CN108864069B - Rivaroxaban particle and preparation method and application thereof - Google Patents
Rivaroxaban particle and preparation method and application thereof Download PDFInfo
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- CN108864069B CN108864069B CN201810415257.1A CN201810415257A CN108864069B CN 108864069 B CN108864069 B CN 108864069B CN 201810415257 A CN201810415257 A CN 201810415257A CN 108864069 B CN108864069 B CN 108864069B
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention discloses a method for preparing rivaroxaban particles, which comprises the following steps: a) dissolving rivaroxaban in an organic solvent to obtain an organic phase; b) dissolving hydroxypropyl methylcellulose and bovine serum albumin in deionized water to obtain a water phase; c) and mixing the organic phase and the water phase under a stirring state, separating out white particles, and carrying out solid-liquid separation to obtain the rivaroxaban particles. According to the preparation method, the combination use of the bovine serum albumin and the hydroxypropyl methyl cellulose is adopted, and the rivaroxaban particles which are stable in crystal form and have the particle size distribution of 1-10 mu m are obtained in the elution process. The method has simple process, low equipment requirement and low energy consumption, not only achieves the effect of traditional micronization, but also reduces the production cost. The rivaroxaban particles prepared by the method are small in particle size and stable in crystal form, the dissolution rate of the rivaroxaban particles is greatly improved, and the bioavailability can be greatly improved when the rivaroxaban particles are used for replacing bulk drugs to prepare medicines for preventing and/or treating thrombus.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to rivaroxaban particles and a preparation method and application thereof.
Background
Rivaroxaban (Rivaroxaban, RXB), chemical name 5-chloro-nitrogen- ({ (5S) -2-oxo-3- [ -4- (3-oxo-4-morpholinyl) phenyl]-1, 3-oxazolidin-5-yl } methyl) -2-thiophene-carboxamide having the formula C19H18ClN3O5The anticoagulant drug is a novel anticoagulant drug jointly developed by Bayer and Qiangsheng companies, plays an anticoagulant role by inhibiting Xa (blood coagulation factor) and blocking endogenous and exogenous blood coagulation paths, and is mainly used for adult patients in selective hip joint or knee joint replacement surgery to prevent the formation of venous thrombosis.
Rivaroxaban belongs to class II drugs in the Biopharmaceutical Classification System (BCS) and is characterized by low solubility (about 5-7mg/L) which is the limiting factor for in vivo absorption and high permeability. Therefore, the improvement of the solubility of rivaroxaban is of great significance to the development of oral solid preparations thereof.
According to the Noyes-Whitney equation, the reduction of the particle size can increase the specific surface area, thereby increasing the dissolution rate of the drug. Conventional methods for reducing the particle size of the drug include micronization, media milling or high-pressure homogenization, but these methods have the problems of time and energy consumption, and the mechanical force is liable to cause the degradation of the drug during the process of breaking up the particles, and is not particularly suitable for the drug which is unstable under heat. Methods for increasing the dissolution of rivaroxaban have been patented. Wherein, Chinese patent CN103550166A, a rivaroxaban oral microsphere preparation, prepares a rivaroxaban oral microsphere, the average particle size of the microsphere is 38-79 μm, but tetrahydrofuran which has stronger toxicity and carcinogenicity is used as a solvent in the preparation process, so that potential risk exists; chinese patent CN105796492A rivaroxaban nanosuspension and a preparation method thereof prepares rivaroxaban nanosuspension, but in the preparation process, equipment such as a high-pressure homogenizer, a freeze dryer and the like is needed, and the cost is higher, so that the development of a preparation method for reducing the particle size of the medicine, which has the advantages of simple operation, low equipment requirement and low energy consumption, has very practical significance.
Disclosure of Invention
Aiming at the technical problems of inconvenient operation, high equipment requirement and high energy consumption of the method for improving the dissolution rate of rivaroxaban in the prior art, the invention aims to provide the method for preparing the rivaroxaban particles, and the method has the advantages of simple process, low equipment requirement and low energy consumption. The rivaroxaban particles prepared by the method are small in particle size and stable in crystal form, the solubility of rivaroxaban can be effectively improved, the bioavailability of rivaroxaban is further improved, and a new choice is provided for the development of rivaroxaban oral solid preparations.
The preparation of rivaroxaban particles is realized by a solventing-out crystallization method, which is an effective method for reducing the particle size of a medicament. In general, during the elution crystallization process, most of the initially formed drug particles are in an unstable crystal form or amorphous form, and are easy to further grow under the driving of the supersaturation degree of the solution, so that the particle size is enlarged.
Through a large number of experimental screens, we find that the combination use of Bovine Serum Albumin (BSA) and hydroxypropyl methyl cellulose (HPMC) can obtain rivaroxaban particles with the particle size distribution of 1-10 μm and stable crystal form in the dissolution process. The bovine serum albumin is a main component in the bovine plasma protein, is highly similar to human serum albumin in structure, is frequently used as a substitute research product of the human serum albumin due to rich source and low cost, has a hydrophobic cavity and a large number of hydrogen bond donor receptors in the structure, is easy to interact with drug micromolecules, and is used as a stabilizer for inhibiting the crystal growth to inhibit the growth of rivaroxaban crystals. Hydroxypropyl methylcellulose is a hydrophilic polymer widely used in the pharmaceutical industry, shows different viscosities according to hydroxypropyl groups and methoxyl groups with different degrees of substitution in the structure, and is used for controlling the crystal form of rivaroxaban and avoiding the generation of unstable crystal forms. The combined use of bovine serum albumin and hydroxypropyl methylcellulose effectively controls the crystallization process of rivaroxaban, and effectively improves the dissolution rate of the medicament.
The method for preparing rivaroxaban particles provided by the invention specifically comprises the following steps:
a) dissolving rivaroxaban in an organic solvent to obtain an organic phase;
b) dissolving hydroxypropyl methylcellulose and bovine serum albumin in deionized water to obtain a water phase;
c) and mixing the organic phase and the water phase under a stirring state, separating out white particles, and carrying out solid-liquid separation to obtain the rivaroxaban particles.
According to the method, bovine serum albumin and hydroxypropyl methyl cellulose are dissolved in a poor solvent (deionized water) of the medicine in advance and mixed with the medicine solution, and the supersaturation degree of the system is increased so that the medicine is separated out, so that the crystallization process of the medicine is controlled, and the medicine particles with small particle size and stable crystal form are obtained. The invention has simple preparation process, low equipment requirement and low energy consumption, but achieves the effect of traditional micronization and reduces the production cost.
Preferably, the organic solvent is dimethyl sulfoxide or N, N-dimethylformamide or a mixed solution of dimethyl sulfoxide and N, N-dimethylformamide.
The dosage of the organic solvent should be at least capable of completely dissolving rivaroxaban, and preferably, the dosage of the organic solvent is more than 5 times, preferably 5-30 times, and more preferably 8-20 times of the mass of rivaroxaban.
Preferably, the solubility of rivaroxaban can be increased by heating (e.g., heating in a water bath) during the dissolution of rivaroxaban, typically by heating to 30-70 deg.C, more preferably 40-60 deg.C.
The invention leads the medicine to be completely separated out by changing the supersaturation degree of the medicine in the solvent system, therefore, the volume ratio of the organic phase to the water phase needs to be controlled, and in order to lead the medicine to be completely separated out, the volume ratio of the organic phase to the water phase is preferably 1:40-200, and preferably 1: 60-150.
In the process of dissolving bovine serum albumin and hydroxypropyl methyl cellulose in water, the processes of stirring, ultrasonic treatment or vortex treatment and the like can be adopted for assisting dissolution, so that the system is uniformly mixed.
Preferably, the mass ratio of rivaroxaban to hydroxypropyl methylcellulose to bovine serum albumin is 1:0.5-10:0.3-15, preferably 1:1-8: 0.5-10.
Preferably, the temperature of the organic phase is controlled to be 5 to 35 ℃ after mixing with the aqueous phase, preferably 15 to 30 ℃. Can be controlled by circulating water bath.
In the invention, the method for separating rivaroxaban particles by solid-liquid separation can be used for carrying out separation operation according to a conventional method in the field, preferably, the solid-liquid separation operation comprises suction filtration and reduced pressure drying, a filter cake is washed by deionized water for 1-6 times, preferably 2-5 times, and the mass of the deionized water in each time is 40-200 times, preferably 80-150 times that of rivaroxaban; the reduced pressure drying conditions were:
drying at 40-100 deg.C, preferably 50-80 deg.C under reduced pressure for 4-12 hr, preferably 5-8 hr, under vacuum condition of 76mmHg-450mmHg, preferably 150 mmHg.
Rivaroxaban particles prepared by the method of the present invention have a particle size D90 of 1 to 10 μm (wherein D90 means that 90% of the particles have the size shown and below, and hereinafter D10 and D50 have similar meanings), and include the following characteristic peaks measured at 2 θ diffraction angles in an X-ray powder diffraction pattern: 14.3 +/-0.2 degrees, 16.5 +/-0.2 degrees, 17.4 +/-0.2 degrees, 18.1 +/-0.2 degrees, 19.5 +/-0.2 degrees, 19.9 +/-0.2 degrees, 21.6 +/-0.2 degrees, 22.5 +/-0.2 degrees, 23.3 +/-0.2 degrees, 24.1 +/-0.2 degrees, 24.7 +/-0.2 degrees, 25.6 +/-0.2 degrees, 26.6 +/-0.2 degrees, 27.1 +/-0.2 degrees, 28.7 +/-0.2 degrees and 30.0 +/-0.2 degrees.
The rivaroxaban particles are small in particle size and stable in crystal form, and the dissolution rate of the rivaroxaban particles is greatly improved, so that the rivaroxaban particles can be used for preparing a medicine for preventing and/or treating thrombus by replacing a raw material medicine, and the bioavailability can be greatly improved.
The positive progress effects of the invention are as follows:
according to the preparation method, the combination use of the bovine serum albumin and the hydroxypropyl methyl cellulose is adopted, and the rivaroxaban particles which are stable in crystal form and have the particle size distribution of 1-10 mu m are obtained in the elution process. The bovine serum albumin has a hydrophobic cavity and a large number of hydrogen bond donor receptors in the structure, so that the bovine serum albumin is easy to interact with small drug molecules, and is used as a stabilizer for inhibiting the growth of crystals and used for inhibiting the growth of rivaroxaban crystals. Hydroxypropyl methylcellulose is a hydrophilic polymer widely used in the pharmaceutical industry, shows different viscosities according to hydroxypropyl groups and methoxyl groups with different degrees of substitution in the structure, and is used for controlling the crystal form of rivaroxaban and avoiding the generation of unstable crystal forms. The combined use of bovine serum albumin and hydroxypropyl methylcellulose effectively controls the crystallization process of rivaroxaban, and effectively improves the dissolution rate of the medicament.
The method is realized only by the steps of dissolution and precipitation, solid-liquid separation, reduced pressure drying and the like, the whole process is simple, the equipment requirement is low, the energy consumption is low, the traditional micronization effect is achieved, and the production cost is reduced. Moreover, solvents such as tetrahydrofuran and the like which are carcinogenic are not introduced, so that the safety is higher.
The rivaroxaban particles prepared by the method have small particle size and stable crystal form, the dissolution rate is greatly improved, and the bioavailability can be greatly improved when the rivaroxaban particles are used for replacing raw material medicines to prepare medicines for preventing and/or treating thrombus.
Drawings
FIG. 1 is a particle size distribution diagram of rivaroxaban microparticles prepared in example 1;
FIG. 2 is a scanning electron micrograph (20 μm) of rivaroxaban microparticles prepared in example 1;
FIG. 3 is a scanning electron micrograph (5 μm) of rivaroxaban microparticles prepared in example 1;
FIG. 4 is an X-ray diffraction pattern of rivaroxaban particles;
FIG. 5 is a dissolution profile of rivaroxaban microparticles in 0.2% sodium lauryl sulfate solution;
FIG. 6 is an X-ray diffraction pattern of rivaroxaban microparticles after accelerated stability testing;
figure 7 is a dissolution profile of rivaroxaban microparticles after accelerated stability experiments.
Detailed Description
The following series of specific examples are given to further illustrate the present invention, but the present invention is not limited to these specific examples, and any modification of the present invention that would be obvious to those skilled in the art to achieve similar results would also be included in the present invention.
Example 1
80mg of rivaroxaban bulk drug was dissolved in 1mL of dimethyl sulfoxide at room temperature to obtain an organic phase. 420mg of bovine serum albumin and 530mg of hydroxypropylmethylcellulose were dissolved in 80mL of deionized water to obtain an aqueous phase. The organic phase was injected into the aqueous phase at 20 ℃ and stirred for 30 minutes to give a suspension in which rivaroxaban: bovine serum albumin: the mass ratio of the hydroxypropyl methyl cellulose to the hydroxypropyl methyl cellulose is 1: 5.2: 6.6; and then carrying out suction filtration, washing with deionized water for 2-5 times (8 mL each time), collecting a filter cake, drying in a vacuum drying oven at the drying temperature of 50 ℃ for 5 hours under the vacuum condition of 150mmHg, and drying to obtain powdery rivaroxaban particles.
The particle size distribution of the obtained rivaroxaban microparticles is shown in fig. 1, and the scanning electron micrographs are shown in fig. 2 and fig. 3.
Example 2
170.3mg of rivaroxaban drug substance was dissolved in 1mL of dimethyl sulfoxide at room temperature, and dissolved by heating at 50 ℃ to obtain an organic phase. 172.0mg of bovine serum albumin and 200.3mg of hydroxypropylmethylcellulose were dissolved in 170mL of deionized water to obtain an aqueous phase. The organic phase was injected into the aqueous phase at 20 ℃ and stirred for 30 minutes to give a suspension in which rivaroxaban: bovine serum albumin: the mass ratio of the hydroxypropyl methyl cellulose to the hydroxypropyl methyl cellulose is 1: 1: 1.2; and then carrying out suction filtration, washing with deionized water for 2-5 times (17 mL each time), collecting a filter cake, drying in a vacuum drying oven at the drying temperature of 80 ℃ for 5 hours under the vacuum condition of 150mmHg, and drying to obtain powdery rivaroxaban particles.
Example 3
160.0mg of rivaroxaban drug substance was dissolved in 2mL of dimethyl sulfoxide at 30 ℃ to obtain an organic phase. 801.2mg of bovine serum albumin and 162.0mg of hydroxypropylmethylcellulose were dissolved in 100mL of deionized water to obtain an aqueous phase. The organic phase was injected into the aqueous phase at 20 ℃ and stirred for 30 minutes to give a suspension in which rivaroxaban: bovine serum albumin: the mass ratio of the hydroxypropyl methyl cellulose to the hydroxypropyl methyl cellulose is 1: 5: 1; and then carrying out suction filtration, washing with deionized water for 2-5 times (16 mL each time), collecting a filter cake, drying in a vacuum drying oven at 60 ℃ for 8 hours under the vacuum condition of 150mmHg, and drying to obtain powdery rivaroxaban particles.
Example 4
120mg of rivaroxaban bulk drug was dissolved in 1mL of dimethyl sulfoxide at room temperature to obtain an organic phase. An aqueous phase was obtained by dissolving 1g of bovine serum albumin and 1g of hydroxypropylmethylcellulose in 90mL of deionized water. The organic phase was injected into the aqueous phase at 20 ℃ and stirred for 30 minutes to give a suspension in which rivaroxaban: bovine serum albumin: the mass ratio of the hydroxypropyl methyl cellulose to the hydroxypropyl methyl cellulose is 1: 8.3: 8.3; and then carrying out suction filtration, washing with deionized water for 2-5 times (16 mL each time), collecting a filter cake, drying in a vacuum drying oven at 60 ℃ for 6 hours under the vacuum condition of 150mmHg, and drying to obtain powdery rivaroxaban particles.
Comparative example 1
Dissolve 81.2mg rivaroxaban drug substance in 1mL dimethyl sulfoxide at room temperature to obtain an organic phase. 80mL of deionized water was used as the aqueous phase. The subsequent organic and aqueous phase mixing and solid-liquid separation steps refer to example 1.
Comparative example 1 is a blank control experiment without any polymer and protein added to the aqueous phase, compared to example 1.
Comparative example 2
80.3mg of rivaroxaban drug substance was dissolved in 1mL of dimethyl sulfoxide at room temperature to obtain an organic phase. 530mg of hydroxypropylmethylcellulose was dissolved in 80mL of deionized water to obtain an aqueous phase. The subsequent organic and aqueous phase mixing and solid-liquid separation steps refer to example 1.
Comparative example 2 is a control experiment with the addition of only hydroxypropylmethylcellulose to the aqueous phase compared to example 1.
Comparative example 3
80.2mg of rivaroxaban drug substance was dissolved in 1mL of dimethyl sulfoxide at room temperature to obtain an organic phase. 420mg of bovine serum albumin was dissolved in 80mL of deionized water to obtain an aqueous phase. The subsequent organic and aqueous phase mixing and solid-liquid separation steps refer to example 1.
Comparative example 3 is a control experiment in which only bovine serum albumin was added to the aqueous phase compared to example 1.
Effects of the embodiment
(1) Particle size and Crystal form determination
In examples 1 to 4 and comparative examples 1 to 3, the particle size of the suspension was measured by a Malvern 2000 particle size analyzer before the particles were collected by solid-liquid separation, and the results are shown in table 1.
Table 1 particle size of rivaroxaban microparticles
Wherein, bovine serum albumin is not added into the water phase of the comparative examples 1-2, and the particle size of the prepared rivaroxaban particles is larger; and bovine serum albumin is added into the water phase of the comparative example 3 and the water phase of the examples 1 to 4, so that the particle size of the prepared rivaroxaban particles is greatly reduced, and the bovine serum albumin can effectively reduce the particle size of the rivaroxaban.
Part a in fig. 4 shows the X-ray powder diffraction pattern of three known crystalline forms of rivaroxaban, wherein form I and form II are more stable and form III is unstable. In order to avoid further growth of the crystal and ensure the crystal form stability and the particle size of rivaroxaban, the crystal form III needs to be avoided in the crystallization process. The X-ray diffraction patterns of the rivaroxaban microparticles prepared in examples 1-4 and comparative examples 1-3 are shown in FIG. 4B. Wherein, the rivaroxaban particles prepared in examples 1-4 and comparative example 2, in which hydroxypropyl methylcellulose was added to the aqueous phase, were in a stable I crystal form, and the X-ray powder diffraction pattern included characteristic peaks measured at 2 θ diffraction angles shown in table 1: 14.3 +/-0.2 degrees, 16.5 +/-0.2 degrees, 17.4 +/-0.2 degrees, 18.1 +/-0.2 degrees, 19.5 +/-0.2 degrees, 19.9 +/-0.2 degrees, 21.6 +/-0.2 degrees, 22.5 +/-0.2 degrees, 23.3 +/-0.2 degrees, 24.1 +/-0.2 degrees, 24.7 +/-0.2 degrees, 25.6 +/-0.2 degrees, 26.6 +/-0.2 degrees, 27.1 +/-0.2 degrees, 28.7 +/-0.2 degrees and 30.0 +/-0.2 degrees. Whereas rivaroxaban microparticles prepared in comparative examples 1 and 3 without hydroxypropyl methylcellulose added to the aqueous phase were in the unstable form III.
From the measurement results of the particle size and crystal form,
in the preparation process of the comparative example 1, no polymer or protein is added into the water phase, the separated rivaroxaban is in an unstable III crystal form, the particle size is large, and D90 is 21.251 microns.
In the preparation process of comparative example 2, only hydroxypropyl methylcellulose is added into the water phase, although the hydroxypropyl methylcellulose can control the crystal form of rivaroxaban to obtain stable crystal form I, particles with the particle size distribution of 1-10 mu m cannot be obtained. The particle size of the precipitated rivaroxaban was large, and D90 was 21.527 μm.
In the preparation process of comparative example 3, only bovine serum albumin is added into the water phase, although the particle size of rivaroxaban can be reduced by the bovine serum albumin, D90 is 6.286 mu m, the separated particles are unstable III crystal forms, and crystal transformation occurs at room temperature for 10 days.
In examples 1 to 4, bovine serum albumin and hydroxypropyl methylcellulose were used in combination, and the prepared rivaroxaban particles were small in particle size, D90 was 9.509 μm, 8.470 μm, 10.994 μm, and 8.878 μm, respectively, and the crystal form was a stable I crystal form.
(2) Dissolution determination
Rivaroxaban bulk drug and rivaroxaban particles prepared in example 1 and comparative examples 1-3 were respectively sieved through a 100-mesh sieve, and then powder corresponding to 10mg of the main drug was weighed, and according to a dissolution determination method (first method in the fourth part of the chinese pharmacopoeia 2015), 900mL of dissolution medium (0.2% sodium dodecyl sulfate solution) was taken, the rotation speed was 50rpm, and the medium temperature was 37 ± 0.5 ℃, the operation was performed according to the method. Sampling 5mL at 5, 10, 20, 30, 45 and 60 minutes respectively, simultaneously supplementing 5mL of dissolution medium with the same temperature, filtering the sample solution by using a 0.45-micrometer filter membrane, taking the subsequent filtrate, measuring the ultraviolet absorbance at 250nm, measuring the content of the filtrate, and calculating the dissolution rate.
The measurement result is shown in fig. 5, and the result shows that the rivaroxaban particles prepared in example 1 have a small particle size, so that the surface area is increased, the dissolution rate is greatly improved, and the release rate within 60 minutes is more than 90% and is 3 times of that of the bulk drug. The dissolution rate of the rivaroxaban particles prepared in the comparative examples 1-3 is improved compared with that of the bulk drug, but is obviously lower than that of the rivaroxaban particles prepared in the example 1 because the dissolution rate is influenced by the particle size and the crystal form, and the crystal form in the comparative example 2 is a stable crystal form I, but the dissolution rate is influenced by the larger particle size; and the grain size of the comparative example 3 is smaller, but the dissolution rate is still lower because the crystal form III is unstable, and the comparative example is equivalent to the comparative example 1.
(3) Stability survey
Rivaroxaban microparticle powder prepared in example 1 was taken, a commercially available package was simulated, placed in a stability box at 40 ℃/75% RH, and samples were taken after 1, 3, 6 months to test for crystal form and dissolution. The results (fig. 6 and 7) show that the rivaroxaban particles prepared in the examples have no change in crystal form after accelerated test for 6 months, are still in crystal form I, have no great change in dissolution behavior, and have stable product quality. Meanwhile, the rivaroxaban particles prepared in the comparative example 3 are tested to be unstable crystal form III, and the crystal transformation occurs at room temperature for 10 days.
The key point of the method is the combined use of bovine serum albumin and hydroxypropyl methyl cellulose, and the aim of the invention can be realized only by the combined use of the bovine serum albumin and the hydroxypropyl methyl cellulose, namely rivaroxaban particles with small particle size and stable crystal form are prepared by simple and easy preparation steps. According to the preparation method, the combination use of the bovine serum albumin and the hydroxypropyl methyl cellulose is adopted, and the rivaroxaban particles which are stable in crystal form and have the particle size distribution of 1-10 mu m are obtained in the elution process. The bovine serum albumin has a hydrophobic cavity and a large number of hydrogen bond donor receptors in the structure, so that the bovine serum albumin is easy to interact with small drug molecules, and is used as a stabilizer for inhibiting the growth of crystals and used for inhibiting the growth of rivaroxaban crystals. Hydroxypropyl methylcellulose is a hydrophilic polymer widely used in the pharmaceutical industry, shows different viscosities according to hydroxypropyl groups and methoxyl groups with different degrees of substitution in the structure, and is used for controlling the crystal form of rivaroxaban and avoiding the generation of unstable crystal forms. The combined use of bovine serum albumin and hydroxypropyl methylcellulose effectively controls the crystallization process of rivaroxaban, and effectively improves the dissolution rate of the medicament.
The method is realized only by the steps of dissolution and precipitation, solid-liquid separation, reduced pressure drying and the like, the whole process is simple, the equipment requirement is low, the energy consumption is low, the traditional micronization effect is achieved, and the production cost is reduced. Moreover, solvents such as tetrahydrofuran and the like which are carcinogenic are not introduced, so that the safety is higher.
While the preferred embodiments of the present invention have been described in detail, it will be understood by those skilled in the art that the invention is not limited thereto, and that various changes and modifications may be made without departing from the spirit of the invention, and the scope of the appended claims is to be accorded the full range of equivalents.
Claims (2)
1. A method of preparing rivaroxaban microparticles comprising the steps of:
a) dissolving rivaroxaban in an organic solvent to obtain an organic phase;
b) dissolving hydroxypropyl methylcellulose and bovine serum albumin in deionized water to obtain a water phase;
c) mixing the organic phase and the water phase under a stirring state, separating out white particles, and carrying out solid-liquid separation to obtain rivaroxaban particles;
the dosage of the organic solvent is 5-30 times of the mass of rivaroxaban;
the volume ratio of the organic phase to the aqueous phase is 1: 40-200;
the mass ratio of rivaroxaban to hydroxypropyl methylcellulose to bovine serum albumin is 1:0.5-10: 0.3-15;
mixing the organic phase and the water phase, and controlling the temperature to be 5-35 ℃;
the organic solvent is dimethyl sulfoxide or N, N-dimethylformamide or a mixed solution of dimethyl sulfoxide and N, N-dimethylformamide.
2. The method according to claim 1, wherein the solid-liquid separation operation comprises suction filtration and reduced pressure drying, and a filter cake is washed 1-6 times by using deionized water; the reduced pressure drying conditions were: drying at 40-100 deg.C under vacuum of 76-450 mmHg for 4-12 hr.
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| CN103550166A (en) * | 2013-10-31 | 2014-02-05 | 江苏阿尔法药业有限公司 | Rivaroxaban oral microsphere preparation |
| CN103877060A (en) * | 2014-03-25 | 2014-06-25 | 江苏正大清江制药有限公司 | Rivaroxaban composition and preparation method thereof |
| CN105503849A (en) * | 2014-09-26 | 2016-04-20 | 重庆华邦制药有限公司 | Method for preparing rivaroxaban bulk drug with small particle size |
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| CN1886120A (en) * | 2003-11-27 | 2006-12-27 | 拜耳医药保健股份公司 | Method for the production of a solid, orally applicable pharmaceutical composition |
| CN103550166A (en) * | 2013-10-31 | 2014-02-05 | 江苏阿尔法药业有限公司 | Rivaroxaban oral microsphere preparation |
| CN103877060A (en) * | 2014-03-25 | 2014-06-25 | 江苏正大清江制药有限公司 | Rivaroxaban composition and preparation method thereof |
| CN105503849A (en) * | 2014-09-26 | 2016-04-20 | 重庆华邦制药有限公司 | Method for preparing rivaroxaban bulk drug with small particle size |
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