CN109464415B - Apixaban pharmaceutical composition and preparation method thereof - Google Patents
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Abstract
The apixaban preparation has the advantages of good stability, small friability, high dissolution rate, high in-vivo bioavailability, small dissolution difference among batches, small dosage of a surfactant, no agglomeration and no sticking phenomenon in the preparation process, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to an apixaban pharmaceutical composition and a preparation method thereof.
Background
Apixaban (Apixaban, trade name: aileron, aileton/Eliquis) is an oral anticoagulant developed by the combination of behmere and feverfew, and is a novel oral factor Xa inhibitor for the treatment of venous thrombotic disorders including Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE). In 5 months 2011, the european union approved the oral factor Xa direct inhibitor apixaban (trade name Eliquis) for marketing to adult patients in elective hip or knee replacement surgery to prevent Venous Thrombosis (VTE).
Apixaban is of the formula 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxopiperidin-1-yl) phenyl ] -4, 5, 6, 7-tetrahydro-1H-pyrazolo [3, 4-C ] pyridine-3-carboxamide, having the molecular formula C25H25N5O4, molecular weight 459.50, and the structural formula:
apixaban is insoluble in water, has a solubility of 0.04mg/mL in an aqueous medium (pH1.2-pH6.8), has the defects of slow dissolution rate, low in-vitro dissolution rate and low bioavailability, and has a certain influence on the absorption of the medicament. Various methods have been disclosed in the prior art for increasing the dissolution of apixaban.
Patent CN102770126A provides a crystalline form of N-1 or H2-2 as the active substance in a pharmaceutical composition comprising crystalline apixaban particles having a D90 (measured by laser light scattering method) equal to or less than about 89 μm and a pharmaceutically acceptable diluent or carrier, most preferably D90 is less than 25 μm, prepared using a dry granulation process. The invention increases dissolution by reducing the granularity of raw materials, but the granularity is too small, so that serious agglomeration phenomenon is often generated, and the invention is not suitable for industrial production.
Patent CN 102908324A prepares apixaban into a solid dispersion, which is then mixed with a prescribed amount of microcrystalline cellulose; crospovidone; mixing the micro silica gel powder uniformly and tabletting directly. The solid dispersion was prepared as follows: heating polyethylene glycol 6000 to be melted at 60 ℃, adding apixaban, and violently stirring to 10000-20000 r/min; rapidly cooling the stirred melt at-20 ℃ to 0 ℃ and solidifying for 2 h; and crushing the cured substance, sieving the crushed cured substance by a 80-mesh sieve, and drying the crushed cured substance for 4 hours at 20 ℃ under reduced pressure to obtain the apixaban solid dispersion. The method increases the dissolution rate of Apixaban by increasing the dosage of the surfactant, and uses 10-20 parts of the surfactant polyethylene glycol 6000, so that a large amount of polyethylene glycol brings more side effects and adverse reactions to patients.
Therefore, the method which is safe, effective and suitable for industrial production is urgently sought for increasing the dissolution rate of the apixaban.
Disclosure of Invention
The invention aims to provide an apixaban pharmaceutical composition, and the obtained apixaban preparation has the advantages of good stability, small friability, high dissolution rate, high in-vivo bioavailability, small dissolution difference among batches, small dosage of a surfactant, no agglomeration and sticking phenomenon in the preparation process, and suitability for industrial production.
Specifically, the invention is realized by the following technical scheme:
an apixaban pharmaceutical composition comprises lactose, microcrystalline cellulose, a disintegrating agent and a lubricant, wherein the weight ratio of the lactose to the microcrystalline cellulose is (3-6): 1, preferably, the weight ratio of lactose to microcrystalline cellulose is 4-5: 1.
in one embodiment of the invention, the apixaban has a particle size d (0.9). ltoreq.30 μm, preferably d (0.9). ltoreq.25 μm.
In one embodiment of the invention, the disintegrant is selected from one or more of croscarmellose sodium, sodium starch glycolate, low substituted hydroxypropyl cellulose, crospovidone, preferably croscarmellose sodium.
In one embodiment of the invention, the lubricant is selected from magnesium stearate, sodium stearyl fumarate, talc, preferably magnesium stearate.
In one embodiment of the invention, the apixaban pharmaceutical composition is free of surfactant.
In one embodiment of the present invention, the apixaban pharmaceutical composition contains less than 0.5% of surfactant by total weight of the composition, wherein the surfactant is one or more of sodium dodecyl sulfate, polysorbate, sodium dodecyl benzene sulfonate, preferably sodium dodecyl sulfate.
In one embodiment of the invention, the coating material used for coating is a film coating premix (gastric soluble type), for example
In one embodiment of the invention, the apixaban is present in an amount of 1% to 10% by weight of the total composition, preferably 2.0% to 7.5% by weight of the total composition.
In one embodiment of the invention, the apixaban is present in an amount of 3.0% by weight based on the total weight of the composition.
In one embodiment of the invention, the apixaban is present in an amount of 6.0% by weight based on the total weight of the composition.
In one embodiment of the invention, the weight of lactose and microcrystalline cellulose is 60% to 95% of the total weight of the composition, preferably 80% to 92% of the total weight of the composition.
In one embodiment of the present invention, the total weight of the disintegrant is 2% to 8% of the total weight of the composition, preferably 3.0% to 4.0% of the total weight of the composition.
In one embodiment of the present invention, the lubricant is 0.1 to 2% by weight of the total composition, preferably 0.2 to 0.8% by weight of the total composition.
In one embodiment of the invention, the coating weight gain is 1% to 6% of the total weight of the composition, preferably 2% to 5% of the total weight of the composition.
The invention also aims to provide a preparation method of the apixaban pharmaceutical composition, which comprises the following steps:
(1) pulverizing Apixaban, and controlling the particle size d (0.9) to be less than or equal to 30 μm;
(2) mixing the crushed lactose, microcrystalline cellulose and disintegrant with Apixaban in a hopper mixer, and then mixing with a lubricant;
(3) and (3) carrying out dry granulation on the intermediate material obtained in the step (2), and mixing with a lubricant.
(4) Adding the mixed material obtained in the step (3) into a tabletting machine for tabletting, and controlling the hardness of the plain tablets to be 3.00-10.00 kg/cm2
(5) And (4) coating.
In one embodiment of the present invention, the pulverization treatment may be pulverization with a pulverizer. Generally, the raw material can be pulverized by a universal pulverizer, a micro pulverizer, a turbo pulverizer, a ball mill, a jet mill or the like, and preferably pulverized by a universal pulverizer.
In one embodiment of the present invention, the lactose and microcrystalline cellulose in step (2) are pre-treated by sieving through a 50-80 mesh sieve, preferably 60-70 mesh sieve.
In one embodiment of the present invention, when the surfactant is used, the surfactant in step (2) is first ground by a 60-100 mesh screen, preferably 60-80 mesh screen.
In one embodiment of the present invention, in step (2), the rotation speed of the hopper mixer is 8 to 20rpm, preferably 13 to 18rpm,
in one embodiment of the present invention, in the step (2), the mixing time of the auxiliary materials and the raw materials is 5min to 30min, preferably 10min to 25 min.
In one embodiment of the present invention, in the step (3), the aperture of the granulation screen of the dry granulator is 0.8-1.5 mm, preferably 0.8-1.0 mm.
In one embodiment of the present invention, the tablet pressing speed of the tablet press in step (4) is 10.0-100.0 kplate/hr, preferably 20.0-50.0 kplate/hr (the starting and ending speed of tablet pressing is low, and the middle is 40-50 kplate/hr more).
In one embodiment of the present invention, in step (4), the mean value of the main pressure of the tablet press is 3.00 to 25.00KN, preferably 7.00 to 11.00 KN.
In one embodiment of the invention, in the step (4), the hardness of the obtained plain sheet is 4.00-7.00 kg/cm2。
In one embodiment of the present invention, the method specifically comprises the following steps:
(1) pulverizing Apixaban, and controlling the particle size d (0.9) to be less than or equal to 25 μm;
(2) the lactose and the microcrystalline cellulose are sieved by a sieve of 60-70 meshes for pretreatment, the lactose, the microcrystalline cellulose, the croscarmellose sodium and the crushed apixaban are mixed for 15-25 min in a hopper mixer, and then the intermediate material is mixed with the magnesium stearate for 5-15 min.
(3) And (3) adding the intermediate material obtained in the step (2) into a dry-method granulator for granulation, wherein the feeding frequency is controlled to be 8-30 Hz, the tabletting frequency is controlled to be 10-30 Hz, and the granulation frequency is controlled to be 10-30 Hz.
(4) And (4) mixing the intermediate material obtained in the step (3) with magnesium stearate, and mixing for 5-15 min.
(5) Adding the intermediate material obtained in the step (4) into a tabletting machine for tabletting, wherein the tabletting speed is controlled to be 30.0-50.0 thousand tablets/hour, and the average value of the main pressure is8.00 to 10.00KN and a plain film hardness of 4.00 to 7.00kg/cm2。
(6) And (3) adding the plain tablets into a coating pan for coating, controlling the temperature of a tablet bed to be 35-45 ℃, and stopping when the weight of the coating is increased to 2-4%.
The preparation method of the apixaban pharmaceutical composition has the advantages of good particle fluidity, no agglomeration, smooth tabletting process and no sticking impact; the Apixaban tablet has complete and smooth surface, uniform color, and no fracture, crack or pulverization.
Drawings
FIG. 1: dissolution behavior of 3 batches of tablets of example 1 with commercially available Eliquis in 0.1mol/L hydrochloric acid solution.
FIG. 2: dissolution behavior of 3 batches of tablets of example 1 with commercially available Eliquis in phosphate buffer at pH 6.8.
FIG. 3: dissolution behavior in water of the 3 batches of tablets of example 1 with the commercially available Eliquis.
Detailed Description
To further illustrate the present invention, the present invention will be specifically described with reference to specific examples, but the scope of the present invention is not limited to the specific examples.
Example 1
Tablet formulation:
the preparation process comprises the following steps:
(1) pretreating raw materials and auxiliary materials: pulverizing Apixaban to obtain powder with d (0.9) of 21.0 μm, sieving lactose and microcrystalline cellulose with 60 mesh sieve, and pulverizing sodium laurylsulfate with 60 mesh sieve;
(2) adding anhydrous lactose, microcrystalline cellulose, sodium dodecyl sulfate, croscarmellose sodium and Apixaban in prescribed amount into a fixed hopper mixer, setting rotation speed at 10rpm, and mixing for 20min
(3) Mixing the intermediate material obtained in (2) with magnesium stearate for 5 min.
(4) And (3) adding the intermediate material obtained in the step (3) into a dry granulating machine for granulation, adjusting feeding frequency conversion within the range of 8-30 Hz, adjusting tabletting frequency conversion within the range of 10-30 Hz, adjusting granulating frequency conversion within the range of 10-30 Hz, and adjusting a whole grain screen to be 1.0 mm.
(5) Adding the intermediate material obtained in the step (4) into a hopper mixer, adding the magnesium stearate with the prescription amount into the hopper mixer, setting the rotating speed to be 10rpm, and mixing for 15 min;
(6) tabletting, wherein the tabletting speed of the rotary tablet press is set to be 30.0 thousand tablets/hour, the rotating speed of a filling device is set to be 90rpm, the average main pressure value is 7.9-8.5 KN, and the hardness of the obtained plain tablets is 5.45kg/cm2。
(7) Coating: and adding the plain tablets into a coating pan, controlling the coating temperature to be 35-45 ℃, and stopping coating after the weight of the coating is increased to 3.0%.
Example 2
Tablet formulation:
the preparation process comprises the following steps:
(1) pretreating raw materials and auxiliary materials: pulverizing Apixaban to obtain powder with d (0.9) of 20.1 μm, sieving lactose and microcrystalline cellulose with 60 mesh sieve, and pulverizing sodium laurylsulfate with 60 mesh sieve;
(2) adding anhydrous lactose, microcrystalline cellulose, sodium dodecyl sulfate, croscarmellose sodium and Apixaban in prescribed amount into a fixed hopper mixer, setting rotation speed at 10rpm, and mixing for 20min
(3) Mixing the intermediate material obtained in (2) with magnesium stearate for 5 min.
(4) And (3) adding the intermediate material obtained in the step (3) into a dry granulating machine for granulation, adjusting feeding frequency conversion within the range of 8-30 Hz, adjusting tabletting frequency conversion within the range of 10-30 Hz, adjusting granulating frequency conversion within the range of 10-30 Hz, and adjusting a whole grain screen to be 1.0 mm.
(5) Adding the intermediate material obtained in the step (4) into a hopper mixer, adding the magnesium stearate with the prescription amount into the hopper mixer, setting the rotating speed to be 10rpm, and mixing for 15 min;
(6) tabletting, wherein the tabletting speed of the rotary tablet press is set to be 30.0 thousand tablets/hour, the rotating speed of a filling device is set to be 90rpm, the average main pressure value is 7.9-8.5 KN, and the hardness of the obtained plain tablets is 5.75kg/cm2。
(7) Coating: and adding the plain tablets into a coating pan, controlling the coating temperature to be 35-45 ℃, and stopping coating after the weight of the coating is increased to 3.0%.
Example 3
Tablet formulation:
the preparation process comprises the following steps:
(1) pretreating raw materials and auxiliary materials: pulverizing Apixaban to obtain powder with d (0.9) of 12.8 μm, sieving lactose and microcrystalline cellulose with 70 mesh sieve, and pulverizing sodium laurylsulfate with 80 mesh sieve;
(2) adding the anhydrous lactose, the microcrystalline cellulose, the croscarmellose sodium and the Apixaban in the prescribed amounts into a fixed hopper mixer, setting the rotating speed at 10rpm, and mixing for 20min
(3) Mixing the intermediate material obtained in (2) with magnesium stearate for 5 min.
(4) And (3) adding the intermediate material obtained in the step (3) into a dry granulating machine for granulation, adjusting feeding frequency conversion within the range of 8-30 Hz, adjusting tabletting frequency conversion within the range of 10-30 Hz, adjusting granulating frequency conversion within the range of 10-30 Hz, and adjusting a whole grain screen to be 1.0 mm.
(5) Adding the intermediate material obtained in the step (4) into a hopper mixer, adding the magnesium stearate with the prescription amount into the hopper mixer, setting the rotating speed to be 10rpm, and mixing for 15 min;
(6) tabletting, wherein the tabletting speed of the rotary tablet press is set to be 50.0 kilo tablets/hour, the rotating speed of a filling device is set to be 80rpm, the average main pressure is 10.6-11.5 KN, and the hardness of the obtained plain tablets is 6.90kg/cm2。
(7) Coating: and adding the plain tablets into a coating pan, controlling the coating temperature to be 35-45 ℃, and stopping coating after the weight of the coating is increased to 2.5%.
Example 4
Tablet formulation:
the preparation process comprises the following steps:
(1) pretreating raw materials and auxiliary materials: processing Apixaban micropowder with d (0.9) of 25.5 μm by sieving lactose and microcrystalline cellulose with 70 mesh sieve;
(2) adding anhydrous lactose, microcrystalline cellulose, croscarmellose sodium and Apixaban in prescribed amounts into a fixed hopper mixer, setting the rotation speed at 10rpm, and mixing for 20min
(3) Mixing the intermediate material obtained in (2) with magnesium stearate for 5 min.
(4) And (3) adding the intermediate material obtained in the step (3) into a dry granulating machine for granulation, adjusting feeding frequency conversion within the range of 8-30 Hz, adjusting tabletting frequency conversion within the range of 10-30 Hz, adjusting granulating frequency conversion within the range of 10-30 Hz, and adjusting a whole grain screen to be 1.0 mm.
(5) Adding the intermediate material obtained in the step (4) into a hopper mixer, adding the magnesium stearate with the prescription amount into the hopper mixer, setting the rotating speed to be 10rpm, and mixing for 15 min;
(6) tabletting, wherein the tabletting speed of the rotary tablet press is set to be 40.0 thousand tablets/hour, the rotating speed of a filling device is set to be 80rpm, the average main pressure value is 7.2-9.0 KN, and the hardness of the obtained plain tablets is 5.81kg/cm2。
(7) Coating: and adding the plain tablets into a coating pan, controlling the coating temperature to be 35-45 ℃, and stopping coating after the weight of the coating is increased to 4.0%.
Example 5
Tablet formulation:
the preparation process comprises the following steps:
(1) pretreating raw materials and auxiliary materials: processing Apixaban micropowder with d (0.9) of 18.4 μm by sieving lactose and microcrystalline cellulose with 60 mesh sieve;
(2) adding anhydrous lactose, microcrystalline cellulose, carboxymethyl starch sodium and Apixaban in formula amount into a fixed hopper mixer, setting rotation speed at 10rpm, and mixing for 20min
(3) Mixing the intermediate material obtained in (2) with magnesium stearate for 5 min.
(4) And (3) adding the intermediate material obtained in the step (3) into a dry granulating machine for granulation, adjusting feeding frequency conversion within the range of 8-30 Hz, adjusting tabletting frequency conversion within the range of 10-30 Hz, adjusting granulating frequency conversion within the range of 10-30 Hz, and adjusting a whole grain screen to be 1.0 mm.
(5) Adding the intermediate material obtained in the step (4) into a hopper mixer, adding the magnesium stearate with the prescription amount into the hopper mixer, setting the rotating speed to be 10rpm, and mixing for 15 min;
(6) tabletting, wherein the tabletting speed of the rotary tablet press is set to be 30.0 thousand tablets/hour, the rotating speed of a filling device is set to be 90rpm, the average main pressure value is 7.9-8.5 KN, and the hardness of the obtained plain tablets is 5.65kg/cm2。
(7) Coating: and adding the plain tablets into a coating pan, controlling the coating temperature to be 35-45 ℃, and stopping coating after the weight of the coating is increased to 3.0%.
Example 5 friability examination
The friability of the plain tablets obtained in examples 1 to 4 was measured according to the method of "examination method of friability of 0923 tablets" in the fourth pharmacopoeia of china, edition 2015.
TABLE 1
The results show that all batches of tablets did not experience breakage, cracking and crushing, and the average weight loss was < 0.3%, indicating that these tablets have excellent friability.
Example 6 drug dissolution study
Dissolution medium: 0.1mol/L hydrochloric acid, pH6.8 phosphate buffer solution and water, 900 ml;
the dissolution method comprises the following steps: paddle method, 50 rpm;
temperature of the medium: 37.0 +/-0.5 ℃;
sampling: sampling 10ml after 5min, 10min, 15min, 30min and 45min respectively, filtering by a polyether sulfone membrane, and simultaneously supplementing the isothermal same medium;
sample preparation: from examples 1-5, 5 samples were randomly drawn.
The measurement results are shown in Table 2.
TABLE 2
Example 7 stability study
Samples of examples 1-4 were randomly sampled and allowed to stand for 6 months under accelerated conditions of 40 ℃. + -. 2 ℃/RH 75%. + -. 5%, and the changes in the relevant substances were observed, with the specific results shown in Table 3.
TABLE 3
Example 8 inter-batch dissolution Studies
Completely following the recipe and process of example 1, 3 batches of formulation samples, corresponding to batches 1-1, 1-2, and 1-3, were continuously produced, 30 samples were randomly sampled from each batch, and the dissolution of each batch in different dissolution media was examined.
The measurement results are shown in FIGS. 1 to 3.
As can be seen from comparison of dissolution curves of various batches, the commercially available Eliquis has large dissolution fluctuation before 15min, but the dissolution behaviors of the batches of the Eliquis are almost the same, the difference is small, and the Eliquis suitable for industrial mass production.
The dissolution between batches of examples 2-5 was similar to that of example 1.
Claims (12)
1. An apixaban pharmaceutical composition comprises lactose, microcrystalline cellulose, a disintegrating agent and a lubricant, wherein the weight ratio of the lactose to the microcrystalline cellulose is (4-5): 1, the weight of the lactose and the microcrystalline cellulose accounts for 60 to 95 percent of the total weight of the composition; the granularity d (0.9) of the apixaban is less than or equal to 30 mu m, and the weight of the apixaban accounts for 1 to 10 percent of the total weight of the composition; the disintegrant is selected from one or more of croscarmellose sodium, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose and crospovidone, and the weight of the disintegrant accounts for 2-8% of the total weight of the composition; the lubricant is selected from magnesium stearate, sodium stearyl fumarate and talcum powder, and accounts for 0.1-2% of the total weight of the composition.
2. Apixaban pharmaceutical composition according to claim 1, wherein the particle size d (0.9) of apixaban is less than or equal to 25 μm.
3. Apixaban pharmaceutical composition according to claim 1, wherein the disintegrant is selected from croscarmellose sodium.
4. Apixaban pharmaceutical composition according to claim 1, wherein the lubricant is selected from magnesium stearate.
5. An apixaban pharmaceutical composition according to claim 1, wherein the apixaban is present in an amount of 2.0% to 7.5% by weight based on the total weight of the composition.
6. An apixaban pharmaceutical composition according to claim 1, wherein the weight of the lactose and microcrystalline cellulose is 80-92% of the total weight of the composition.
7. A process for the preparation of an apixaban pharmaceutical composition according to any one of claims 1-6 comprising the steps of:
1) pulverizing Apixaban, and controlling the particle size d (0.9) to be less than or equal to 30 μm;
2) mixing lactose, microcrystalline cellulose and a disintegrating agent with the pulverized apixaban in a hopper mixer, and then mixing with a lubricant;
3) dry granulating the intermediate material obtained in the step 2), and mixing with a lubricant;
4) adding the mixed material obtained in the step 3) into a tabletting machine for tabletting, wherein the hardness of the plain tablets is controlled to be 3.00-10.00 kg/cm2；
5) And (4) coating.
8. The method of claim 7, wherein the filler in step 2) is pre-treated by passing through a 50-80 mesh screen.
9. The preparation method of claim 7, wherein the filler in the step 2) is pre-treated by sieving with a 60-70 mesh sieve.
10. The method according to claim 8 or 9, wherein in step 3), the mesh size of the granulating screen of the dry granulator is 0.8-1.5 mm.
11. The method according to claim 8 or 9, wherein in step 3), the mesh size of the granulating screen of the dry granulator is 0.8-1.0 mm.
12. The method of claim 8 or 9, comprising the steps of:
1) pulverizing Apixaban, and controlling the particle size d (0.9) to be less than or equal to 25 μm;
2) the preparation method comprises the following steps of firstly, sieving lactose and microcrystalline cellulose by a 60-70-mesh sieve for pretreatment, mixing the lactose, the microcrystalline cellulose, the croscarmellose sodium and the crushed apixaban in a hopper mixer for 15-25 min, and then mixing the intermediate material and magnesium stearate for 5-15 min;
3) adding the intermediate material obtained in the step 2) into a dry-method granulator for granulation, wherein the feeding frequency is controlled to be 8-30 Hz, the tabletting frequency is controlled to be 10-30 Hz, and the granulation frequency is controlled to be 10-30 Hz;
4) mixing the intermediate material obtained in the step 3) with magnesium stearate, and mixing for 5-15 min;
5) adding the intermediate material obtained in the step 4) into a tablet press for tabletting, wherein the tabletting speed is controlled to be 30.0-50.0 kilo tablets/hour, the average value of the main pressure is 8.00-10.00 KN, and the hardness of the plain tablets is 4.00-7.00 kg/cm2；
6) And (3) adding the plain tablets into a coating pan for coating, controlling the temperature of a tablet bed to be 35-45 ℃, and stopping when the weight of the coating is increased to 2-4%.
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| CN113577035A (en) * | 2021-09-07 | 2021-11-02 | 山东仁和制药有限公司 | Apixaban tablet and preparation method thereof |
| CN117562900A (en) * | 2023-12-01 | 2024-02-20 | 广东万泰科创药业有限公司 | New apixaban preparation composition with obvious clinical advantage and preparation method thereof |
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| CN102770126A (en) * | 2010-02-25 | 2012-11-07 | 百时美施贵宝公司 | Apixaban formulations |
| EP2554159A1 (en) * | 2011-08-04 | 2013-02-06 | ratiopharm GmbH | Dosage forms comprising apixaban and content uniformity enhancer |
| CN104095823A (en) * | 2014-07-08 | 2014-10-15 | 成都克莱蒙医药科技有限公司 | Method for preparing Apixaban tablets |
| CN107661301A (en) * | 2016-07-29 | 2018-02-06 | 天津市汉康医药生物技术有限公司 | A kind of Eliquis pharmaceutical composition and preparation method thereof |
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| CN102770126A (en) * | 2010-02-25 | 2012-11-07 | 百时美施贵宝公司 | Apixaban formulations |
| EP2554159A1 (en) * | 2011-08-04 | 2013-02-06 | ratiopharm GmbH | Dosage forms comprising apixaban and content uniformity enhancer |
| CN104095823A (en) * | 2014-07-08 | 2014-10-15 | 成都克莱蒙医药科技有限公司 | Method for preparing Apixaban tablets |
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Effective date of registration: 20191213 Address after: Room 902, 268 Huanghe West Road, Xinbei District, Changzhou City, Jiangsu Province Applicant after: Changzhou Hengbang Pharmaceutical Co., Ltd. Address before: 222047 Lianyungang economic and Technological Development Zone, Jiangsu Applicant before: Jiangsu Hausen Pharmaceutical Group Co., Ltd. |
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