WO2023115593A1

WO2023115593A1 - Apixaban tablet and preparation process therefor

Info

Publication number: WO2023115593A1
Application number: PCT/CN2021/141416
Authority: WO
Inventors: 袁承烨; 马晶; 陆鹏; 项燕飞
Original assignee: 浙江海正药业股份有限公司
Priority date: 2021-12-26
Filing date: 2021-12-26
Publication date: 2023-06-29

Abstract

The present invention relates to an apixaban tablet and a preparation process therefor. A hydrophilic polymer material is introduced into a prescription as a water-soluble carrier. Apixaban and the hydrophilic polymer material are mixed and then subjected to hot melt granulation to form a solid dispersion. The problem that apixaban tablets have poor in-vitro solubility is effectively solved without adding an surfactant. The hot melt granulation process is simple, has good reproducibility, and can be easily industrialized.

Description

A kind of tablet of apixaban and its preparation process

technical field

The invention belongs to the technical field of medicine, and in particular relates to a tablet of apixaban and a preparation method thereof.

Background technique

Cardiovascular and cerebrovascular diseases have seriously threatened human health due to their high incidence, high recurrence rate, high disability rate and high mortality rate. The incidence of cardiovascular and cerebrovascular diseases in my country is increasing year by year. Thrombosis is a common vascular disease caused by narrowing of vascular lumen, blood embolism and occlusion of circulatory system.

Antithrombotic drugs can be divided into three types according to their mechanism of action: antiplatelet drugs, anticoagulant drugs, and thrombolytic drugs. Apixaban is a new type of oral anticoagulant. US6967208 first described that apixaban has the function of coagulation factor Xa inhibitor, and it is developed as an oral administration for various indications that require the use of antithrombotic drugs. medicine way.

Apixaban (Apxiaban) is a novel oral selective inhibitor of activated factor Xa, chemical name: 4,5,6,7-tetrahydro-1-(4-methoxyphenyl)-7- Oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-1H-pyrazolo[3,4-C]pyridine-3-carboxamide, the molecular formula is C ₂₅ H ₂₅ N ₅ O ₄ , its structural formula is as follows:

Under all physiological pH conditions, apixaban has poor water solubility and low in vitro dissolution rate, which affects the bioavailability of the drug. In order to improve the dissolution rate of apixaban in vitro, the conventional method is to add a large amount of surfactant in the prescription, but this method will bring corresponding toxic and side effects to the human body when increasing the dissolution rate of the drug. Therefore, it is very important to find a safe method to increase the dissolution rate of apixaban and improve the absorption of apixaban.

Contents of the invention

The invention provides an apixaban tablet with good dissolution rate and high bioavailability. The apixaban tablet comprises the following components: apixaban bulk drug, water-soluble carrier material, carrier, filler and lubricant.

In a preferred embodiment, in parts by weight, the tablet comprises 1 part of apixaban raw material drug; 4-20 parts of water-soluble carrier material; 1-20 parts of carrier; 5-22 parts of filler; The dose is 0.1 to 1 part. Further preferably, the tablet comprises 1 part of apixaban bulk drug; 5-20 parts of water-soluble carrier material; 1-10 parts of carrier; 5-20 parts of filler; and 0.1-1 part of lubricant.

In a preferred embodiment, the water-soluble carrier material is a hydrophilic polymer material, preferably polyethylene glycol; the carrier is crospovidone, preferably crospovidone-XL ; The filler is lactose monohydrate and microcrystalline cellulose; the lubricant is magnesium stearate.

In a preferred embodiment, the specification of the apixaban tablet is 2.5 mg.

The present invention also provides a preparation method of Apixaban tablets, the steps are as follows:

(1) Weigh the prescribed amount of apixaban and polyethylene glycol, mix the two, heat in a water bath at 70°C-90°C until melted, and stir at 180-220rpm for 15-25 minutes after they are all melted;

(2) Weigh the crospovidone of prescription quantity, add in the granulating pot with water-bath jacket, stir with 90-110rpm rotating speed, heat material with 70 ℃-90 ℃ hot water bath;

(3) When the temperature of the material in step (2) is greater than or equal to 70°C, put the molten material obtained in step (1) into the granulation pot for granulation, the stirring blade is 140-160rpm, the cutter is 1800-2200rpm, and the granulation is 8-12 minutes ;

(4) Pass the granules obtained in step (3) through a 20-mesh sieve, cool to room temperature, then carry out dry sizing, and pass through a 20-mesh sieve;

(5) Mix the granules obtained in step (4) with the lactose monohydrate and microcrystalline cellulose of the prescribed amount;

(6) Mix the mixed granules obtained in the step (5) with the prescribed amount of magnesium stearate evenly, and then compress into tablets to obtain apixaban tablets.

In a preferred embodiment, the steps are as follows:

1) Weigh the prescribed amount of apixaban and polyethylene glycol, mix the two, heat in a water bath at 80°C until melted, and stir at 200rpm for 20 minutes after melting;

2) Weigh the prescribed amount of crospovidone-XL, add it into the granulation pot with a water bath jacket, stir at a speed of 100 rpm, and heat the material with a hot water bath at 80°C;

3) When the temperature of the material in step (2) is greater than or equal to 70°C, put the molten material obtained in step (1) into the granulation pot for granulation, the stirring blade is 150rpm, the cutter is 2000rpm, and the granulation is 10 minutes;

4) Pass the granules obtained in step (3) through a 20-mesh sieve, cool to room temperature, then carry out dry sizing, and pass through a 20-mesh sieve;

5) mixing the granules obtained in step (4) with lactose monohydrate and microcrystalline cellulose of the prescribed amount;

6) Mix the mixed granules obtained in step (5) with the prescribed amount of magnesium stearate evenly, and then compress into tablets to prepare apixaban tablets.

Compared with the prior art, the Apixaban tablet and preparation process of the present invention have the following advantages:

1) The present invention utilizes solid dispersion technology to make apixaban and polyethylene glycol form a colloidal solution, improve drug dissolution rate and solubility, increase drug absorption, and improve bioavailability.

2) The present invention adopts crospovidone as the carrier of the above-mentioned colloidal solution, utilizes the characteristics of its large specific surface area, granules the colloidal solution after being evenly adsorbed on crospovidone, and further improves dissolution rate and solubility.

3) Traditional solid dispersion technology requires higher melt cooling and drying conditions and longer cooling and drying time. The process steps of the apixaban tablet of the present invention are completed in a short time under milder conditions. It is simple, reduces the production cost and improves the production efficiency.

4) The present invention improves the dissolution rate of the insoluble drug apixaban, reduces the toxic and side effects of the product, and improves the safety of medication while not using the method of adding a large amount of surfactant.

Description of drawings

Figure 1 shows the apixaban tablets and commercially available Eliquis in Example 7

In vitro dissolution test results chart

Detailed ways

The present invention will be further illustrated by the following examples. It must be noted that the examples of the present invention are used to illustrate the present invention, and should not be construed as limiting the present invention.

Example 1

This example provides the prescription (Table 1) and preparation process for preparing 8000 Apixaban tablets (specification 2.5mg/tablet):

Table 1 Prescription of Apixaban Tablets

成分作用Component role	成份ingredients	用量Dosage
活性成分active ingredient	阿哌沙班Apixaban	20g20g
分散剂Dispersant	聚乙二醇polyethylene glycol	100g100g
载体carrier	交联聚维酮-XLCrospovidone-XL	320g320g
填充剂filler	单水乳糖lactose monohydrate	180g180g
填充剂filler	微晶纤维素microcrystalline cellulose	176g176g

lubricant

Magnesium stearate

4g

Preparation:

1) Weigh the prescribed amount of apixaban and polyethylene glycol, mix the two, heat in a water bath at 80°C until melted, and stir at 200 rpm for 20 minutes after all melted.

2) Weigh the prescribed amount of crospovidone-XL, add it into a granulation pot with a water bath jacket, stir at a speed of 100 rpm, and heat the material with a hot water bath at 80°C.

3) When the temperature of the material in step (2) is greater than or equal to 70°C, put the molten material obtained in step (1) into the granulation pot for granulation. Stirring paddle 150rpm, cutter 2000rpm. Granulate for 10 minutes.

4) Pass the granules obtained in step (3) through a 20-mesh sieve, and cool to room temperature. Carry out dry granulation again, cross 20 mesh sieves.

5) Mix the granules obtained in step (4) with the prescribed amount of lactose monohydrate and microcrystalline cellulose evenly.

Example 2

This example provides the prescription (Table 2) and preparation process for preparing 8000 Apixaban tablets (specification 2.5mg/tablet):

Table 2 Prescription of Apixaban Tablets

成分作用Component role	成份ingredients	用量Dosage
活性成分active ingredient	阿哌沙班Apixaban	20g20g
分散剂Dispersant	聚乙二醇polyethylene glycol	100g100g
载体carrier	交联聚维酮-XLCrospovidone-XL	240g240g
填充剂filler	单水乳糖lactose monohydrate	220g220g
填充剂filler	微晶纤维素microcrystalline cellulose	216g216g
润滑剂lubricant	硬脂酸镁Magnesium stearate	4g4g

Preparation:

1) Weigh the prescribed amount of apixaban and polyethylene glycol, mix the two, heat in a water bath at 80°C until melted, and stir at 200rpm for 20 minutes after they are completely melted.

3) When the temperature of the material in step (2) is greater than or equal to 70°C, put the molten material obtained in step (1) into the granulation pot for granulation, the stirring blade is 150rpm, and the cutter is 2000rpm. Granulate for 10 minutes.

4) The granules obtained in step (3) are passed through a 20-mesh sieve, cooled to room temperature, then dry sized, and passed through a 20-mesh sieve.

Example 3

This example provides the prescription (Table 3) and preparation process for preparing 8000 Apixaban tablets (specification 2.5 mg/tablet):

Table 3 Prescription of Apixaban Tablets

成分作用Component role	成份ingredients	用量Dosage
活性成分active ingredient	阿哌沙班Apixaban	20g20g
分散剂Dispersant	聚乙二醇polyethylene glycol	80g80g
载体carrier	交联聚维酮-XLCrospovidone-XL	320g320g
填充剂filler	单水乳糖lactose monohydrate	190g190g
填充剂filler	微晶纤维素microcrystalline cellulose	186g186g
润滑剂lubricant	硬脂酸镁Magnesium stearate	4g4g

Preparation:

6) Mix the mixed granules obtained in step (5) with the prescribed amount of magnesium stearate evenly, and then compress into tablets to obtain Apixaban tablets.

Example 4

This example provides the prescription (Table 4) and preparation process for preparing 8000 Apixaban tablets (specification 2.5mg/tablet):

Table 4 Prescription of Apixaban Tablets

成分作用Component role	成份ingredients	用量Dosage
活性成分active ingredient	阿哌沙班Apixaban	20g20g
分散剂Dispersant	聚乙二醇polyethylene glycol	120g120g
载体carrier	交联聚维酮-XLCrospovidone-XL	320g320g
填充剂filler	单水乳糖lactose monohydrate	170g170g
填充剂filler	微晶纤维素microcrystalline cellulose	166g166g
润滑剂lubricant	硬脂酸镁Magnesium stearate	4g4g

Preparation:

Example 5

This example provides the prescription (Table 5) and preparation process for preparing 8000 Apixaban tablets (specification 2.5mg/tablet):

Table 5 Prescription of Apixaban Tablets

Component role

ingredients

Dosage

活性成分active ingredient	阿哌沙班Apixaban	20g20g
分散剂Dispersant	聚乙二醇polyethylene glycol	100g100g
载体carrier	交联聚维酮-XLCrospovidone-XL	400g400g
填充剂filler	单水乳糖lactose monohydrate	140g140g
填充剂filler	微晶纤维素microcrystalline cellulose	136g136g
润滑剂lubricant	硬脂酸镁Magnesium stearate	4g4g

Preparation:

3) When the temperature of the material in step (2) is greater than or equal to 70°C, put the molten material obtained in step (1) into the granulation pot for granulation, the stirring blade is 150 rpm, the cutter is 2000 rpm, and the granulation is 10 minutes.

Example 6

This example provides the preparation of 3000 Apixaban tablets (specification 2.5 mg/tablet) by conventional wet granulation method, the prescription (Table 6) and preparation process are as follows:

Table 6 Prescription of Apixaban Tablets

成分作用Component role	成份ingredients	用量Dosage
活性成分active ingredient	阿哌沙班Apixaban	7.50g7.50g
填充剂filler	单水乳糖lactose monohydrate	150.75g150.75g
填充剂filler	微晶纤维素microcrystalline cellulose	126.00g126.00g
崩解剂(内加)Disintegrant (internal addition)	交联羧甲基纤维素钠Croscarmellose Sodium	6.00g6.00g
粘合剂Adhesive	羟丙甲纤维素hypromellose	7.86g7.86g

崩解剂(外加)Disintegrant (additional)	交联羧甲基纤维素钠Croscarmellose Sodium	6.00g6.00g
润滑剂lubricant	硬脂酸镁Magnesium stearate	2.25g2.25g

Preparation:

1) Weigh the prescribed amount of apixaban, lactose monohydrate, microcrystalline cellulose and croscarmellose sodium, put them into a granulation pot and mix them, and the rotation speed of the stirring paddle is 150rpm.

2) Weighing the prescribed amount of hypromellose, dissolving in an appropriate amount of purified water, and preparing a slurry with a concentration of 5%.

3) Add the slurry in step (2) to the mixed powder in step (1) to granulate, the rotation speed of the stirring blade is 150rpm, and the cutter is 3000rpm.

4) Pass the wet sized granules obtained in step (3) through a 20-mesh sieve, oven-dry at 55° C., and then pass through a 20-mesh sieve through dry sized.

5) Weighing the croscarmellose sodium and magnesium stearate of the prescribed amount, mixing with the materials obtained in step (4), and compressing into tablets to obtain apixaban tablets.

Example 7

Apixaban tablets (Examples 1-6) and commercially available Eliquis

In vitro dissolution assay, the results are shown in Table 7 and Figure 1:

Table 7 In vitro dissolution test results

Conclusion: From the above research results, it can be known that the Apixaban tablet of the present invention is comparable to that of the commercially available Eliquis without adding a surfactant.

The dissolution rate and dissolution rate were basically the same, which was better than that of apixaban tablets prepared by conventional wet granulation process.

Claims

An apixaban tablet, characterized in that the apixaban tablet comprises the following components: apixaban raw material drug, water-soluble carrier material, carrier, filler and lubricant.
The apixaban tablet according to claim 1, wherein, in parts by weight, the tablet comprises 1 part of apixaban raw material drug; 4-20 parts of water-soluble carrier material; 1-20 parts of carrier parts; filler 5-22 parts; lubricant 0.1-1 part.
The apixaban tablet according to claim 1 or 2, wherein the water-soluble carrier material is a hydrophilic polymer material, preferably polyethylene glycol.
The apixaban tablet according to any one of claims 1-3, wherein the carrier is crospovidone, preferably crospovidone-XL.
The Apixaban tablet according to any one of claims 1-4, wherein the filler is lactose monohydrate and microcrystalline cellulose.
The Apixaban tablet according to any one of claims 1-5, wherein the lubricant is magnesium stearate.
The Apixaban tablet according to any one of claims 1-6, wherein the specification of the Apixaban tablet is 2.5 mg.
A preparation method of the Apixaban tablet according to any one of claims 1-7, characterized in that it comprises the following steps:

(1) Weigh the prescribed amount of apixaban and polyethylene glycol, mix the two, heat in a water bath at 70°C-90°C until melted, and stir at 180-220rpm for 15-25 minutes after they are all melted;

(2) Weigh the crospovidone of prescription quantity, add in the granulating pot with water-bath jacket, stir with 90-110rpm rotating speed, heat material with 70 ℃-90 ℃ hot water bath;

(3) When the temperature of the material in step (2) is greater than or equal to 70°C, put the molten material obtained in step (1) into the granulation pot for granulation, the stirring blade is 140-160rpm, the cutter is 1800-2200rpm, and the granulation is 8-12 minutes ;

(4) Pass the granules obtained in step (3) through a 20-mesh sieve, cool to room temperature, then carry out dry sizing, and pass through a 20-mesh sieve;

(5) Mix the granules obtained in step (4) with the lactose monohydrate and microcrystalline cellulose of the prescribed amount;

(6) Mix the mixed granules obtained in the step (5) with the prescribed amount of magnesium stearate evenly, and then compress into tablets to obtain apixaban tablets.