CN112741812A - Adoxaban solid pharmaceutical composition and preparation method thereof - Google Patents
Adoxaban solid pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN112741812A CN112741812A CN202110162720.8A CN202110162720A CN112741812A CN 112741812 A CN112741812 A CN 112741812A CN 202110162720 A CN202110162720 A CN 202110162720A CN 112741812 A CN112741812 A CN 112741812A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K9/2813—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K9/2853—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Abstract
The invention relates to an Adoxaban solid pharmaceutical composition and a preparation method thereof, and provides an Adoxaban solid pharmaceutical composition which has simple process steps, good compressibility, better stability and less related substances, and has the advantages of good compressibility, excellent stability and less related substancesDissolution profile and commercially available pharmaceutical compositions
Description
Technical Field
The invention relates to the field of pharmaceutical compositions, and in particular relates to an idoxaban solid pharmaceutical composition containing a polyvinyl alcohol-polyethylene glycol copolymer and a preparation method thereof.
Background
The chemical name of the idoxaban tosylate monohydrate is: n- (5-chloro-2-pyridyl) -N' - [ (1S,2R,4S) -4- [ (dimethylamino) formyl ] -2- [ [4,5,6, 7-tetrahydro-5-methylthiazolo [5,4-C ] pyridin-2-yl) formyl ] amino ] cyclohexyl ] ethanediamide p-toluenesulfonate monohydrate, is a selective inhibitor of coagulation factor Xa, reduces thrombin generation and thrombosis, and has the following structural formula:
idoxaban tosylate exhibits good solubility in strongly acidic aqueous solutions, but its solubility in neutral aqueous solutions (neutral buffers, etc.) decreases, leading to a decrease in clinical efficacy.
CN104324015B improves dissolution by coating the edoxaban tablet with a coating agent containing 1 or more than 2 kinds selected from hydroxypropyl methylcellulose, ethylcellulose, hydroxypropyl cellulose and polyvinyl alcohol, however, the tablet prepared by the coating agent has more impurities and poor stability.
CN108743556A also discloses an idoxaban tablet, and the coating agent used is opadry coating powder. However, the formulation in this patent is complex and the process steps are cumbersome, wherein the idoxaban is sprayed onto the filler in dissolved form, on the one hand the idoxaban undergoes a process of dissolution and recrystallization, the crystal form is at risk of transformation, on the other hand, the idoxaban is added in slurry form, and the final content in the tablet cannot be accurately controlled.
Disclosure of Invention
Based on the technical problems, the invention provides an idoxaban solid pharmaceutical composition which has simple process steps, good compressibility, better stability and less related substances, and has a dissolution curve and a commercially available pharmaceutical composition
The dissolution curves were consistent.
In order to achieve the purpose, the technical scheme provided by the invention is as follows:
in one aspect, the invention provides an idoxaban solid medicamentA composition comprises idoxaban, a filler, a disintegrant, a binder, a lubricant, and a coating agent comprising
The adhesive is hydroxypropyl cellulose.
In some embodiments, the idoxaban is idoxaban tosylate monohydrate.
In some embodiments, the solid pharmaceutical composition comprises 75-85 parts of idoxaban tosylate monohydrate, 300 parts of filler 200-25 parts, 20-25 parts of disintegrant, 10-25 parts of binder, 2.5-5 parts of lubricant and 10-25 parts of coating agent by weight.
In some embodiments, the solid pharmaceutical composition comprises 12 to 22 parts of the coating agent, by weight.
In some embodiments, the solid pharmaceutical composition comprises 14 to 20 parts of the coating agent by weight.
In some embodiments, the filler is selected from mannitol, pregelatinized starch, microcrystalline cellulose, or a combination thereof.
In some embodiments, the bulking agent is mannitol and pregelatinized starch.
In some embodiments, the filler comprises 200 parts by weight of mannitol and 50-100 parts by weight of pregelatinized starch.
In some embodiments, the disintegrant is selected from crospovidone, sodium carboxymethyl starch, croscarmellose sodium, or combinations thereof.
In some embodiments, the disintegrant is crospovidone.
In some embodiments, the lubricant is selected from magnesium stearate, calcium stearate, or a combination thereof.
In some embodiments, the lubricant is magnesium stearate.
In some embodiments, the coating agent comprises titanium dioxide, talc, yellow iron oxide, and Kollicoat
In some embodiments, the coating agent comprises 5-20 parts by weight of titanium dioxide, 10-25 parts by weight of talcum powder, 1-15 parts by weight of yellow ferric oxide,
50-100 parts.
In some embodiments, the coating agent comprises titanium dioxide 10-15 parts, talc 15-20 parts, yellow iron oxide 5-10 parts, Kollicoat
60-70 parts.
In some embodiments, the idoxaban solid pharmaceutical composition is a tablet.
In another aspect, the invention provides a preparation method of the idoxaban solid pharmaceutical composition, which comprises the following steps: dissolving the adhesive in water to obtain slurry; according to the prescription, the Aidoxaban, the filler and the disintegrant are uniformly mixed, the slurry is added, then the mixture is granulated in a fluidized bed, dried and granulated, the lubricant is added and mixed, and the tablet core is obtained by tabletting, and the coating is obtained.
In some embodiments, the method of making comprises the steps of: dissolving hydroxypropyl cellulose in water to obtain slurry; according to the prescription amount, the idoxaban tosylate monohydrate, mannitol, pregelatinized starch and crospovidone are uniformly mixed, the slurry is added, then granulation is carried out in a fluidized bed, drying and granulation are carried out, magnesium stearate is added for mixing, tablet core is obtained by tabletting, and coating is carried out.
In some embodiments, the core has a hardness of 10-20 kg.
In some embodiments, the core has a hardness of 10-15 kg.
Has the advantages that: the idoxaban solid pharmaceutical composition provided by the invention has better compressibility, less impurity generation and better stability, and the dissolution curve of the composition is similar to that of a commercially available medicamentComposition comprising a metal oxide and a metal oxide
The dissolution curves were consistent.
Unless defined otherwise herein, scientific and technical terms used in connection with the present invention shall have the meanings that are understood by those of ordinary skill in the art.
Drawings
FIG. 1 shows the dissolution profile of example 1.
FIG. 2 shows the dissolution profile of example 2.
FIG. 3 shows the dissolution profile of example 3.
Detailed Description
The invention will be further described with reference to specific embodiments, and the advantages and features of the invention will become apparent as the description proceeds. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The examples are exemplary only and do not limit the scope of the invention in any way. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention, and that such changes and modifications may be made without departing from the spirit and scope of the invention.
EXAMPLE 1 examination of core hardness
Dissolving hydroxypropyl cellulose in water to prepare uniform slurry, uniformly mixing the idoxaban tosylate monohydrate, mannitol, pregelatinized starch and crospovidone according to the prescription amount, adding the slurry, granulating in a fluidized bed, drying, granulating, adding magnesium stearate, mixing, tabletting, and testing the hardness of the tablet core by a hardness tester to obtain tablet cores with the hardness of 6kg, 11kg and 14kg, namely the tablet core 1, the tablet core 2 and the tablet core 3. The formulation composition is shown in table 1:
TABLE 1
Taking the product, taking 900ml of pH6.6 phosphate buffer solution as dissolution medium according to dissolution and release rate determination method (0931, second method in the general rules of Chinese pharmacopoeia 2015 edition), rotating at 50 rpm, sampling at 10, 15, 20, 30, 45 and 60 minutes according to the method, detecting, and calculating cumulative dissolution rate. The dissolution data are shown in table 2.
Chromatographic conditions are as follows: octadecylsilane chemically bonded silica is used as a filler or a chromatographic column with equivalent efficiency, and phosphate buffer solution/acetonitrile is used as a mobile phase; the column temperature was 40 ℃; the detection wavelength is 290nm, and the sample injection amount is 10 muL. The amount of elution was calculated by the peak area according to the external standard method, and the results are shown in Table 2, and the elution curve is shown in FIG. 1. As Tween is added for solubilization after sampling is finished at 45min in the dissolution process, the dissolution data of 60min does not participate in the similar factor f2And (4) calculating.
TABLE 2
| Time/min | 10 | 15 | 20 | 30 | 45 | 60 |
| Tablet core 1 | 71.4 | 78.9 | 81.1 | 84.3 | 90.1 | 93.3 |
| Tablet core 2 | 70.0 | 75.3 | 79.7 | 84.6 | 89.4 | 90.8 |
| Tablet core 3 | 66.6 | 72.8 | 77.8 | 82.8 | 88.5 | 93.0 |
As can be seen from table 2, there is no significant difference in dissolution rate of the three hardness tablets at the hardness of the present invention.
EXAMPLE 2 examination of coating Agents
The preparation method of example 1 was adopted, tablet cores were prepared by controlling the hardness range to 10-15kg during tabletting, and then coating was performed separately, except that a self-grinding coating agent and Kollicoat were used as the coating agent
03F42132 (i.e., a coating agent containing hydroxypropylmethylcellulose as a main component as described in CN 104324015B); the coating was performed to give recipe 1, recipe 2 and recipe 3. The formulation composition is shown in Table 3, and the composition of the self-grinding coating agent is shown in Table 4.
TABLE 3
The preparation method of the self-grinding coating agent comprises the following steps: the prescribed amounts of titanium dioxide, talc, yellow iron oxide and
mixing was carried out to obtain a homogeneous yellow solid powder.
TABLE 4
The dissolution profiles of formulation 1, formulation 2, and the reference formulation in dissolution medium of phosphate buffer at ph6.6 were examined in the same manner as in example 1, and the results are shown in table 5 and fig. 2.
Wherein, the reference preparation is Aidoxaban tosylate tablet
The standard of 60mg from the first three-Co-Ltd of Japan, and reference preparations I and II were prepared for two batches.
TABLE 5
| Time (min) | 10 | 15 | 20 | 30 | 45 | 60 | f2 |
| Prescription 1 | 62.0 | 75.7 | 81.6 | 87.3 | 91.4 | 97.9 | 80 |
| Prescription 2 | 56.9 | 73.5 | 79.6 | 85.8 | 89.5 | 95.3 | 76 |
| Reference preparation II | 58.2 | 75.7 | 83.1 | 89.5 | 93.6 | 99.4 | / |
The results show that the dissolution rate of the formula 2 coated tablet is slower than that of formula 1, and compared with the dissolution data of the original study, formula 1 is found to be closer to the dissolution of the original study.
Example 3 examination of weight gain of coating
Tablet cores are obtained after tabletting by adopting the preparation method of the formula 1. The influence of different coating weight gains of the self-ground coating powder on the dissolution is examined. Taking the average tablet weight calculated by 100 preheated tablet cores as the initial tablet weight, and stopping coating when the dosage of the coating solution reaches 3.5% and 5.0% of the theoretical weight gain. Prescription 4 and prescription 5 are obtained, and the prescriptions are shown in table 6:
TABLE 6
The dissolution profiles of each formulation and reference formulation in dissolution medium of phosphate buffer at ph6.6 were examined in the same manner as in example 1 and the results are shown in table 7 and fig. 3.
TABLE 7
| Time/min | 10 | 15 | 20 | 30 | 45 | 60 | f2 |
| Prescription 4 | 64.8 | 72.8 | 76.7 | 82.2 | 86.5 | 96.5 | 74 |
| |
62.2 | 70.2 | 75.5 | 81.2 | 86.8 | 88.4 | 79 |
| Reference preparation I | 61.5 | 71.2 | 73.2 | 78.5 | 82.9 | 85.9 | / |
The results show that the coating agent dosage is within the range of 10-25mg, preferably 12-22mg, more preferably 14-20mg, the qualified idoxaban tosylate tablet can be obtained, and the dissolution behavior is similar to the original preparation.
EXAMPLE 4 detection of related substances
The related substances were measured for recipe 1 and recipe 3.
The related substances are determined by high performance liquid chromatography (China pharmacopoeia 2020 edition four-part general regulation 0512).
The test solution is prepared by respectively taking appropriate amount of coated tablets of formula 1 and formula 3, precisely weighing, adding appropriate amount of solvent to dissolve, and quantitatively diluting to obtain solution containing about 1.2mg of Adoxaban per 1 ml.
The control solution is precisely measured to obtain 1ml of the control solution, the control solution is placed in a 200ml measuring flask, diluted to the scale with the solvent and shaken up.
The system applicability solution takes a proper amount of an idoxaban tosylate reference substance and an impurity I reference substance, is dissolved by a solvent and is quantitatively diluted to prepare a solution containing about 1.2mg of idoxaban and 2.4 mu g of impurity I in every 1ml, and the solution is used as a positioning solution.
In the chromatographic condition, octadecylsilane chemically bonded silica is used as a filler or a chromatographic column with equivalent efficiency; phosphate buffer solution-acetonitrile is used as a mobile phase, and the detection wavelength is 290 nm; the column temperature was 40 ℃; the temperature of the sample chamber was 10 ℃ and the injection volume was 10. mu.L.
Through detection, the impurity I with the following structure is detected in the formula 3, the content is 0.05%, and the impurity I is not detected in the formula 1; neither recipe 1 nor recipe 3 detected other impurities.
Impurity I is 2- { [ (1R,2S,5S) -2- (2- ((5-chloropyridin-2-yl) amino) -2-oxoacetamido) -5- (dimethylcarbamoyl) cyclohexyl ] carbamoyl } -5-methyl-4, 5,6, 7-tetrahydro [1,3] thiazolo [5,4-c ] pyridine-5-oxide, of the formula:
it can be seen that the self-grinding coating agent of the present invention has less impurities.
Example 5
Preparing a prescription 1 into two batches, namely a batch 1 and a batch 2, respectively carrying out stability investigation under accelerated and long-term conditions, detecting the dissolution rate, and comparing the dissolution rate with a reference preparation namely the Aidoxaban tosylate tablet
Reference formulation ii was compared.
Taking the product, and according to determination method (0931, second method of the general rules of Chinese pharmacopoeia 2015 edition) of dissolution rate and release rate, using 900ml of pH6.0 phosphate buffer solution as dissolution medium, rotating speed is 50 r/min, operating according to the method, after 30 minutes, detecting dissolution rate, the dissolution rate with limit of 30min is 75% of labeled amount. Dissolution results are shown in tables 8-9 below.
TABLE 8
| Batch number (40 ℃ C. + -. 2 ℃ C., RH 75% + -. 5%) | 0 | 3 months old |
| Batch 1 | 89％ | 89％ |
| Batch 2 | 88％ | 88％ |
| Reference preparation II | 91％ | 82％ |
TABLE 9
| Batch number (25 ℃ C. + -. 2 ℃ C., |
0 | 3 months old |
| Batch 1 | 89％ | 87％ |
| Batch 2 | 88％ | 86％ |
| Reference preparation II | 91％ | 85％ |
Dissolution rate results under accelerated test and long-term test conditions show that the 3-month dissolution rate of the pharmaceutical composition of idoxaban tosylate is consistent with that of 0 in the accelerated condition (40 +/-2 ℃ and RH 75% +/-5%), but the dissolution rate of the pharmaceutical composition of idoxaban tosylate is reduced from 91% to 82% in the reference preparation II, and the dissolution rate of the pharmaceutical composition of idoxaban tosylate is reduced less in the long-term condition (25 +/-2 ℃ and RH 60% +/-5%), which indicates that the pharmaceutical composition of idoxaban tosylate has better stability.
Claims (10)
1. A solid pharmaceutical composition of Adoxaban comprises Adoxaban, filler, disintegrant, binder, lubricant and coating agent, wherein said coating agent comprises Kollicoat
The adhesive is hydroxypropyl cellulose; preferably, the idoxaban is idoxaban tosylate monohydrate.
2. The pharmaceutical composition as claimed in claim 1, wherein the solid pharmaceutical composition comprises 75-85 parts by weight of idoxaban tosylate monohydrate, 300 parts by weight of filler 200-; preferably, the solid pharmaceutical composition comprises 12 to 22 parts of coating agent; further preferably, the solid pharmaceutical composition contains 14 to 20 parts of coating agent.
3. A pharmaceutical composition according to claim 1, wherein the filler is selected from mannitol, pregelatinized starch, microcrystalline cellulose, or a combination thereof; preferably, the bulking agent is mannitol and pregelatinized starch; further preferably, the filler comprises, by weight, 150-200 parts of mannitol and 50-100 parts of pregelatinized starch.
4. A pharmaceutical composition according to claim 1, wherein the disintegrant is selected from crospovidone, sodium carboxymethyl starch, croscarmellose sodium, or combinations thereof; preferably, the disintegrant is crospovidone.
5. A pharmaceutical composition according to claim 1, wherein said lubricant is selected from the group consisting of magnesium stearate, calcium stearate, and combinations thereof; preferably, the lubricant is magnesium stearate.
6. The pharmaceutical composition of claim 1, wherein the coating agent comprises titanium dioxide, talc, yellow iron oxide, Kollicoat
Preferably, the coating agent comprises 5-20 parts of titanium dioxide, 10-25 parts of talcum powder, 1-15 parts of yellow ferric oxide and Kollicoat by weight
50-100 parts; preferably, the coating agent comprisesComprises 10-15 parts of titanium dioxide, 15-20 parts of talcum powder, 5-10 parts of yellow ferric oxide and Kollicoat
60-70 parts.
7. The pharmaceutical composition of claim 1, wherein the idoxaban solid pharmaceutical composition is a tablet.
8. A process for the preparation of a pharmaceutical composition according to any one of claims 1 to 7, comprising the steps of: dissolving the adhesive in water to obtain slurry; according to the prescription, the Aidoxaban, the filler and the disintegrant are uniformly mixed, the slurry is added, then the mixture is granulated in a fluidized bed, dried and granulated, the lubricant is added and mixed, and the tablet core is obtained by tabletting, and the coating is obtained.
9. A process for preparing a pharmaceutical composition according to claim 8, comprising the steps of: dissolving hydroxypropyl cellulose in water to obtain slurry; according to the prescription amount, the idoxaban tosylate monohydrate, mannitol, pregelatinized starch and crospovidone are uniformly mixed, the slurry is added, then granulation is carried out in a fluidized bed, drying and granulation are carried out, magnesium stearate is added for mixing, tablet core is obtained by tabletting, and coating is carried out.
10. A process for the preparation of a pharmaceutical composition according to any of claims 8 to 9 wherein the core has a hardness of 10 to 20 kg; preferably, the hardness of the tablet core is 10-15 kg.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114939111A (en) * | 2022-06-17 | 2022-08-26 | 哈药集团技术中心 | Preparation method of Aiduoshaban tablets |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017107857A1 (en) * | 2015-12-24 | 2017-06-29 | 江苏恒瑞医药股份有限公司 | Solid pharmaceutical composition comprising diamine derivative or salt thereof |
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2021
- 2021-02-05 CN CN202110162720.8A patent/CN112741812A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017107857A1 (en) * | 2015-12-24 | 2017-06-29 | 江苏恒瑞医药股份有限公司 | Solid pharmaceutical composition comprising diamine derivative or salt thereof |
Non-Patent Citations (1)
| Title |
|---|
| 第一三共英国有限公司: "Lixiana 30mg 薄膜包衣片", 《LIXIANA 30MG 薄膜包衣片》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114939111A (en) * | 2022-06-17 | 2022-08-26 | 哈药集团技术中心 | Preparation method of Aiduoshaban tablets |
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