CN111346064B

CN111346064B - Rivaroxaban tablet and preparation method thereof

Info

Publication number: CN111346064B
Application number: CN202010160895.0A
Authority: CN
Inventors: 杨勇
Original assignee: Nanjing Jia Chen Medicine Technology Co ltd
Current assignee: SHANGHAI PUKANG PHARMACEUTICAL CO Ltd
Priority date: 2020-03-10
Filing date: 2020-03-10
Publication date: 2022-03-29
Anticipated expiration: 2040-03-10
Also published as: CN111346064A

Abstract

The invention discloses a rivaroxaban tablet and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. The preparation method comprises the step of carrying out wet granulation on the rivaroxaban-containing composition by using a hot-melt extruder, wherein the hot-melt extruder is additionally provided with a liquid adding port at a second station, and the rivaroxaban is micronized. In addition, the technological process and parameters for realizing rivaroxaban wet granulation by using the hot-melt extrusion granulator are optimized. The invention extends the function of the hot-melting extrusion granulator, solves the problems of severe process, complex production process and the like of the traditional batch method medicine preparation process, realizes continuous production, and reduces the content uniformity of finished products and the difference between batches of dissolution behaviors.

Description

Rivaroxaban tablet and preparation method thereof

Technical Field

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to rivaroxaban tablets and a preparation method thereof.

Background

Rivaroxaban (Rivaroxaban, RIV) is the first global oral anticoagulant with high selectivity and direct inhibition of factor Xa, has been approved in more than 100 countries of the world, is marketed in china in 2014 by bayer corporation under the trade name of bairemotal

Approved indications are for adult patients in phase selective hip or knee replacement surgery to prevent Venous Thrombosis (VTE), mainly for clinical antithrombotic anticoagulant therapy, and in addition, the drug has the potential to prevent stroke and other clinical diseases in patients with atrial fibrillation. Rivaroxaban has the following structural formula:

rivaroxaban was a white to slightly yellow powder with poor water solubility (about 7 mg/L). Therefore, when the rivaroxaban is used as an insoluble drug and is prepared into oral solid preparations such as tablets, the dissolution problem of the preparation products needs to be solved, and the requirements of other tablet quality indexes such as content uniformity and the like need to be met.

Chinese patent application CN 106491514a discloses a rivaroxaban solid preparation and a preparation method thereof, which is granulated by a preparation process of wet centrifugal granulation. The centrifugal granulator mainly comprises a rounding base plate and an air supply heating device, wherein the rotating speed of the rounding base plate is 0-1000rpm, and the prepared granules are round and uniform, have excellent fluidity and good compressibility. However, the process has quite high requirements on parameter control in the production process, and has some problems in the aspect of continuous production, such as complicated production process, long production period and difficulty in industrial mass production.

Chinese patent application CN 105267169a discloses a rivaroxaban tablet and a preparation method thereof. The rivaroxaban tablet comprises the following components in parts by weight: 10-20 parts of rivaroxaban, 4 parts of inner added micro-powder silica gel, 21-25 parts of inner added microcrystalline cellulose, 22.9-24.9 parts of lactose monohydrate, 2 parts of inner added cross-linked sodium carboxymethyl cellulose, 10-14 parts of outer added microcrystalline cellulose, 1 part of outer added cross-linked sodium carboxymethyl cellulose, 5cp3 parts of hydroxypropyl methyl cellulose, 0.5 part of sodium dodecyl sulfate and 0.6 part of outer added micro-powder silica gel, and the compound is prepared by shearing and granulating through a wet granulator. The method improves stability of tablet product, and is beneficial for ensuring safety, effectiveness and long-term storage of clinical medicine. However, shear granulation by a wet granulator requires high parameter control, and additionally, the prepared tablets have large batch-to-batch and intra-batch differences, which results in high risks in clinical use.

Chinese patent application CN201910026670.3 discloses a method for continuous granulation of a drug, the method for continuous production of the drug granules comprises: the active pharmaceutical substance, the binder (liquid or solid), the auxiliary material and other auxiliary agents are continuously added into a reciprocating single-screw extruder and evenly mixed, and then the pharmaceutical granules are prepared. By virtue of the excellent mixing capability of the reciprocating single-screw extruder, the active ingredients of the medicine can be effectively dispersed, and all the ingredients are fully contacted with the binder to form medicine particles with uniform particle size and shape, thereby being beneficial to improving the product quality in the subsequent process. However, the material conveying of the single screw extruder mainly depends on friction, so that the charging performance is limited, powder, pasty materials, glass fibers, inorganic fillers and the like are difficult to be added, and in addition, when the head pressure is higher, the countercurrent is increased, so that the productivity is reduced.

It can be seen that the conventional batch-type pharmaceutical process includes high-speed wet granulation, spray-drying granulation, fluidized bed granulation, etc., and these methods all have the problems of severe process control, complex production process, etc. The hot melt extrusion technology emerging recently has multi-unit operation and can be monitored on line, has the advantages of shortening the processing time, realizing continuous production and enabling the medicine to be distributed in a carrier more uniformly when being applied to the preparation of solid dispersion, and mainly has the advantages of improving the solubility and bioavailability of the medicine, preparing a slow release or delayed release preparation, preparing a positioning release preparation, a non-gastrointestinal tract storage and a local medicine delivery system and covering the unpleasant taste of API in the application of the preparation field. At present, 11 drugs including verapamil hydrochloride and griseofulvin are prepared by FDA approved hot-melt extrusion technology. No study on the rivaroxaban wet granulation by using a hot melt extruder is reported, and suitable process parameters need to be studied.

In view of the above, the invention provides a new method for realizing rivaroxaban wet granulation by using a hot-melt extrusion granulator, wherein a liquid adding port is additionally arranged at the second station, the technological process and parameters for realizing rivaroxaban wet granulation by using the hot-melt extrusion granulator are optimized, the function of the hot-melt extrusion granulator is extended, the problems of the traditional batch method medicine preparation technology are solved, and the content uniformity of a finished product and the difference between batches of dissolution behaviors are reduced.

Disclosure of Invention

Rivaroxaban is a high-selectivity anticoagulant, and has high requirements on the content uniformity and in-vivo release rate of a medicine in the clinical use process.

The technical scheme of the invention is as follows:

a process for preparing rivaroxaban tablets comprising the step of wet granulating a rivaroxaban-containing composition using a hot melt extruder; and a liquid adding port is additionally arranged at a second station of the hot-melt extruder, and the rivaroxaban is micronized rivaroxaban.

Specifically, the method comprises the following steps:

(1) uniformly mixing micronized rivaroxaban and auxiliary materials to obtain an intercrystalline phase;

(2) adding the intergranular phase prepared in the step (1) into a feeding hopper of a hot-melt extruder, and continuously feeding; meanwhile, continuously adding the adhesive at a liquid adding port of the second station; the prepared wet particles are connected at a discharge port;

(3) drying the wet granules prepared in the step (2) to obtain dry granules;

(4) mixing the dry particles obtained in the step (3) with external materials to obtain intermediate particles;

(5) and (4) processing the intermediate granules obtained in the step (4) to obtain rivaroxaban tablets.

Wherein the content of the first and second substances,

the auxiliary materials in the step (1) comprise pregelatinized starch, microcrystalline cellulose, lactose monohydrate, crospovidone and hydroxypropyl cellulose.

In the step (1), the weight ratio of the micronized rivaroxaban to the auxiliary materials is 1:7.4-7.9, and preferably 1: 7.4.

The step (1) of uniformly mixing refers to uniformly mixing according to an equivalent increasing principle.

The screw speed of the feed in step (2) is set to 30 to 50rpm, preferably 40 rpm.

The step (2) of adding the adhesive means adding by a peristaltic pump, wherein the rotating speed of the peristaltic pump is set to be 15-25rpm, and is preferably 20 rpm.

The adhesive in the step (2) comprises sodium dodecyl sulfate and water, and the weight ratio of the sodium dodecyl sulfate to the water is 1: 40.

The weight ratio of the binder and micronized rivaroxaban in step (2) was 2.05: 1.

And (3) a screen is arranged at the discharge hole in the step (2), and the aperture is 20-40 meshes, preferably 30 meshes.

The drying manner in step (3) includes, but is not limited to, oven static drying, boiling dryer drying, and preferably drying in a boiling dryer.

The moisture content of the dried granules obtained in the step (3) is controlled to be 0.5-4%, preferably 1-3%.

The external additive in the step (4) is a substance capable of playing a lubricating role in tabletting, and is preferably magnesium stearate.

In step (4), the weight ratio of the external charge to the micronized rivaroxaban is 0.9-1.1:10, preferably 1: 10.

In the step (5), the processing method for preparing the tablet comprises the following steps: tabletting the intermediate granules by using 6mm shallow recesses, and controlling the hardness of the plain tablets to be 50-100N, preferably 60-90N; the plain tablets are coated by a film, and the weight gain of the coating is controlled to be 2-4%, preferably 2.5-3.5%.

In addition, the invention also provides rivaroxaban tablets prepared according to the above method.

Wherein the content of the first and second substances,

the tablet comprises the following components in parts by weight:

10 parts of rivaroxaban (micronized), 18-22.5 parts of pregelatinized starch, 18-22.5 parts of microcrystalline cellulose, 25-32 parts of lactose monohydrate, 3 parts of crospovidone, 3 parts of hydroxypropyl cellulose, 0.5 part of sodium dodecyl sulfate, 0.9-1.1 parts of magnesium stearate and 2-3 parts of opadry.

Preferably, the composition comprises 10 parts of rivaroxaban (micronized), 20 parts of pregelatinized starch, 20 parts of microcrystalline cellulose, 28 parts of lactose monohydrate, 3 parts of crospovidone, 3 parts of hydroxypropyl cellulose, 0.5 part of sodium dodecyl sulfate, 1 part of magnesium stearate and 2.5 parts of Opadry.

The invention has the following beneficial effects:

1. the invention provides a novel method for preparing rivaroxaban tablets by wet granulation, which extends the functions of a hot-melt extrusion granulator and provides a new idea for preparing the rivaroxaban tablets.

2. According to the invention, the liquid adding port is additionally arranged at the second station of the hot-melting extruder, and the hot-melting extruder is used for granulating, so that the variable parameters are less, the influence on the granules for granulating is less, the parameters are more controllable, and the content uniformity and the intra-batch and inter-batch difference of the dissolution behavior of the finished product tablet are smaller.

3. The water amount of the hot-melt extrusion granulator added with the lubricant is less than that of the conventional fluidized bed and wet granulator in the granulating process, the drying time is shorter in the drying process, the energy consumption is lower, and the cost is saved.

Drawings

FIG. 1 is the dissolution profile of example 1;

FIG. 2 is the dissolution profile of example 2;

FIG. 3 is the dissolution profile of example 3;

FIG. 4 is the dissolution profile of example 4;

FIG. 5 is the dissolution profile of example 5;

FIG. 6 is a dissolution profile of comparative example 1;

FIG. 7 is a dissolution profile of comparative example 2;

FIG. 8 is a dissolution profile of comparative example 3;

FIG. 9 is a dissolution profile of comparative example 4;

FIG. 10 is a dissolution profile of comparative example 5;

FIG. 11 is a comparison graph of dissolution curves of different preparation processes;

FIG. 12 is a schematic view of a hot melt extruder station set-up.

Detailed Description

The present invention will be further explained with reference to specific embodiments in order to make the technical means, the original characteristics, the achieved objects and the effects of the present invention easy to understand, but the following embodiments are only preferred embodiments of the present invention, and not all embodiments are possible. Based on the embodiments in the implementation, other embodiments obtained by those skilled in the art without any creative efforts belong to the protection scope of the present invention.

In the following examples, unless otherwise specified, all the procedures and equipment used were conventional procedures and equipment used was conventional equipment.

Examples 1 to 3

The formulations of examples 1-3 are shown in Table 1:

table 1.

Examples 1-3 were all prepared as follows:

(1) uniformly mixing the micronized rivaroxaban and other auxiliary materials according to an equivalent increasing principle to obtain an intercrystalline phase;

(2) adding the intergranular phase prepared in the step (1) into a feeding hopper of a hot-melt extruder, setting the rotating speed of a feeding screw to be 40rpm, and continuously feeding; meanwhile, continuously adding an adhesive for granulation (the adhesive is obtained by uniformly mixing the formula dosage and the components) through a peristaltic pump at a liquid adding port of the second station, and setting the rotating speed of the peristaltic pump to be 20 rpm; the prepared material is connected at a discharge port, and the aperture of a sieve mesh at the discharge port is 30 meshes, so that wet particles are obtained;

(3) drying the wet granules prepared in the step (2) in a boiling dryer, and controlling the water content to be 1% -3%;

(4) mixing the dried granules obtained in the step (3) with magnesium stearate to obtain intermediate granules;

(5) tabletting the intermediate particles obtained in the step (4) by using 6mm shallow pits, and controlling the hardness of the plain tablets to be 60-90N; and (3) performing film coating on the plain tablets, and controlling the weight increment of the coating to be 2.5-3.5%.

Example 4

Example 4 the formulation was the same as in example 1, except that the screw was fed at 30rpm and the peristaltic pump was 15rpm, all the other being the same.

Example 5

Example 5 the formulation was the same as in example 1, except that the screw was fed at 50rpm and the peristaltic pump was 25rpm, all the other being the same.

Comparative example 1

The composition of comparative example 1 is shown in table 2:

table 2.

Comparative example 1 was prepared according to the following procedure:

uniformly mixing all components of the intergranular phase in a wet granulator according to an equivalent increasing principle; preparing a soft material by a wet method by using an adhesive (the adhesive is obtained by uniformly mixing the components according to the formula dosage); carrying out 20-mesh wet finishing by using a granulator; drying the prepared particles in a boiling dryer, and controlling the water content to be 1-3%; mixing the dried granules with magnesium stearate to obtain intermediate granules; tabletting by using a 6mm shallow groove, and controlling the hardness of the plain tablets to be 60-90N; and (3) performing film coating on the plain tablets, and controlling the weight increment of the coating to be 2.5-3.5%.

Comparative example 2

The composition of comparative example 2 is shown in table 3:

table 3.

Comparative example 2 was prepared according to the following procedure:

premixing auxiliary materials in a fluidized bed, carrying out top spraying granulation on a suspension (obtained by uniformly mixing the components according to the formula amount) containing the main medicine in the fluidized bed, and controlling the water content of the final granules to be 1-3%; mixing the dried granules with magnesium stearate to obtain intermediate granules; tabletting by using a 6mm shallow groove, and controlling the hardness of the plain tablets to be 60-90N; and (3) performing film coating on the plain tablets, and controlling the weight increment of the coating to be 2.5-3.5%.

Comparative example 3

Comparative example 3 the formulation was the same as in example 1, except that the screw speed of the feed was 25rpm and the peristaltic pump speed was 10rpm, as in example 1, and the rest was the same.

Comparative example 4

Comparative example 4 the formulation was the same as in example 1, except that the screw speed was 55rpm and the peristaltic pump speed was 30rpm, and the rest were the same as in example 1.

Comparative example 5

Comparative example 5 the formulation is the same as comparative example 1, the intergranular phase is prepared into a soft material by using suspension in a wet granulator, after the soft material with moderate softness is prepared, the soft material is transferred to a granulator of a single screw extruder, the rotating speed of the screw is set, and continuous granulation is carried out; drying the prepared particles in a boiling dryer, and controlling the water content to be 1-3%; mixing the dried granules with magnesium stearate to obtain intermediate granules; tabletting by using a 6mm shallow groove, and controlling the hardness of the plain tablets to be 60-90N; and (3) performing film coating on the plain tablets, and controlling the weight increment of the coating to be 2.5-3.5%.

The result of the detection

And (3) content uniformity determination: 1 tablet prepared in each of examples 1 to 5 and comparative examples 1 to 5 was taken, placed in a 100ml measuring flask, added with an appropriate amount of a solvent [ acetonitrile-water (60: 40) ] and subjected to ultrasonic treatment for 10 minutes to dissolve rivaroxaban, cooled, diluted to the scale with the solvent, shaken well, filtered, and the subsequent filtrate was taken as a sample solution and the content was measured according to the specifications (CP2015 edition four parts general rule 0941).

The results of the content uniformity measurements are shown in tables 4-7:

table 4.

Table 5.

Table 6.

Table 7.

As can be seen from tables 4-7, the content average values of the finished products prepared in the examples and the comparative examples are close to 100%, and the content uniformity result is the best in the example 1 which adopts the finished product obtained by wet granulation of a hot melt extrusion granulator; the comparative example 1 adopts the finished product obtained by granulating by the traditional wet granulator, and the content uniformity result is the worst and is close to the limit; comparative example 2 the content uniformity of the finished product obtained by the fluidized bed top spray granulation process was centered; comparative examples 3-4 show that the rotational speed has an effect on the experimental results, and the rotational speed of the screw for feeding is 40rpm, and the rotational speed of the peristaltic pump is 20rpm is the best; comparative example 5 the uniformity of the content of the sample obtained using a single screw extrusion granulator was also not very good. In the embodiment 1, the hot-melting extrusion granulator and the process conditions thereof are adopted, so that the raw and auxiliary materials can be ensured to be in maximum contact with the wetting agent, the wetting is more thorough, and the intra-batch and inter-batch differences of the content uniformity of the prepared finished product are minimum, thereby being worthy of advocation.

And (3) determination of dissolution curve: the tablets prepared in examples 1 to 5 and comparative examples 1 to 5 were sampled at a rotation speed of 75 rpm according to the dissolution rate and release rate measurement method (second method of 0931 in the fourth general rule of the pharmacopoeia 2015 edition of China), using 900ml of acetate buffer (2.99 g of sodium acetate, 1000ml of water, 1.6ml of glacial acetic acid and 2.0g of sodium dodecyl sulfate, and adjusting the pH value to 4.5 +/-0.1 with sodium hydroxide or glacial acetic acid) as a dissolution medium, and the dissolution results were measured by the method at 5, 10, 15, 30, 45 and 60 minutes.

Example 1 dissolution data results are shown in table 8:

table 8.

Dissolution curves referring to fig. 1, it can be seen that the RSD difference between batches and within batches of example 1 is small at a single point.

Example 2 dissolution data results are shown in table 9:

table 9.

Dissolution curves referring to fig. 2, it can be seen that the RSD difference between batches and within batches of example 2 is small for the different single points.

Example 3 dissolution data results are shown in table 10:

table 10.

Dissolution curves referring to fig. 3, it can be seen that the RSD difference between and within the different single points of example 3 batches is small.

Example 4 dissolution data results are shown in table 11:

table 11.

Dissolution curves referring to fig. 4, it can be seen that the RSD difference between batches and within batches of example 4 is small for the different single points.

Example 5 dissolution data results are shown in table 12:

table 12.

Dissolution curves referring to fig. 5, it can be seen that the RSD difference between and within the different single points of example 5 batches is small.

Comparative example 1 dissolution data results are shown in table 13:

table 13.

Referring to fig. 6, it can be seen that the RSD of the different single points between batches and within the batch of comparative example 1 is very different.

Comparative example 2 dissolution data results are shown in table 14:

table 14.

Dissolution curves referring to fig. 7, it can be seen that the RSD difference between batches and within a single point of comparative example 2 is greater than that of comparative example 1.

Comparative example 3 dissolution data results are shown in table 15:

table 15.

Dissolution curves referring to fig. 8, it can be seen that the RSD difference between batches and within a single point of comparative example 3 is greater than that of comparative example 1.

Comparative example 4 dissolution data results are shown in table 16:

table 16.

Dissolution curves referring to fig. 9, it can be seen that the RSD difference between batches and within a single point of comparative example 4 is greater than that of comparative example 1.

Comparative example 5 dissolution data results are shown in table 17:

table 17.

Dissolution curves referring to fig. 10, it can be seen that the RSD differences were large for both the comparative example 5 batches and for the single points within the batch.

The batch dissolution data results are shown in table 18:

table 18.

Dissolution rate between batches	5	10	15	30	45	60
							Example 1	58.31	80.95	92.56	95.57	99.38	100.30
Comparative example 1	48.73	72.76	84.90	89.34	94.94	98.82
							Comparative example 2	50.23	71.26	82.94	87.69	94.82	99.70
Comparative example 5	45.61	69.46	80.83	86.57	92.53	95.27

Dissolution curves referring to fig. 11, it can be seen that the dissolution rate of example 1 is faster, the dissolution at 15min is already over 90%, the dissolution rate of comparative example 1 is comparable to that of comparative example 2, and the dissolution rate of comparative example 5 is the slowest, i.e. the dissolution rate is significantly increased by the process of granulation using a hot melt extruder.

The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.

Claims

1. A process for preparing rivaroxaban tablets comprising the steps of:

(1) uniformly mixing micronized rivaroxaban and auxiliary materials to obtain an intercrystalline phase, wherein the weight ratio of the micronized rivaroxaban to the auxiliary materials is 1:7.4-7.9, and the auxiliary materials comprise pregelatinized starch, microcrystalline cellulose, lactose monohydrate, crospovidone and hydroxypropyl cellulose;

(2) adding the intergranular phase prepared in the step (1) into a feeding hopper of a hot-melt extruder, and continuously feeding; meanwhile, continuously adding the adhesive at a liquid adding port of the second station; the prepared wet particles are connected at a discharge port; the screw speed of the feed is set to 30-50 rpm; adding the adhesive is adding through a peristaltic pump, the rotating speed of the peristaltic pump is set to be 15-25rpm, the adhesive comprises sodium dodecyl sulfate and water, the weight ratio of the sodium dodecyl sulfate to the water is 1:40, and the weight ratio of the adhesive to the micronized rivaroxaban is 2.05: 1;

(3) drying the wet granules prepared in the step (2) to obtain dry granules;

(4) mixing the dry particles obtained in the step (3) with external materials to obtain intermediate particles; the external addition is magnesium stearate, and the weight ratio of the external addition to the micronized rivaroxaban is 0.9-1.1: 10;

2. The method of claim 1, wherein the outlet in step (2) is fitted with a screen.

3. Rivaroxaban tablets prepared according to the process of any one of claims 1-2, characterized in that the tablets comprise the following ingredients in parts by weight: 10 parts of micronized rivaroxaban, 18-22.5 parts of pregelatinized starch, 18-22.5 parts of microcrystalline cellulose, 25-32 parts of lactose monohydrate, 3 parts of crospovidone, 3 parts of hydroxypropyl cellulose, 0.5 part of sodium dodecyl sulfate, 0.9-1.1 parts of magnesium stearate and 2-3 parts of Opadry.