CN111053753A - Rivaroxaban pharmaceutical composition and preparation method thereof - Google Patents

Rivaroxaban pharmaceutical composition and preparation method thereof Download PDF

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Publication number
CN111053753A
CN111053753A CN201811203606.XA CN201811203606A CN111053753A CN 111053753 A CN111053753 A CN 111053753A CN 201811203606 A CN201811203606 A CN 201811203606A CN 111053753 A CN111053753 A CN 111053753A
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rivaroxaban
pharmaceutical composition
lubricant
prepared
spraying
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龙文
张伟明
陶安进
袁建成
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Hybio Pharmaceutical Co Ltd
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Hybio Pharmaceutical Co Ltd
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Priority to PCT/CN2019/092744 priority patent/WO2020078034A1/en
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    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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Abstract

The invention belongs to the field of pharmaceutical preparations, and discloses a rivaroxaban pharmaceutical composition and a preparation method thereof. The rivaroxaban pharmaceutical composition is prepared from rivaroxaban, polyethylene glycol, an adhesive, a filler, a disintegrant, a surfactant and a lubricant in a certain ratio, wherein the total weight of the components is 100 wt%. The rivaroxaban tablet is prepared by crushing rivaroxaban, dispersing the crushed rivaroxaban in a water solution of polyethylene glycol to prepare a rivaroxaban suspension dispersion liquid, spraying the rivaroxaban suspension dispersion liquid to a mixed material of other components except a lubricant for granulation, drying the mixed material, and mixing the dried rivaroxaban suspension dispersion liquid with the lubricant. The prepared granules have good fluidity and compressibility, the granulation end point is easy to control, and the granules do not have large agglomeration. The prepared granules are further mixed with a lubricant and tabletted to obtain the rivaroxaban tablets. Experiments show that the rivaroxaban tablets prepared by the method have good external dissolution, and the dissolution rate can reach more than 80% in 30 minutes.

Description

Rivaroxaban pharmaceutical composition and preparation method thereof
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a rivaroxaban pharmaceutical composition and a preparation method thereof.
Background
Rivaroxaban was jointly developed by bayer and qiangsheng corporation, and EMA was approved for marketing in 2008 at 9, with specifications of 2.5mg, 10mg, 15mg, and 20 mg. Was approved for sale in china in 2010. FDA approval was obtained in the united states in 7 months of 2011 under the trade designation "xarotelto", with specifications of 10mg, 15mg, and 20mg, approved for use in knee or hip replacement surgery patients to prevent deep vein thrombosis and pulmonary embolism; 2011, 11 months, is approved for the prevention of stroke of patients with non-valvular atrial fibrillation; FDA approval for an expanded indication at 11 months 2012, new for the treatment of Deep Vein Thrombosis (DVT) or Pulmonary Embolism (PE) and for the prevention of DVT and PE recurrence.
As known from the drug evaluation report of EMA to bexastal by the european medicines agency, the BCS of rivaroxaban is classified as a class II (low solubility, high permeability) drug, and the solubility of the drug substance and the dissolution of the formulation will be the limiting factors for the absorption of the drug in vivo.
Chinese patent CN104721156A discloses a rivaroxaban-containing tablet, which is prepared by mixing micronized rivaroxaban and hydrophilic excipients and then pulverizing to improve dissolution of rivaroxaban. However, this pulverization method has a limited improvement in dissolution.
Patent CN200680045548.1 discloses that rivaroxaban in amorphous state and crystal form II is prepared by a dissolution method, a melting method and a melt extrusion method, and then is applied to an oral solid pharmaceutical preparation to improve the dissolution rate and bioavailability. However, the used amorphous or metastable rivaroxaban is influenced by the stability problem, and the solubility of the rivaroxaban bulk drug is poor, so that a large amount of solvent is needed by adopting a dissolution method, and the industrial production is difficult.
Patent CN104055743B discloses that rivaroxaban tablets are prepared by a powder direct compression method, but rivaroxaban is an insoluble drug, and the powder direct compression method is not beneficial to improving the dissolution of the insoluble drug.
In the original patent CN1886120B, the raw material is micronized, and the micronized active ingredients are dispersed in a granulating solution prepared from a hydrophilic adhesive, a solvent and a wetting agent, and then the drug-containing granules are prepared by wet granulation through a fluidized bed, and then the drug-containing granules are mixed and tabletted. And adding micronized rivaroxaban into the granulating solution to prepare rivaroxaban suspension so as to perform hydrophilization treatment on rivaroxaban. However, the hydrophilic adhesive needs a large amount of solvent treatment when added into the granulating solution, has high viscosity, long time for preparing uniform rivaroxaban suspension, relatively long time for granulating the material after spraying, and great technical difficulty for controlling the granulating end point, such as easy agglomeration of the granules.
Disclosure of Invention
In view of the above, the present invention aims to provide a rivaroxaban pharmaceutical composition with high drug dissolution rate, aiming at the defects of the prior art.
In order to realize the purpose of the invention, the invention adopts the following technical scheme:
a rivaroxaban pharmaceutical composition comprises the following components:
Figure BDA0001830646310000021
the sum of all the components is 100 wt%.
Preferably, the weight ratio of the rivaroxaban to the polyethylene glycol in the rivaroxaban pharmaceutical composition is 1: 0.5-1: 5. More preferably 1:1 to 1: 2.5.
Preferably, the molecular weight of the polyethylene glycol is 1000-10000. More preferably one or both of polyethylene glycol 4000 and polyethylene glycol 6000.
Preferably, the filler is selected from one or more of lactose, microcrystalline cellulose, starch and mannitol. In some embodiments, the filler is microcrystalline cellulose PH 101. In some embodiments, the filler is a mixture of corn starch, lactose, and microcrystalline cellulose PH 101. In some embodiments, the filler is a mixture of corn starch and microcrystalline cellulose PH 101.
Preferably, the adhesive is one or more selected from polyvinylpyrrolidone, sodium carboxymethylcellulose, hydroxypropyl cellulose, polyvinyl alcohol and hypromellose. In some embodiments, the binder is polyvinylpyrrolidone K29/32. In some embodiments, the binder is sodium carboxymethyl cellulose. In some embodiments, the binder is hypromellose (6 cP).
Preferably, the disintegrating agent is selected from one or more of sodium carboxymethyl starch, croscarmellose sodium, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone and pregelatinized starch. In some embodiments, the disintegrant is crosslinked carboxymethyl cellulose. In some embodiments, the disintegrant is crosslinked polyvinylpyrrolidone.
Preferably, the lubricant is selected from one or more of talcum powder, magnesium stearate, sodium stearyl fumarate and colloidal silicon dioxide. In some embodiments, the lubricant is magnesium stearate.
Preferably, the surfactant is one or two selected from poloxamer and sodium lauryl sulfate. In some embodiments, the surfactant is sodium lauryl sulfate. In some embodiments, no surfactant may be added.
The pharmaceutical composition has a preparation size range of 2.5 mg-20 mg, such as 2.5mg or 10mg or 15mg or 20 mg.
The invention also provides a preparation method of the rivaroxaban pharmaceutical composition, which comprises the steps of crushing rivaroxaban, dispersing the crushed rivaroxaban in a water solution of polyethylene glycol to prepare rivaroxaban suspension dispersion, spraying the rivaroxaban suspension dispersion to a mixed material of other components except a lubricant, granulating, drying, grading, and mixing with the lubricant.
Wherein the pulverization is air jet pulverization.
Preferably, the rivaroxaban is crushed to D90Less than 50 microns, D50Less than 25 microns. More preferably rivaroxaban to D90Less than 30 microns, D50Less than 15 microns.
Preferably, the solid content of the rivaroxaban suspension dispersion liquid is 5 wt% -12 wt%.
Further, in the preparation method of the rivaroxaban pharmaceutical composition, the granulation is specifically to mix and transfer other components except the lubricant into a mixing granulator, and uniformly spray the rivaroxaban suspension dispersion liquid into the mixed materials in the mixing granulator.
Wherein the other components except the lubricant include a binder, a filler, a disintegrant, and a surfactant. In some embodiments, the surfactant may not be added. In some embodiments, the disintegrant may be added in an additive manner, i.e., the disintegrant is not included in the other components except the lubricant, and is added when mixed with the lubricant after spray granulation and drying.
Preferably, the mixing granulator is a fluid bed granulator or a high shear mixing granulator, more preferably a fluid bed granulator.
Preferably, the spraying is top spraying or bottom spraying, namely the rivaroxaban suspension dispersion is uniformly sprayed in the mixed materials in the mixing granulator by adopting the top spraying method or the bottom spraying method.
Preferably, the temperature of the mixed material is controlled below 50 ℃ in the granulating process.
Preferably, in the preparation method of the rivaroxaban pharmaceutical composition, the drying after granulation is carried out until the water content of the granules is 1.5-2.5%.
The invention also provides a rivaroxaban tablet, which comprises the rivaroxaban pharmaceutical composition and a water-soluble film coat.
In some embodiments, the water-soluble film coat is opadry
Figure BDA0001830646310000041
II, providing a formulated powder mixture by Carlekang. The weight of the film coating is increased by 2.0-4.0%.
According to the technical scheme, the invention provides a rivaroxaban pharmaceutical composition and a preparation method thereof. The rivaroxaban pharmaceutical composition comprises 4-30 wt% of rivaroxaban, 2-60 wt% of polyethylene glycol, 2-10 wt% of adhesive, 5-85 wt% of filler, 2-10 wt% of disintegrant, 0-1 wt% of surfactant and 0.1-3 wt% of lubricant, wherein the total weight of the components is 100 wt%. The invention adopts the solid dispersion technology to disperse the bulk drug which is crushed by airflow in the polyethylene glycol carrier solution. The polyethylene glycol is a hydrophilic polymer, has low viscosity and good water solubility, and the rivaroxaban polyethylene glycol dispersion solution requires relatively less solvent for preparation, is simple to prepare and requires short time. In addition, the required binding agent is mixed with the filling agent, the disintegrating agent and a small amount of surfactant which is present according to requirements in a fluidized bed or a high-shear granulator in a powder form, and then the rivaroxaban polyethylene glycol dispersion liquid is uniformly sprayed in the mixed motion state material for granulation and drying. The prepared granules have good fluidity and compressibility, the granulation end point is easy to control, and the granules do not have large agglomeration. The prepared granules are further mixed with a lubricant and tabletted to obtain rivaroxaban tablets, and the rivaroxaban tablets can be further coated. The rivaroxaban tablets prepared by the method can achieve good in vitro dissolution without adding a surfactant or adding a small amount of surfactant in the components. Experiments show that the rivaroxaban tablets prepared by the invention have the advantages of excellent compressibility, tablet weight stability, small friability, good in-vitro dissolution, and the dissolution rate in 30 minutes can reach more than 80%.
Detailed Description
The invention discloses a rivaroxaban pharmaceutical composition and a preparation method thereof. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the methods and products of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention without departing from the spirit and scope of the invention.
In order to further understand the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Unless otherwise specified, the reagents involved in the examples of the present invention are all commercially available products, and all of them are commercially available.
Example 1
The formula is as follows:
components Proportion (wt%)
Rivaroxaban 11.8
Polyethylene glycol 4000 14.1
Polyvinylpyrrolidone K29/32 5.8
Microcrystalline cellulose PH101 63.2
Croscarmellose sodium 4.2
Sodium dodecyl sulfate 0.3
Magnesium stearate 0.6
Total up to 100
The preparation method comprises the following steps:
1: pretreatment of materials: rivaroxaban jet mill grinding to D90Less than 30 microns, D50Less than 15 microns.
2: adding the formula amount of the crushed rivaroxaban and polyethylene glycol 4000 into pure water to prepare a suspension dispersion liquid, and stirring the rivaroxaban suspension dispersion liquid all the time after the rivaroxaban suspension dispersion liquid is prepared.
3: transferring the microcrystalline cellulose PH101, the polyvinylpyrrolidone K29/32, the croscarmellose sodium and the sodium dodecyl sulfate in the prescription amount into a fluidized bed, uniformly spraying rivaroxaban suspension dispersion liquid into a mixed material in a fluidized bed state by adopting a top spraying method, controlling the temperature of the material granulated by the fluidized bed to be below 50 ℃, and stopping drying when the water content of dried particles is 1.5-2.5%.
4: and (4) screening the dried granules prepared in the step (3) by a 40-mesh screen, drying, grading, adding magnesium stearate according to the prescription ratio, and mixing to obtain the total mixture.
5: and further tabletting the total mixture to obtain rivaroxaban tablets.
6: further coating rivaroxaban tablets with a film, wherein the film coating powder adopts Opadry
Figure BDA0001830646310000061
II, increasing the weight of the coating by 2-4%.
Example 2
The formula is as follows:
components Proportion (wt%)
Rivaroxaban 11.8
Polyethylene glycol 6000 17.6
Sodium carboxymethylcellulose 3.5
Corn starch 15.9
Lactose 11.8
Microcrystalline cellulose PH101 35.3
Crosslinked polyvinylpyrrolidone 3.5
Magnesium stearate 0.6
Total up to 100
The preparation method comprises the following steps:
1: pretreatment of materials: rivaroxaban jet mill grinding to D90Less than 30 microns, D50Less than 15 microns.
2: adding the formula amount of the crushed rivaroxaban and polyethylene glycol 6000 into pure water to prepare a suspension dispersion liquid, and stirring the rivaroxaban suspension dispersion liquid all the time after the rivaroxaban suspension dispersion liquid is prepared.
3: transferring the microcrystalline cellulose PH101, lactose, corn starch, sodium carboxymethylcellulose and crospolyvinylpyrrolidone with the prescription amount into a fluidized bed, uniformly spraying rivaroxaban suspension dispersion liquid into a mixed material in a fluidized bed state by adopting a top spraying method, controlling the temperature of the material granulated by the fluidized bed to be below 50 ℃, and stopping drying when the water content of dried particles is 1.5-2.5%.
4: and (4) screening the dried granules prepared in the step (3) by a 40-mesh screen, drying, grading, adding magnesium stearate according to the prescription ratio, and mixing to obtain the total mixture.
5: and further tabletting the total mixture to obtain rivaroxaban tablets.
6: further coating rivaroxaban tablets with a film, wherein the film coating powder adopts Opadry
Figure BDA0001830646310000071
II, increasing the weight of the coating by 2-4%.
Example 3
The formula is as follows:
components Proportion (wt%)
Rivaroxaban 23.5
Polyethylene glycol 6000 23.5
Hydroxypropyl methylcellulose (6cP) 3.5
Corn starch 12.1
Microcrystalline cellulose PH101 33.0
Croscarmellose sodium 3.5
Sodium dodecyl sulfate 0.2
Magnesium stearate 0.7
Total up to 100
The preparation method comprises the following steps:
1: pretreatment of materials: rivaroxaban jet mill grinding to D90Less than 30 microns, D50Less than 15 microns.
2: adding the formula amount of the crushed rivaroxaban and polyethylene glycol 6000 into pure water to prepare a suspension dispersion liquid, and stirring the rivaroxaban suspension dispersion liquid all the time after the rivaroxaban suspension dispersion liquid is prepared.
3: transferring the microcrystalline cellulose PH101, the corn starch, the hydroxypropyl methylcellulose (6cP), the croscarmellose sodium and the sodium dodecyl sulfate with the prescription amount into a fluidized bed, uniformly spraying rivaroxaban suspension dispersion liquid into a mixed material in a fluidized bed state by adopting a top spraying method, controlling the temperature of the material granulated by the fluidized bed to be below 50 ℃, and stopping drying when the water content of dried particles is 1.5-2.5%.
4: and (4) screening the dried granules prepared in the step (3) by a 40-mesh screen, drying, grading, adding magnesium stearate according to the prescription ratio, and mixing to obtain the total mixture.
5: and further tabletting the total mixture to obtain rivaroxaban tablets.
6: further coating rivaroxaban tablets with a film, wherein the film coating powder adopts Opadry
Figure BDA0001830646310000082
II, increasing the weight of the coating by 2-4%.
Comparative example 1
The formula is as follows:
components Proportion (wt%)
Rivaroxaban 11.8
Sodium carboxymethylcellulose 3.5
Corn starch 15.9
Lactose 11.8
Microcrystalline cellulose PH102 52.9
Crosslinked polyvinylpyrrolidone 3.5
Magnesium stearate 0.6
Total up to 100
The preparation method comprises the following steps of: micronizing rivaroxaban (D)90Less than 30 microns, D50Less than 15 microns), sodium carboxymethylcellulose, corn starch, lactose, microcrystalline cellulose PH102 and crospolyvinylpyrrolidone are put into a mixing hopper for preliminary mixing, the mixing time is 10min, and the mixing rotating speed is 15 rpm. And after primary mixing, adding magnesium stearate for total mixing, wherein the total mixing time is 5min, and the mixing rotating speed is 15 rpm. And tabletting the total mixture to obtain rivaroxaban tablets. Further coating rivaroxaban tablets with a film, wherein the film coating powder adopts Opadry
Figure BDA0001830646310000083
II, increasing the weight of the coating by 2-4%.
Comparative example 2
The formula is as follows:
Figure BDA0001830646310000081
Figure BDA0001830646310000091
the preparation method comprises the following steps:
1: pretreatment of materials: rivaroxaban jet mill grinding to D90Less than 30 microns, D50Less than 15 microns.
2: adding the formula amount of the crushed rivaroxaban and polyvinylpyrrolidone K29/32 into pure water to prepare a suspension dispersion liquid, and stirring the rivaroxaban suspension dispersion liquid all the time after preparation.
3: transferring the formula amount of microcrystalline cellulose PH101, croscarmellose sodium and lactose into a fluidized bed, uniformly spraying rivaroxaban suspension dispersion liquid into a mixed material in a fluidized bed state by adopting a top spraying method, controlling the temperature of the material granulated by the fluidized bed to be below 50 ℃, and stopping drying when the water content of dried particles is 1.5-2.5%.
4: and (4) screening the dried granules prepared in the step (3) by a 40-mesh screen, drying, grading, adding magnesium stearate according to the prescription ratio, and mixing to obtain the total mixture.
5: and further tabletting the total mixture to obtain rivaroxaban tablets.
6: further coating rivaroxaban tablets with a film, wherein the film coating powder adopts Opadry
Figure BDA0001830646310000093
II, increasing the weight of the coating by 2-4%.
Comparative example 3
The formula is as follows:
Figure BDA0001830646310000092
Figure BDA0001830646310000101
the preparation method comprises the following steps:
1: pretreatment of materials: rivaroxaban is crushed to D through a jet mill90About 106.1 microns, D50About 30.3 microns.
2: the crushed raw material medicine and polyethylene glycol 4000 with the prescription amount are added into pure water to prepare suspension dispersion liquid, and the rivaroxaban suspension dispersion liquid is always in a stirring state after being prepared.
3: the prescribed amounts of polyvinylpyrrolidone K29/32, microcrystalline cellulose PH101, croscarmellose sodium and sodium lauryl sulfate were transferred to a fluidized bed, and rivaroxaban suspension was sprayed uniformly onto the fluidized bed mixture by top-spraying. The temperature of the material granulated by the fluidized bed is controlled below 50 ℃; and stopping drying when the water content of the dried particles is 1.5-2.5%.
4: and (4) screening the dried granules prepared in the step (3) by a 40-mesh screen, drying, grading, adding magnesium stearate according to the prescription ratio, and mixing to obtain the total mixture.
5: and further tabletting the total mixture to obtain rivaroxaban tablets.
6: further coating rivaroxaban tablets with a film, wherein the film coating powder adopts Opadry
Figure BDA0001830646310000102
II, increasing the weight of the coating by 2-4%.
Comparative example 4
The formula is as follows:
components Proportion (wt%)
Rivaroxaban 11.8
Polyethylene glycol 6000 17.6
Sodium carboxymethylcellulose 3.5
Corn starch 15.9
Lactose 12.8
Microcrystalline cellulose PH101 36.3
Crosslinked polyvinylpyrrolidone 1.5
Magnesium stearate 0.6
Total up to 100
The preparation method comprises the following steps:
1: pretreatment of materials: rivaroxaban jet mill grinding to D90Less than 30 microns, D50Less than 15 microns.
2: adding the formula amount of the crushed rivaroxaban and polyethylene glycol 6000 into pure water to prepare a suspension dispersion liquid, and stirring the rivaroxaban suspension dispersion liquid all the time after the rivaroxaban suspension dispersion liquid is prepared.
3: transferring the microcrystalline cellulose PH101, lactose, corn starch, sodium carboxymethylcellulose and crospolyvinylpyrrolidone with the prescription amount into a fluidized bed, uniformly spraying rivaroxaban suspension dispersion liquid into a mixed material in a fluidized bed state by adopting a top spraying method, controlling the temperature of the material granulated by the fluidized bed to be below 50 ℃, and stopping drying when the water content of dried particles is 1.5-2.5%.
4: and (4) screening the dried granules prepared in the step (3) by a 40-mesh screen, drying, grading, adding magnesium stearate according to the prescription ratio, and mixing to obtain the total mixture.
5: and further tabletting the total mixture to obtain rivaroxaban tablets.
6: further coating rivaroxaban tablets with a film, wherein the film coating powder adopts Opadry
Figure BDA0001830646310000111
II, increasing the weight of the coating by 2-4%.
Comparative example 5
The formula is as follows:
components Proportion (wt%)
Rivaroxaban 23.5
Polyethylene glycol 6000 23.5
Hydroxypropyl methylcellulose (6cP) 3.5
Corn starch 12.1
Microcrystalline cellulose PH101 30.2
Croscarmellose sodium 3.5
Sodium dodecyl sulfate 0.2
Magnesium stearate 3.5
Total up to 100
The preparation method comprises the following steps:
1: pretreatment of materials: rivaroxaban jet mill grinding to D90Less than 30 microns, D50Less than 15 microns.
2: adding the formula amount of the crushed rivaroxaban and polyethylene glycol 6000 into pure water to prepare a suspension dispersion liquid, and stirring the rivaroxaban suspension dispersion liquid all the time after the rivaroxaban suspension dispersion liquid is prepared.
3: transferring the microcrystalline cellulose PH101, the corn starch, the hydroxypropyl methylcellulose (6cP), the croscarmellose sodium and the sodium dodecyl sulfate with the prescription amount into a fluidized bed, uniformly spraying rivaroxaban suspension dispersion liquid into a mixed material in a fluidized bed state by adopting a top spraying method, controlling the temperature of the material granulated by the fluidized bed to be below 50 ℃, and stopping drying when the water content of dried particles is 1.5-2.5%.
4: and (4) screening the dried granules prepared in the step (3) by a 40-mesh screen, drying, grading, adding magnesium stearate according to the prescription ratio, and mixing to obtain the total mixture.
5: and further tabletting the total mixture to obtain rivaroxaban tablets.
6: further coating rivaroxaban tablets with a film, wherein the film coating powder adopts Opadry
Figure BDA0001830646310000122
II, increasing the weight of the coating by 2-4%.
Test example:
1. investigation of tablet quality
Rivaroxaban tablets prepared in the above examples and comparative examples were examined according to the following methods and the results are shown in table 1. Wherein, the average hardness of the plain film is examined: average hardness of continuous 10 plain tablets pressed by a tablet press under the same pressing force; slice weight difference investigation method: adopting a check method of 0101 tablet weight difference of general rules of four preparations in Chinese pharmacopoeia 2015 edition; friability examination method: the friability test method of four 0923 tablets in chinese pharmacopoeia 2015 edition was adopted.
TABLE 1 test results of tableting
Figure BDA0001830646310000121
Figure BDA0001830646310000131
The results show that the plain sheet samples prepared in examples 1 to 3 of the present invention all have an average hardness of 55N or more, are stable in sheet weight, and have good friability. In contrast, the average hardness of the plain sheet samples prepared in comparative examples 1 to 5 is below 55N. In addition, the difference between the sheet weights of comparative example 1 and comparative example 2 is relatively large. The results show that the samples of examples 1-3 of the invention have better compressibility, more stable tablet weight and smaller friability compared with other comparative samples.
2. In vitro dissolution study
Taking 6 samples of examples 1-3 and comparative examples 1-5, respectively, adopting a dissolution rate determination method II: in vitro dissolution tests were performed by paddle method (75rpm) in 900mL 0.2% SDS in acetate buffer pH 4.5 and samples were examined for dissolution at 15 min, 30 min, 45 min, and 60 min, and the results are shown in Table 2.
Table 2 in vitro dissolution test results
Time of day 15 minutes 30 minutes 45 minutes 60 minutes
Example 1 75.7％ 87.3％ 93.0％ 96.2％
Example 2 79.6％ 93.5％ 98.2％ 99.8％
Example 3 77.8％ 90.4％ 95.1％ 97.6％
Comparative example 1 69.7％ 79.8％ 88.7％ 92.8％
Comparative example 2 63.5％ 78.3％ 89.6％ 92.3％
Comparative example 3 43.3％ 62.8％ 73.6％ 85.1％
Comparative example 4 58.6％ 72.1％ 83.8％ 90.2％
Comparative example 5 67.3％ 78.2％ 86.9％ 93.6％
The results in Table 2 show that the dissolution rates of the samples prepared in the embodiments 1 to 3 of the invention are all over 80% in 30 minutes and are all close to the dissolution platform. Whereas the dissolution rates of the samples prepared in the comparative examples 1 to 5 are all below 80% in 30 minutes and far from the dissolution platform.
The sample prepared in comparative example 1 using the powder direct compression process was dissolved out less than 80% in vitro for 30 minutes, and the tablet weight stability of the sample in comparative example 1 was poor. Comparative example 2 polyvinylpyrrolidone K29/32 and micronized drug substance were used to prepare a suspension solution, and the sample was prepared by fluid bed granulation, and the dissolution time of the sample was not as high as 80% even after 30 minutes. Comparative example 3 adopts bulk drug with particle size exceeding D90Less than 50 microns, D50Particle size range of less than 25 microns, with coarser particle size, D90About 106.1 microns, D50About 30.3 microns. The formula sample prepared by using the rivaroxaban raw material with the coarser particle size has the advantages that even if the dosage of polyethylene glycol reaches 60.2%, the dosage of disintegrant reaches 10.0%, the dosage of surfactant lauryl sodium sulfate reaches 1.0%, the 30-minute dissolution rate is only 62.8%, and the compressibility and friability of comparative example 3 are poor. Comparative example 4 samples using rivaroxaban starting material in the particle size range but with only 1.5% disintegrant were only 72.1% dissolved in 30 minutes. Example 3 as with the comparative example 5 process, the lubricant usage of comparative example 5 was only over 3% on the recipe, up to 3.5%. The dissolution of comparative example 5 was slower than that of example 3, and the 30 minute dissolution was only 78.2%.
In conclusion, the sample prepared by the invention has the advantages of excellent compressibility, tablet weight stability, small friability and good in-vitro dissolution, and the dissolution rate in 30 minutes can reach more than 80%.
The above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.

Claims (10)

1. A rivaroxaban pharmaceutical composition comprises the following components:
Figure FDA0001830646300000011
2. the rivaroxaban pharmaceutical composition according to claim 1, wherein the weight ratio of rivaroxaban to polyethylene glycol is 1: 0.5-1: 5.
3. Rivaroxaban pharmaceutical composition according to claim 1 or 2 wherein the polyethylene glycol has a molecular weight of 1000 to 10000; the filler is selected from one or more of lactose, microcrystalline cellulose, starch and mannitol; the adhesive is selected from one or more of polyvinylpyrrolidone, sodium carboxymethylcellulose, hydroxypropyl cellulose, polyvinyl alcohol and hydroxypropyl methylcellulose; the disintegrating agent is selected from one or more of sodium carboxymethyl starch, croscarmellose sodium, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone and pregelatinized starch; the lubricant is selected from one or more of talcum powder, magnesium stearate, sodium stearyl fumarate and colloidal silicon dioxide; the surfactant is one or two of poloxamer and sodium dodecyl sulfate.
4. The method for preparing the rivaroxaban pharmaceutical composition according to any one of claims 1-3, wherein rivaroxaban is pulverized and dispersed in an aqueous solution of polyethylene glycol to prepare a rivaroxaban suspension dispersion, which is sprayed to a mixture of the other components except the lubricant for granulation, dried and mixed with the lubricant.
5. The production method according to claim 4, wherein the pulverization is a jet pulverization; the rivaroxaban is crushed to D90Less than 50 microns, D50Less than 25 microns.
6. The preparation method of claim 4, wherein the rivaroxaban suspension dispersion has a solid content of 5 wt% to 12 wt%.
7. The preparation method according to claim 4, wherein the granulation is realized by mixing and transferring other components except the lubricant into a mixing granulator, and uniformly spraying the rivaroxaban suspension dispersion liquid into the mixed materials in the mixing granulator.
8. The method of manufacturing of claim 7, the mixing granulator being a fluid bed granulator or a high shear mixing granulator; the spraying is top spraying method spraying or bottom spraying method spraying; the temperature of the mixed material is controlled below 50 ℃.
9. The method according to claim 4, wherein the drying is carried out until the water content of the granules is 1.5-2.5%.
10. A rivaroxaban tablet comprising the rivaroxaban pharmaceutical composition of any one of claims 1-3 and a coating film.
CN201811203606.XA 2018-10-16 2018-10-16 Rivaroxaban pharmaceutical composition and preparation method thereof Pending CN111053753A (en)

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