal experiments show that the toxicity of the L-isomer of clopidogrel is significantly higher than that of the D-isomer of clopidogrel, which will greatly increase its use in the heart and The risk of vascular stent surgery, so the content of clopidogrel L-isomer has become an important parameter for production quality control. However, the content control of the levorotatory isomer of clopidogrel has not been effectively resolved.

Contents of the invention

The technical problem to be solved by this invention is to provide a solid preparation of clopidogrel free base and a preparation method thereof, which solves the problem of clopidogrel hydrolyzate in the production of solid preparations of clopidogrel free base and improves the production rate of clopidogrel. The safety and stability of the solid preparation of the free base make it more effective to play a therapeutic role.

The technical solution adopted by the present invention to solve the above problems is: a solid preparation of clopidogrel free base, characterized in that clopidogrel free base is used as the main drug, and anhydrous lactose, microcrystalline cellulose, mannitol , hydroxypropyl cellulose, partly pregelatinized starch, fumed silicon dioxide, and magnesium stearate are auxiliary materials; the content of anhydrous lactose by weight percentage is 24-36.5% of the weight of the solid preparation, and the content of microcrystalline cellulose is solid 30-40% of the weight of the preparation, the content of mannitol is 2.5-4% of the weight of the solid preparation, the content of hydroxypropyl cellulose is 2.5-4% of the weight of the solid preparation, and the content of partly pregelatinized starch is 7.5-4% of the weight of the solid preparation 10%, the content of fumed silicon dioxide is 1.5-2% of the weight of the solid preparation, the content of magnesium stearate is 0.7-1% of the weight of the solid preparation, and the balance is clopidogrel free base.

The use of mannitol and hydroxypropyl cellulose in the present invention can effectively inhibit the hydrolysis of clopidogrel.

The above-mentioned solid preparations include: tablets, capsules and the like.

A preparation process of the above-mentioned solid preparation of clopidogrel free base, comprising the following steps: 1) mixing anhydrous lactose, microcrystalline cellulose, mannitol, and hydroxypropyl cellulose uniformly, adding clopidogrel free base solution Wet granulation, fluidized boiling drying, the granules are sized through a high-speed crushing and granulating machine with a 1.0mm sieve; 2) After the granules obtained in operation 1) are mixed evenly with part of the pregelatinized starch, fumed silica, and magnesium stearate Made into solid preparations.

In summary, the beneficial effects of the present invention are: the solid preparation of the present invention solves the problem of clopidogrel hydrolyzate in the solid preparation of clopidogrel free base, improves the safety and security of the solid preparation of clopidogrel free base Stability, making it more effective to play a therapeutic role.

Detailed ways

The solid preparation of clopidogrel free base of the present invention uses clopidogrel free base as the main ingredient, and anhydrous lactose, microcrystalline cellulose, mannitol, hydroxypropyl cellulose, partially pregelatinized starch, and fumed silica , magnesium stearate is an auxiliary material, wet granulation process tablet; its content of clopidogrel free base is 15-18.8% of solid preparation weight, hydroxypropyl cellulose content is 2.5-4% of solid preparation weight, mannitol The content is 2.5-4% of the weight of the solid preparation. The content of anhydrous lactose is 24-36.5% of the weight of the solid preparation, the content of microcrystalline cellulose is 30-40% of the weight of the solid preparation, the content of partly pregelatinized starch is 7.5-10% of the weight of the solid preparation, and the content of fumed silica The filler is 1.5-2% of the weight of the solid preparation, and the content of magnesium stearate as a lubricant is 0.7-1% of the weight of the solid preparation.

The preparation method of the solid preparation of the above-mentioned clopidogrel free base, the method is prepared by wet granulation, and the specific steps are as follows:

1) Mix anhydrous lactose, microcrystalline cellulose, mannitol, and hydroxypropyl cellulose evenly, add clopidogrel free base solution for wet granulation, fluidize boiling drying, and sieve the granules through a high-speed crushing and sizing machine with a size of 1.0mm grain.

2) Mix the granules obtained in operation 1) with part of the pregelatinized starch, fumed silicon dioxide, and magnesium stearate, and then make a solid preparation through a suitable method.

In the above operation 1), in order to meet the uniformity of clopidogrel free base, fully stirring and cutting in a high-speed wet granulator is adopted. In order to meet the uniformity of particle size, use a high-speed crushing and sizing machine with a 1.0mm sieve for sizing.

In the above-mentioned operation 2), appropriate methods are used to make solid preparations, including direct compression to obtain tablets, mixing uniformly and filling capsules, etc.

Example 1:

Tablet prescription with unit tablet weight 0.500g, clopidogrel labeled content 75mg/tablet and wet granulation preparation process

Prescription quantity content % Clopidogrel free base 75g 15% Anhydrous Lactose 120g twenty four%   Microcrystalline Cellulose 200g 40% Mannitol 20g 4% Hydroxypropyl Cellulose 20g 4% partially pregelatinized starch 50g 10% Fumed silica 10g 2% Magnesium stearate 5g 1% Total 500g 100%

1) Mix 120g of anhydrous lactose, 200g of microcrystalline cellulose, 20g of mannitol, and 20g of hydroxypropyl cellulose, and add clopidogrel free base (75g) solution for wet granulation, fluidized boiling drying, and granulation by high-speed crushing Granulator 1.0mm sieve for granulation.

2) Mix 343g of the granules obtained in operation 1) with 50g of partially pregelatinized starch, 10g of fumed silicon dioxide, and 5g of magnesium stearate, and then press into tablets.

Example 2:

Tablet prescription with unit tablet weight 0.420g, clopidogrel labeled content 75mg/tablet and wet granulation preparation process

Prescription quantity content % Clopidogrel free base 75g 17.9% Anhydrous Lactose 123g 29.3%   Microcrystalline Cellulose 140g 33.3% Mannitol 15g 3.6% Hydroxypropyl Cellulose 15g 3.6% partially pregelatinized starch 40g 9.5% Fumed silica 8g 1.9% Magnesium stearate 4g 0.9% Total 420g 100%

1) Mix 123g of anhydrous lactose, 140g of microcrystalline cellulose, 15g of mannitol, and 15g of hydroxypropyl cellulose, add clopidogrel free base (75g) solution for wet granulation, fluidize boiling drying, and granulate by high-speed pulverization Granulator 1.0mm sieve for granulation.

2) Mix 374g of the granules obtained in operation 1) with 40g of partially pregelatinized starch, 8g of fumed silicon dioxide, and 4g of magnesium stearate, and then press into tablets.

Example 3:

Tablet prescription and wet granulation preparation process with a unit tablet weight of 0.400g and a labeled content of clopidogrel of 75mg/tablet

Prescription quantity content% Clopidogrel free base 75g 18.8% Anhydrous Lactose 146g 36.5%   Microcrystalline Cellulose 120g 30% Mannitol 10g 2.5% Hydroxypropyl Cellulose 10g 2.5% partially pregelatinized starch 30g 7.5% Fumed silica 6g 1.5% Magnesium stearate 3g 0.7% Total 400g 100%

1) Mix 146g of anhydrous lactose, 120g of microcrystalline cellulose, 10g of mannitol, and 10g of hydroxypropyl cellulose, add clopidogrel free base (75g) solution for wet granulation, fluidize boiling drying, and granulate through high-speed pulverization Granulator 1.0mm sieve for granulation.

2) Mix 365g of the granules obtained in operation 1) with 30g of partially pregelatinized starch, 6g of fumed silicon dioxide, and 3g of magnesium stearate, and then press into tablets.

The tablet of clopidogrel free base prepared by wet granulation of the present invention shows in the stability test that the content of clopidogrel hydrolyzate hardly significantly increases, which further improves the stability of the tablet of clopidogrel free base , while improving clinical safety.

The beneficial effect of the present invention is illustrated through testing below.

1. Detection indicators and methods

Detection indicators: hydrolyzate, left-handed isomer

Test method: high performance liquid chromatography

Two, the detection result of hydrolyzate in embodiment sample and prior art reference substance

1. Long-term stability test

Table 1 Hydrolyzate

Table 2 Levoisomer

2 Accelerated stability test

Table 3 hydrolyzate

Table 4 Levorotatory Isomer

From the above experimental results, it can be seen that the solid preparation of clopidogrel free base prepared by the present invention shows in the stability test that the content of clopidogrel hydrolyzate hardly increases significantly, which is stable compared with the existing clopidogrel solid preparation. On the other hand, the content of clopidogrel L-isomer in the solid preparation of clopidogrel free base prepared by the present invention is significantly reduced compared with the prior art, and the clopidogrel L-isomer The increase degree of the clopidogrel content significantly reduces the increase degree of the clopidogrel L-isomer in the prior art, further improves the stability of the clopidogrel free base tablet, and improves the clinical safety at the same time.

Claims (3)

1. the solid preparation of a clopidogrel free alkali, it is characterized in that, as principal agent, being equipped with Lactis Anhydrous, microcrystalline Cellulose, mannitol, hydroxypropyl cellulose, partially pregelatinized starch, aerosil, magnesium stearate is adjuvant with clopidogrel free alkali; Its content of described clopidogrel free alkali is the 15-18.8% of solid preparation weight, Lactis Anhydrous content is the 24-36.5% of solid preparation weight, the microcrystalline cellulose cellulose content is the 30-40% of solid preparation weight, mannitol content is the 2.5-4% of solid preparation weight, the hydroxy propyl cellulose cellulose content is the 2.5-4% of solid preparation weight, partially pregelatinized starch content is the 7.5-10% of solid preparation weight, aerosil content is the 1.5-2% of solid preparation weight, and magnesium stearate content is the 0.7-1% of solid preparation weight.

2. the solid preparation of clopidogrel free alkali according to claim 1 is characterized in that, described solid preparation comprises tablet, capsule.

3. the preparation technology of the solid preparation of the described clopidogrel free alkali of claim 1 is characterized in that, comprises the steps:

1) with Lactis Anhydrous, microcrystalline Cellulose, mannitol, hydroxypropyl cellulose, add clopidogrel free alkali solution wet granulation, the fluid boiling drying, granule is by high speed pulverization pelletizing machine 1.0mm sieve granulate;

2) will operate 1) make solid preparation behind gained granule and partially pregelatinized starch, aerosil, the magnesium stearate mix homogeneously.