CN111000820A - Apixaban tablet - Google Patents

Abstract

According to the Apixaban tablet prepared by the invention, a high-pressure homogenizer is used for homogenizing apixaban raw material and adhesive suspension, a surfactant is not required to be added in a formula, a fluidized bed one-step granulation method is adopted for preparing granules, and then a finished product is prepared by tabletting and coating; the Apixaban tablet prepared by the prescription process can reach good dissolution speed without adding a surfactant, and simultaneously, the content uniformity of the tablet is improved; the process is beneficial to enhancing oral absorption, improving bioavailability, submitting patients to safe medication, and the prescription process is simple and convenient and is easy for industrial production; the problem that the oral bioavailability of the apixaban is limited due to poor water solubility and low permeability is solved well.

Description

Apixaban tablet

Technical Field

The invention relates to the technical field of pharmaceutical preparations, in particular to a preparation method of apixaban tablets.

Background

Apixaban is a potent, reversible, highly selective factor Xa inhibitor, developed by BMS in combination with feverfew, capable of exerting an antithrombotic effect at a dose level that does not affect the hemostatic function, for clinical use in adult patients with hip or knee joint phase-selective replacements, for the prevention of venous thromboembolic events. In 2011 apixaban was first marketed in the european union and the next year in the us, with product specifications of 2.5mg and 5 mg.

Apixaban can directly inhibit blood coagulation factor Xa and block the conversion of prothrombin to thrombin in the blood coagulation cascade. Factor xa is a vitamin K-dependent serine protease that occupies a central position in the coagulation cascade, is activated by both intrinsic and extrinsic coagulation pathways, and primarily catalyzes the conversion of factor ii (prothrombin) to factor iia (thrombin), and inhibits the production of 1000mol of thrombin by inhibiting 1mol of factor xa. Studies have shown that inhibition of factor Xa can prolong the dose-dependent effect of the lag phase. The structure of the Xa factor contains a S1-S4 pocket, a catalytic region, a cation cavity, a disulfide bridge pocket and the like, wherein the S1 pocket and the S4 pocket are main pockets for drug combination. The process of binding the Apixaban and the Xa active part has high selectivity, the dissociation constant Ki of the binding with the Xa is 0.08 nmol/L (the Ki of rivaroxaban to Xa is 0.4 nmol/L), and the Ki of the binding with other serine proteases is more than 3mol/L, so the Apixaban has high selectivity and strong action on the Xa. In addition, apixaban is characterized by its ability to inhibit not only free Xa and the Xa in the prothrombin complex but also the Xa in the blood clot, and by its absence of antithrombin iii during inhibition, unlike heparin anticoagulants such as fondaparinux sodium.

The main problems of the apixaban tablets at the present stage are as follows:

firstly, the tablet has a small specification, two specifications of 2.5mg and 5mg are available at present, and only one specification of 2.5mg is available in the domestic market. The low content of the main drug causes the mixing uniformity to be difficult to ensure. In addition, the weight of the tablet is small, and the content uniformity is difficult to ensure the qualification.

Secondly, the apixaban is slightly soluble in dimethyl sulfoxide, insoluble in ethanol and almost insoluble in water, and the solubility of the apixaban directly influences the dissolution rate in vivo, thereby influencing the absorption and metabolism in vivo. Therefore, in the preparation process of the apixaban tablet, the dissolution speed needs to be increased, and the absorption in the body needs to be accelerated. At present, the common method for increasing the dissolution rate is to control the particle size of the raw materials, and although the method increases the dissolution rate to a certain extent, the jet milling seriously limits the production efficiency, simultaneously makes the content uniformity more difficult to ensure, and increases the medication risk of patients.

Aiming at the problems, the invention introduces a high-pressure homogenization technology in the preparation of the tablet for the first time, and the technology has the principle that a high-pressure solution quickly passes through a homogenization cavity, so that the material can be simultaneously subjected to mechanical force effects such as high-speed shearing, high-frequency oscillation, cavitation, convection impact and the like, and the mechanical force effect caused by the mechanical force effects can induce the physical structure of the material to change, thereby obtaining the particle size of the raw material with the submicron level. The obtained solution is a submicron dispersion system of pure drug particles, and the drug exists in a crystal or amorphous state in the solution, so that the dissolution rate and the bioavailability of the drug are effectively improved.

Disclosure of Invention

The invention aims to provide an Apixaban tablet which avoids the defects of the prior art. Through comparison of various processes, the wetting agent solution is prepared by adopting a high-pressure homogenization method, and the defects of excessive loss of the micronized raw materials, difficulty in controlling the content uniformity of the tablets, slow dissolution and the like in the prior art are overcome; and simultaneously avoids the use of a surfactant in medicines.

The technical scheme of the invention is as follows:

an apixaban tablet, which mainly comprises an active ingredient apixaban and a pharmaceutical excipient; the content of the active ingredient apixaban in the tablet is 2 to 10 percent by mass; the auxiliary materials comprise a filler, a binder, a disintegrating agent, a lubricant, a coating material and a wetting agent, and the mass percentage of the auxiliary materials in the tablet is 90-98%; the raw materials and the adhesive are subjected to high-pressure homogenization treatment in aqueous solution, and the granulation process adopts one-step granulation of a fluidized bed.

The disintegrant is 2-10% in the tablet by mass, and mainly comprises one or more of croscarmellose sodium, crospovidone and sodium carboxymethyl starch.

The filling agent accounts for 50-95% of the tablet by mass, and mainly comprises one or more of lactose, sucrose, dextrin, microcrystalline cellulose, starch and mannitol.

The lubricant is 0.1-5% by mass in the tablet, and mainly comprises one or more of magnesium stearate, sodium stearyl fumarate, talcum powder and polyethylene glycol.

The mass percentage of the lubricant in the tablet is preferably 0.2-3%.

The adhesive is 1-5% of the tablet by mass, and mainly comprises one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, corn starch and sodium carboxymethylcellulose.

The content of the binder in the tablet is preferably 2-4% by mass.

The wetting agent solution consists of apixaban, an adhesive and purified water, wherein the main medicaments comprise the following components in percentage by mass: adhesive: purified water = 1: 0.5-2: 5-20.

The tablet coating is a film coating, and the weight of the coating is increased by 1-6%, wherein 2-4% is preferred.

The Apixaban tablet is prepared by adopting fluidized bed top spraying granulation tabletting and film coating, and the preparation method of the tablet comprises the following steps

(1) The wetting agent solution was prepared in a high pressure homogenization process using purified water, apixaban and a binder: adding Apixaban and adhesive into purified water under stirring, and performing ultrasonic treatment for 5-10min to disperse the medicine in water; then shearing for 5-10min at the rotating speed of 3000-80000 rpm by using a high-speed disperser to obtain a suspension; then circulating the mixture for 3-10 times by using a high-pressure homogenizer under the pressure of 1000-2000 bar to obtain a wetting agent solution;

(2) premixing auxiliary materials: placing the filler, the residual adhesive in the step (1) and the disintegrating agent in a mixer for mixing for 10-35 min;

(3) granulation and total mixing: placing the premixed auxiliary materials into a fluidized bed, preheating for 3-20min, uniformly pumping the wetting agent solution prepared in the step (1) into a fluidized bed spray gun through a peristaltic pump, granulating at the temperature of 50 ℃, adding a lubricating agent after granulating, and totally mixing for 1-5 min;

(4) tabletting: pressing the total mixed material into tablets with required specifications by using a mould;

(5) coating: preparing coating premix solution with solid content of 15-20%, air inlet temperature of 50-70 deg.C, and host rotation speed of 5-15 r/min.

The invention has the beneficial effects that:

the formula of the apixaban tablet does not use a surfactant, so that the safety of the medicine is better, meanwhile, the apixaban raw material is in a submicron level, the solubility and the dissolution rate of the medicine are increased, the grain diameter of the medicine is reduced, and the adhesion with a mucous membrane can be improved, so that the detention time of the medicine in a body is prolonged, and the bioavailability of the medicine is improved. The raw materials are not subjected to jet milling in the production process, so that the loss of the raw materials is reduced. The fluidized bed is adopted for one-step granulation, the problem of poor content uniformity is solved, and the medication risk of patients is reduced.

The invention has simple production process and low production cost, and is easy for commercial amplification production.

Detailed Description

The examples of the present invention are provided for illustration and description only and should not be construed as limiting the present invention in any way.

Sources of raw materials and auxiliary materials:

homemade by Apixaban New drug industry Co., Ltd

Microcrystalline cellulose, Ridenmel (Shanghai) fiber trade Co., Ltd

Lactose Radenmeil (Shanghai) fiber trade Co., Ltd

Croscarmellose sodium, regen meier (Shanghai) fibers trade Limited

Hydroxypropyl methylcellulose, ashland chemical (Nanjing) Co., Ltd

Carboxymethyl starch sodium Liaoning Aoda pharmaceutical Co., Ltd

Povidone basf (China) Co., Ltd

Sodium dodecyl sulfate Basff (China) Co., Ltd

Magnesium stearate Anhui mountain river pharmaceutic adjuvant, Inc

Coating technology of film coating premix Shanghai Carlekang

Key equipment manufacturers:

GYB1400-15S model high-pressure homogenizer

Model ZP10A rotary tablet press Beijing Xinlongli technology Co

GPCG2 type fluidized bed glatiramer

Example 1 prescription composition of Apixaban tablet and preparation process thereof

Prescription:

apixaban: 2.5mg

Microcrystalline cellulose: 50.25mg

Lactose: 40mg of

Croscarmellose sodium: 4mg of

Hydroxypropyl methylcellulose: 3mg of

Magnesium stearate: 1.25mg

Film coating premix 4mg

The preparation process comprises the following steps:

(1) adding apixaban and hypromellose into purified water under stirring, and performing ultrasonic treatment for 5-10min to disperse the medicine in water; then shearing for 5-10min at the rotating speed of 3000-80000 rpm by using a high-speed disperser to obtain a coarse suspension; circulating for 3-10 times by using a high-pressure homogenizer under the pressure of 1000-2000 bar;

(2) premixing: mixing microcrystalline cellulose, lactose, and croscarmellose sodium in a mixer for 20 min;

(3) and (3) granulating: placing the mixed auxiliary materials in a fluidized bed, preheating for 5min, pumping the wetting agent solution into a fluidized bed spray gun at a constant speed through a peristaltic pump, wherein the atomization pressure of the spray gun is 0.6MPa, and the granulation temperature is 50 ℃;

(4) total mixing: mixing the obtained granules with magnesium stearate for 3 min;

(5) tabletting: and (5) tabletting by using a die with the diameter of 6 mm.

(6) Coating: preparing coating liquid with the solid content of 20 percent, wherein the air inlet temperature is 50-70 ℃, the main engine rotating speed is 5-15r/min, and the coating weight is increased by 4.1 percent.

Example 2 prescription composition of Apixaban tablet and preparation process thereof

Prescription:

apixaban: 5mg of

Microcrystalline cellulose: 100.5mg

Lactose: 80mg of

Croscarmellose sodium: 8mg of

Hydroxypropyl methylcellulose: 6mg of

Magnesium stearate: 2.5mg

Film coating premix 8mg

The preparation process comprises the following steps:

(1) adding apixaban and hypromellose into purified water under stirring, and performing ultrasonic treatment for 5-10min to disperse the medicine in water; then shearing for 5-10min at the rotating speed of 3000-80000 rpm by using a high-speed disperser to obtain a coarse suspension; circulating for 3-10 times by using a high-pressure homogenizer under the pressure of 1000-2000 bar;

(2) premixing: mixing microcrystalline cellulose, lactose, and croscarmellose sodium in a mixer for 20 min;

(3) and (3) granulating: placing the mixed auxiliary materials in a fluidized bed, preheating for 5min, pumping the wetting agent solution into a fluidized bed spray gun at a constant speed through a peristaltic pump, wherein the atomization pressure of the spray gun is 0.6MPa, and the granulation temperature is 50 ℃;

(4) total mixing: mixing the obtained granules with magnesium stearate for 3 min;

(5) tabletting: and (5) tabletting by using a die with the diameter of 6 mm.

(6) Coating: preparing coating liquid with the solid content of 20 percent, wherein the air inlet temperature is 50-70 ℃, the main engine rotating speed is 5-15r/min, and the coating weight is increased by 3.9 percent.

Example 3 prescription composition and preparation process of Apixaban tablets

Prescription:

apixaban: 2.5mg

Microcrystalline cellulose: 50.25mg

Lactose: 36mg of

Sodium carboxymethyl starch: 5mg of

Povidone K30: 6mg of

Magnesium stearate: 1.25mg

Film coating premix 4mg

The preparation process comprises the following steps:

(1) adding Apixaban and polyvidone K30 into purified water under stirring, and performing ultrasonic treatment for 5-10min to disperse the medicine in water; then shearing for 5-10min at the rotating speed of 3000-80000 rpm by using a high-speed disperser to obtain a coarse suspension; circulating for 3-10 times by using a high-pressure homogenizer under the pressure of 1000-2000 bar;

(2) premixing: mixing microcrystalline cellulose, lactose and sodium carboxymethyl starch in a mixer for 20 min;

(3) and (3) granulating: placing the mixed auxiliary materials in a fluidized bed, preheating for 5min, pumping the wetting agent solution into a fluidized bed spray gun at a constant speed through a peristaltic pump, wherein the atomization pressure of the spray gun is 0.6MPa, and the granulation temperature is 50 ℃;

(4) total mixing: mixing the obtained granules with magnesium stearate for 3 min;

(5) tabletting: and (5) tabletting by using a die with the diameter of 6 mm.

(6) Coating: preparing coating liquid with the solid content of 20 percent, wherein the air inlet temperature is 50-70 ℃, the main engine rotating speed is 5-15r/min, and the coating weight is increased by 3.8 percent.

Comparative example

Prescription:

apixaban: 2.5mg

Microcrystalline cellulose: 50.25mg

Lactose: 36mg of

Sodium carboxymethyl starch: 5mg of

Sodium lauryl sulfate: 4mg of

Magnesium stearate: 1.25mg

Film coating premix 4mg

The preparation process comprises the following steps:

(1) premixing: mixing Apixaban, microcrystalline cellulose, lactose, carboxymethyl starch sodium, and sodium dodecyl sulfate in a mixer for 30 min;

(2) total mixing: adding magnesium stearate, and mixing for 5 min;

(3) tabletting: tabletting by using a die with the diameter of 6 mm;

(4) coating: preparing coating liquid with the solid content of 20 percent, wherein the air inlet temperature is 50-70 ℃, the main engine rotating speed is 5-15r/min, and the coating weight is increased by 3.8 percent.

The content uniformity and dissolution curve of the apixaban tablets prepared in the above examples and comparative examples are measured, the content uniformity A +2.2S of each example is less than 2.0, the content uniformity A +2.2S of the comparative example is 13.2, and the measurement results of the dissolution curve are shown in Table 1.

The dissolution curve detection method comprises the following steps: taking the product, using 900ml of 0.05mol/L sodium phosphate solution (pH value is adjusted to 6.8 by phosphoric acid) containing 0.05% sodium dodecyl sulfate as a dissolution medium, rotating at 75 revolutions per minute, taking a proper amount of solution after 5 minutes, 10 minutes, 15 minutes, 20 minutes and 30 minutes according to the method, filtering (using hydrophilic filtering material), and taking the subsequent filtrate as a test solution. Accurately weighing about 25mg of apixaban reference substance, placing into a 100ml measuring flask, adding appropriate amount of methanol to dissolve and dilute to scale, and shaking; precisely measuring 1ml, placing into a 50ml measuring flask, adding dissolution medium to dilute to scale, and shaking to obtain reference solution. Precisely measuring the reference solution and the sample solution at 50ul, respectively, injecting into a liquid chromatograph, recording chromatogram, and calculating the elution amount of each tablet by peak area according to an external standard method.

Table 1: results of measurement of dissolution Profile of each sample of example

Cumulative dissolution sampling time	Example 1	Example 2	Example 3	Comparative example
					5min	75%	77%	73%	26%
10min	92%	89%	91%	37%
					15min	98%	99%	101%	45%
20min	100%	100%	101%	56%
					30min	99%	99%	100%	67%

As can be seen from table 1, the apixaban tablets prepared in the examples of the present invention were rapidly dissolved and had stable quality, and were not affected by the kinds of the disintegrant and the binder.

Claims (10)

1. An apixaban tablet, which is characterized in that: the tablet mainly comprises an active ingredient apixaban and a pharmaceutic adjuvant; the content of the active ingredient apixaban in the tablet is 2 to 10 percent by mass; the auxiliary materials comprise a filler, a binder, a disintegrating agent, a lubricant, a coating material and a wetting agent, and the mass percentage of the auxiliary materials in the tablet is 90-98%; the raw materials and the adhesive are subjected to high-pressure homogenization treatment in aqueous solution, and the granulation process adopts one-step granulation of a fluidized bed.

2. The apixaban tablet according to claim 1, characterized in that: the disintegrant is 2-10% in the tablet by mass, and mainly comprises one or more of croscarmellose sodium, crospovidone and sodium carboxymethyl starch.

3. The apixaban tablet according to claim 1, characterized in that: the filling agent accounts for 50-95% of the tablet by mass, and mainly comprises one or more of lactose, sucrose, dextrin, microcrystalline cellulose, starch and mannitol.

4. The apixaban tablet according to claim 1, characterized in that: the lubricant is 0.1-5% by mass in the tablet, and mainly comprises one or more of magnesium stearate, sodium stearyl fumarate, talcum powder and polyethylene glycol.

5. Apixaban tablets according to claims 1 and 4, wherein: the mass percentage of the lubricant in the tablet is preferably 0.2-3%.

6. The apixaban tablet according to claim 1, characterized in that: the adhesive is 1-5% of the tablet by mass, and mainly comprises one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, corn starch and sodium carboxymethylcellulose.

7. Apixaban tablets according to claims 1 and 6, wherein: the content of the binder in the tablet is preferably 2-4% by mass.

8. The apixaban tablet according to claim 1, characterized in that: the wetting agent solution consists of apixaban, an adhesive and purified water, wherein the main medicaments comprise the following components in percentage by mass: adhesive: purified water = 1: 0.5-2: 5-20.

9. The apixaban tablet according to claim 1, characterized in that: the tablet coating is a film coating, and the weight of the coating is increased by 1-6%, wherein 2-4% is preferred.

10. The Apixaban tablet according to claim 1, which is prepared by fluidized bed top spray granulation tabletting and film coating, and is characterized in that: the preparation method of the tablet is as follows

(1) The wetting agent solution was prepared in a high pressure homogenization process using purified water, apixaban and a binder: adding Apixaban and adhesive into purified water under stirring, and performing ultrasonic treatment for 5-10min to disperse the medicine in water; then shearing for 5-10min at the rotating speed of 3000-80000 rpm by using a high-speed disperser to obtain a suspension; then circulating the mixture for 3-10 times by using a high-pressure homogenizer under the pressure of 1000-2000 bar to obtain a wetting agent solution;

(2) premixing auxiliary materials: placing the filler, the residual adhesive in the step (1) and the disintegrating agent in a mixer for mixing for 10-35 min;

(3) granulation and total mixing: placing the premixed auxiliary materials into a fluidized bed, preheating for 3-20min, uniformly pumping the wetting agent solution prepared in the step (1) into a fluidized bed spray gun through a peristaltic pump, granulating at the temperature of 50 ℃, adding a lubricating agent after granulating, and totally mixing for 1-5 min;

(4) tabletting: pressing the total mixed material into tablets with required specifications by using a mould;

(5) coating: preparing coating premix solution with solid content of 15-20%, air inlet temperature of 50-70 deg.C, and host rotation speed of 5-15 r/min.