CN113827575A

CN113827575A - Rivaroxaban tablet and preparation method thereof

Info

Publication number: CN113827575A
Application number: CN202111292051.2A
Authority: CN
Inventors: 杨勇; 赵颖
Original assignee: SHANGHAI PUKANG PHARMACEUTICAL CO Ltd
Current assignee: SHANGHAI PUKANG PHARMACEUTICAL CO Ltd
Priority date: 2021-11-02
Filing date: 2021-11-02
Publication date: 2021-12-24

Abstract

The invention relates to the field of pharmaceutical preparations, and in particular relates to a rivaroxaban tablet and a preparation method thereof. The composition can overcome the problem of uneven dispersion caused by easy agglomeration of raw materials of conventional rivaroxaban micronized raw materials during tabletting. The process for preparing the tablet by using the composition provided by the invention has fewer steps and simple required equipment, the manpower and fixed asset cost for preparing the rivaroxaban tablet can be greatly reduced, and meanwhile, after the composition is tabletted, the rivaroxaban content uniformity is better, the release rate is high, and the release degree is more stable.

Description

Rivaroxaban tablet and preparation method thereof

Technical Field

The invention relates to the field of pharmaceutical preparations, and in particular relates to a rivaroxaban tablet and a preparation method thereof.

Background

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

Approved indications are for elective hip closureThe medicine is mainly used for the clinical anticoagulation treatment of antithrombotic, and has the potential of preventing stroke and other clinical diseases of patients with atrial fibrillation. Rivaroxaban has the following structural formula:

rivaroxaban is an anticoagulant, has strict requirements on disintegration time limit and dissolution behavior of tablets, and also puts forward higher requirements on content uniformity of the tablets.

In the traditional granulation process, raw materials subjected to micronization treatment are uniformly dispersed in a solution, then suspension containing the raw materials is uniformly sprayed on the surfaces of common auxiliary materials through a fluidized bed and dried in the fluidized bed to obtain granules for tabletting, and magnesium stearate is added into a mixing device and is totally mixed to obtain the granules for tabletting. The process is complicated, firstly the problem of the dispersion uniformity of the micronized raw materials needs to be solved, simultaneously various parameters in the fluidized bed granulation process need to be controlled, and finally the dried granules are subjected to granule finishing and total mixing to obtain the granules for tabletting.

Chinese patent application CN107773548A discloses a rivaroxaban-containing solid composition, which comprises the following components in percentage by weight: 20-80% of micronized rivaroxaban-lactose monohydrate mixture, wherein the ratio of rivaroxaban to lactose monohydrate is 1: 2-1: 10, 20-80% of diluent, 1-10% of adhesive, 2-8% of disintegrant, 0.5-8% of surfactant and 0.5-5% of lubricant. The preparation method of the composition comprises the steps of mixing rivaroxaban and lactose monohydrate, carrying out jet milling to obtain micronized powder, and further preparing rivaroxaban tablets by using a wet granulation method.

Chinese patent application CN104887633A discloses a rivaroxaban tablet and a preparation method thereof, which is prepared by the following method: dispersing rivaroxaban in water solution containing sucrose, grinding in a nanometer bead mill, granulating the suspension on pharmaceutically acceptable adjuvants, drying, adding lubricant, mixing, and tabletting. The dissolution rate of rivaroxaban is improved by dispersing rivaroxaban in a specific solution and dispersing rivaroxaban by using specific equipment.

Chinese patent application CN106491514A discloses a process for the preparation of a solid pharmaceutical composition comprising rivaroxaban and one or more excipients, wherein micronized rivaroxaban is transferred to an orally administrable solid pharmaceutical composition by a process of wet centrifugal granulation. The preparation process of the rivaroxaban micro-powder and the auxiliary materials solves the problem of easy agglomeration through a wet centrifugal granulation method granulation preparation process.

Chinese patent application CN109419778A discloses a method for preparing rivaroxaban tablets by direct compression. The rivaroxaban bulk drug, the adhesive and the surfactant are subjected to air flow crushing, and then are mixed with other auxiliary materials uniformly and then are directly tabletted to obtain the rivaroxaban tablet.

Disclosure of Invention

The invention aims to provide a rivaroxaban composition with high content uniformity and good dissolution and a preparation method thereof aiming at the defects in the prior art.

The object of the present invention is achieved by the following technical means.

A rivaroxaban composition comprises rivaroxaban, mannitol and other pharmaceutically acceptable adjuvants;

wherein, the mannitol and other pharmaceutically acceptable auxiliary materials form a co-processed product by a coprecipitation method, a co-grinding method, a co-rolling method or a co-spray drying method.

Further, the rivaroxaban is rivaroxaban micro-powder.

Furthermore, the particle size of the rivaroxaban micro powder is that d90 is less than or equal to 15 microns.

Further, the other pharmaceutically acceptable auxiliary materials are selected from at least one of microcrystalline cellulose, colloidal silicon dioxide, mannitol, fructose and crospovidone.

Further, the mannitol and other pharmaceutically acceptable auxiliary materials form a co-processed product through a co-spray drying method.

Further, the co-processed matter is selected from one or more of mannitol microcrystalline crospovidone co-processed matter, mannitol-microcrystalline cellulose-carboxymethylcellulose-crospovidone compound and mannitol crospovidone co-processed matter-500;

further, the mannitol microcrystalline crospolyfruit silicon co-processed product is JRS Pharma

Further, the mannitol-microcrystalline cellulose-carboxymethylcellulose-crospovidone complex is NICHIRIN CHEMICAL INDUSTRIES Granfiller-D.

Further, the mannitol cross-polymerization copolymerized Maishan co-processed product-500 is SPI Pharma, Inc.,

500。

further, the weight part ratio of the rivaroxaban to the co-processed substance is 1: 10-20.

Further, the composition also comprises a lubricant, preferably magnesium stearate.

Further, the weight fraction ratio of rivaroxaban to lubricant is 5-20: 1.

the present invention also provides a method for preparing a tablet using the composition, comprising the steps of:

s1: uniformly mixing rivaroxaban and the co-processed matter, and simultaneously adding a lubricant if the lubricant exists, and uniformly mixing to obtain a mixture:

s2: and directly tabletting the mixture of S1 to obtain the rivaroxaban tablet.

Preferably, the present invention also provides another method for preparing the composition, comprising the steps of:

SS 1: uniformly mixing rivaroxaban and the co-processed substance in equal amount, and adding a lubricant if the lubricant exists, and uniformly mixing to obtain a mixture;

SS 2: and continuously adding the blend into the mixture obtained from SS1, physically mixing, uniformly mixing, and directly tabletting to obtain the rivaroxaban tablet.

Furthermore, the weight part ratio of the co-processed material in SS1 to the co-processed material in SS2 is 1: 9-19.

The invention has the advantages that:

1. the composition disclosed by the invention is simple in component, and overcomes the defects that the preparation process of rivaroxaban tablets is not easy to control and the steps are complex.

2. The invention unexpectedly discovers that the auxiliary material co-processed product based on mannitol and the micronized rivaroxaban raw material have good compatibility, while the auxiliary material co-processed product based on mannitol and the micronized rivaroxaban raw material have poor compatibility.

3. After the composition is tabletted, rivaroxaban is released at a high speed, and the release degree is more stable.

4. The process for preparing the tablet by using the composition provided by the invention has fewer steps and simple required equipment, and can greatly reduce the manpower and fixed asset cost for preparing the rivaroxaban tablet.

Detailed Description

Example 1

Formulation compositions of rivaroxaban were prepared according to the formulation of table 1:

table 1.

	Dosage (kg)
		Rivaroxaban (d90 ═ 13.8 μm)	0.5
Mannitol microcrystalline crosspolymer fruit silicon co-processed product	6
		Magnesium stearate	0.03
Total of	6.53

The preparation method comprises the following steps: firstly, rivaroxaban raw material, an equivalent amount of co-processed material auxiliary material and magnesium stearate are primarily mixed in a material bag, then the mixed powder and the rest co-processed material are transferred to an HLS-50 type laboratory hopper mixer, physical mixing is carried out under the conditions that the mixing frequency is set to be 8rpm and the mixing time is set to be 20 minutes, the content of an intermediate is measured, the hardness of an element piece is controlled to be 50-80N, and the intermediate particles are tabletted.

Example 2

Formulation compositions of rivaroxaban were prepared according to the formulation of table 2:

table 2.

The preparation method comprises the following steps: firstly, rivaroxaban raw material, an equivalent amount of co-processed material auxiliary material and magnesium stearate are primarily mixed in a material bag, then the mixed powder and the rest co-processed material are transferred to an HLS-50 type laboratory hopper mixer, physical mixing is carried out under the conditions that the mixing frequency is set to be 12rpm and the mixing time is set to be 12 minutes, the content of an intermediate is measured, the hardness of a tablet is controlled to be 50-80N, and the intermediate particles are tabletted.

Example 3

Formulation compositions of rivaroxaban were prepared according to the formulation of table 3:

table 3.

	Dosage (kg)
		Rivaroxaban (d90 ═ 12.6 μm)	0.3
Mannitol cross-polymerization copolymerization Maishan co-processed product 500	5.4
		Magnesium stearate	0.05
Total of	5.75

The preparation method comprises the following steps: firstly, rivaroxaban raw material, an equivalent amount of co-processed material auxiliary material and magnesium stearate are primarily mixed in a material bag, then the mixed powder and the rest co-processed material are transferred to an HLS-50 type laboratory hopper mixer, physical mixing is carried out under the conditions that the mixing frequency is set to be 15rpm and the mixing time is set to be 8 minutes, the content of an intermediate is measured, the hardness of an element piece is controlled to be 50-80N, and the intermediate particles are tabletted.

Comparative example 1

Formulation compositions of rivaroxaban were prepared according to the formulation of table 4:

table 4.

	Dosage (kg)
		Rivaroxaban (d90 ═ 14.1 μm)	0.5
Mannitol microcrystalline crosspolymer fruit silicon co-processed product	4.5
		Magnesium stearate	0.025
Total of	5.025

The preparation method comprises the following steps: firstly, rivaroxaban raw material, an equivalent amount of co-processed material auxiliary material and magnesium stearate are primarily mixed in a material bag, then the mixed powder and the rest co-processed material are transferred to an HLS-50 type laboratory hopper mixer, physical mixing is carried out under the conditions that the mixing frequency is set to be 15rpm and the mixing time is set to be 20 minutes, the content of an intermediate is measured, the hardness of a tablet is controlled to be 50-80N, and the intermediate particles are tabletted.

Comparative example 2

Formulation compositions of rivaroxaban were prepared according to the formulation of table 5:

TABLE 5

	Dosage (kg)
		Rivaroxaban (d 90)＝13.3μm)	0.4
Mannitol	2.4
		Microcrystalline cellulose	3.2
Cross-linked polyvidone	0.4
		Silicon dioxide	0.08
Fructose	0.38
		Magnesium stearate	0.024
Total up to	6.884

The preparation method comprises the following steps: firstly, rivaroxaban, magnesium stearate, crospovidone, silicon dioxide, fructose and other auxiliary materials are primarily mixed in a material bag, then the mixture is transferred into an HLS-50 type laboratory hopper mixer together with microcrystalline cellulose and mannitol, physical mixing is carried out under the conditions that the mixing frequency is set to be 15rpm and the mixing time is set to be 20 minutes, the content of an intermediate is measured, the hardness of a tablet is controlled to be 50-80N, and the intermediate granules are tabletted.

Comparative example 3

Formulation compositions of rivaroxaban were prepared according to the formulation of table 6:

TABLE 6

	Dosage (kg)
		Rivaroxaban (d90 ═ 14.7 μm)	0.8
Microcrystalline cellulose (PH101)	3.2
		Lactose (120 mesh)	2.24
Croscarmellose sodium (SD-711)	0.24
		Hydroxypropyl methylcellulose (E5 LV)	0.24
Sodium dodecyl sulfate	0.04
		Magnesium stearate	0.048
Purified water	6
		Total of	6.808

The preparation method comprises the following steps:

preparing an adhesive: firstly, preparing a solution of hydroxypropyl methylcellulose, dispersing micronized raw materials in the solution, and then dissolving lauryl sodium sulfate in the liquid medicine.

Fluid bed granulation: mixing croscarmellose sodium, microcrystalline cellulose and lactose in fluidized bed granulator model DPL5, top-spraying the above medicinal liquid, granulating, and continuously drying to control water content at 1-3%.

Total mixed pressing sheet: and (3) totally mixing the magnesium stearate and the intermediate granules, measuring the content of the intermediate, controlling the hardness to be 60-90N, and tabletting according to the content of the intermediate.

Comparative example 4

Formulation compositions of rivaroxaban were prepared according to the formulation of table 7:

table 7.

The preparation is as in example 2.

Comparative example 5

Formulation compositions of rivaroxaban were prepared according to the formulation of table 8:

table 8.

The preparation is as in example 2.

The result of the detection

And (3) content uniformity determination:

the content uniformity of the samples of examples 1 to 3 and comparative examples 1 to 5 was determined, respectively, and the results are shown in Table 9.

Table 9.

As can be seen from Table 9, the mixing uniformity of examples 1-3 was good, the content uniformity of the tablets was in accordance with the quality standards, and the content uniformity was good, and a mixing uniformity similar to or better than that of comparative example 3 could be obtained, indicating that by directly mixing rivaroxaban finely pulverized material with the co-processed product of the present invention, the material could be uniformly dispersed in the adjuvant without complicated process steps such as dispersion of finely pulverized material, fluidized bed granulation, etc.

Comparative example 1 a main drug and a compound auxiliary material were used in the following ratio 1:9, the content uniformity is poor, which indicates that the raw materials are not uniformly dispersed.

The comparative example 2 adopts the components similar to the mannitol microcrystalline polycrystallized fruit silicon co-processed product to be physically mixed with the micronized raw material, and the content uniformity result shows that the rivaroxaban micronized raw material and the conventional auxiliary materials are physically mixed conventionally, so that the effect of uniform mixing is difficult to achieve.

Comparative example 3 the micronized raw materials are uniformly dispersed in the adhesive and granulated by the traditional fluidized bed top spray granulation method, the content uniformity of the prepared finished preparation is better, but the process steps are more, the parameter control points of different procedures are more, and the requirements on equipment and personnel are high.

Determination of disintegration time limit:

the measurement was carried out by disintegration time limit test (0921, the four general guidelines in the 2020 edition of Chinese pharmacopoeia), and the measurement results are shown in Table 10.

Watch 10

Example 1

Example 2

Example 3

Comparative example 1

Comparative example 2

Comparative example 3

Comparative example 4

Comparative example 5

Disintegration time limit

3’32”

3’20”

3’25”

4’47”

4’28”

4’08”

6’13”

7’02”

As can be seen from Table 10, the disintegration time of examples 1 to 3 was remarkably superior to that of comparative examples 1 to 5, and the formulation composition had more excellent disintegration effect. Comparative example 1 the same excipients as in example 1 were also selected, but the best disintegration effect was not achieved due to the smaller proportion; the auxiliary materials with the compositions similar to those of the auxiliary materials in the embodiment 1 are selected in the comparative example 2, but the best disintegration effect of the compounded auxiliary materials can not be achieved; comparative example 3 the sample prepared by the conventional process has slightly poor disintegration effect compared with the examples; in contrast, comparative examples 4 and 5, which also used co-processed adjuvants, did not achieve a good disintegration effect.

And (3) brittle degree determination:

the friability of the tablets was measured by the tablet friability test method (0921, the four-part general rule of the 2020 edition of Chinese pharmacopoeia), and the measurement results are shown in Table 11.

TABLE 11

	Example 1	Example 2	Example 3	Comparative example 1	Comparative example 2	Comparative example 3	Comparative example 4	Comparative example 5
									Friability%	0.02	0.03	0.02	0.16	0.32	0.11	0.08	0.09

As can be seen from Table 11, the friability of examples 1-3 was significantly lower than that of examples 1-5, and the formulation composition had superior mechanical strength of the core. In contrast, comparative example 1 failed to obtain a more excellent friability due to an inappropriate ratio to the major component; in the comparative example 2, the tablet is prepared by directly mixing conventional auxiliary materials, so that the tablet core has the worst friability; comparative example 3 granulation using conventional fluid bed wet granulation also achieved good friability, but slightly worse than in the examples; and in the proportion 4 and the proportion 5, the compound auxiliary materials are also selected for direct mixing and tabletting, but the friability is relatively poor.

And (3) determination of dissolution curve:

according to the determination method of dissolution rate and release rate (second method of 0931 of the four general rules of the 2020 edition of Chinese pharmacopoeia), 900ml of 0.1M hydrochloric acid (containing 0.1% SDS) is used as dissolution medium, the rotation speed is 75 rpm, samples are taken at 5, 10, 15, 30, 45 and 60 minutes according to the method operation, and the dissolution behavior of the samples is determined. The dissolution behavior was determined for the samples of examples 1-3 and comparative examples 1-5, respectively, and the results are shown in Table 12.

TABLE 12

It can be seen from Table 12 that examples 1-3 all achieved faster dissolution behavior and smaller standard deviation at different time points, while comparative example 3 achieved faster dissolution behavior but the standard deviation at different time points was slightly worse than in the examples. In contrast, comparative example 1, in which the raw material was not completely dispersed, had poor dissolution rate and standard deviation in dissolution behavior compared to those of the completely dispersed comparative example; in comparative example 2, the intermediate is prepared by directly mixing the raw materials with the conventional auxiliary materials, and the raw materials are not well dispersed, so that the dissolution rate is reduced finely, and the batch difference is large. Comparative examples 4 and 5 the tablet core did not achieve a faster disintegration time and also faster dissolution behaviour as in examples 1-3 due to the failure to select suitable co-processed excipients.

Finally, it should be noted that the above-mentioned contents are only used for illustrating the technical solutions of the present invention, and not for limiting the protection scope of the present invention, and that the simple modifications or equivalent substitutions of the technical solutions of the present invention by those of ordinary skill in the art can be made without departing from the spirit and scope of the technical solutions of the present invention.

Claims

1. A rivaroxaban composition comprises rivaroxaban, mannitol and other pharmaceutically acceptable adjuvants;

2. The composition of claim 1, wherein the rivaroxaban is rivaroxaban micropowder.

3. The composition according to claim 1, wherein the other pharmaceutically acceptable excipients are selected from at least one of microcrystalline cellulose, colloidal silicon dioxide, mannitol, fructose, crospovidone.

4. The composition of claim 1, wherein the mannitol and other pharmaceutically acceptable excipients form a co-processed product by co-spray drying.

5. The composition according to any one of claims 1 to 4, wherein the co-treatment is selected from one or more of mannitol microcrystalline crospovidone co-treatment, mannitol microcrystalline cellulose carboxymethylcellulose crospovidone complex, and mannitol crospovidone co-treatment-500.

6. The composition according to any one of claims 1 to 4, wherein the ratio of rivaroxaban to co-treatment in parts by weight is 1: 10-20.

7. The composition of any one of claims 1 to 4, further comprising a lubricant.

8. The composition according to any one of claims 7, wherein the weight fraction ratio of rivaroxaban to lubricant is 5-20: 1.

9. a process for preparing a tablet using the composition of any one of claims 1 to 8, comprising the steps of:

s2: and directly tabletting the mixture of S1 to obtain the rivaroxaban tablet.

10. A process for the preparation of a composition as claimed in any one of claims 1 to 8, comprising the steps of:

SS 1: uniformly mixing rivaroxaban and the co-processed substance in equal amount, and simultaneously adding a lubricant if the lubricant exists, and uniformly mixing to obtain a mixture;

SS 2: continuously adding the blend into the mixture obtained from SS1, physically mixing, uniformly mixing, and directly tabletting to obtain rivaroxaban tablets;

the weight part ratio of the co-processed material in SS1 to the co-processed material in SS2 is 1: 9-19.