CN104784147B - A kind of dabigatran etexilate methanesulfonate pharmaceutical capsules composition and preparation method thereof - Google Patents
A kind of dabigatran etexilate methanesulfonate pharmaceutical capsules composition and preparation method thereof Download PDFInfo
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- CN104784147B CN104784147B CN201510024276.8A CN201510024276A CN104784147B CN 104784147 B CN104784147 B CN 104784147B CN 201510024276 A CN201510024276 A CN 201510024276A CN 104784147 B CN104784147 B CN 104784147B
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- dabigatran etexilate
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- 229960000288 dabigatran etexilate Drugs 0.000 title claims abstract description 112
- 239000000203 mixture Substances 0.000 title claims abstract description 107
- 239000002775 capsule Substances 0.000 title claims abstract description 95
- KSGXQBZTULBEEQ-UHFFFAOYSA-N dabigatran etexilate Chemical compound C1=CC(C(N)=NC(=O)OCCCCCC)=CC=C1NCC1=NC2=CC(C(=O)N(CCC(=O)OCC)C=3N=CC=CC=3)=CC=C2N1C KSGXQBZTULBEEQ-UHFFFAOYSA-N 0.000 title claims abstract 13
- 238000002360 preparation method Methods 0.000 title claims description 100
- 239000007931 coated granule Substances 0.000 claims abstract description 85
- 239000002245 particle Substances 0.000 claims abstract description 67
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims abstract description 66
- 239000011975 tartaric acid Substances 0.000 claims abstract description 63
- 235000002906 tartaric acid Nutrition 0.000 claims abstract description 63
- 238000002156 mixing Methods 0.000 claims abstract description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 100
- 235000020985 whole grains Nutrition 0.000 claims description 100
- 239000000853 adhesive Substances 0.000 claims description 92
- 230000001070 adhesive effect Effects 0.000 claims description 92
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 53
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 53
- 239000012530 fluid Substances 0.000 claims description 50
- 238000005469 granulation Methods 0.000 claims description 50
- 230000003179 granulation Effects 0.000 claims description 50
- 238000003756 stirring Methods 0.000 claims description 50
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 50
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 42
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 37
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 238000000034 method Methods 0.000 abstract description 9
- 239000000463 material Substances 0.000 abstract description 4
- 238000000605 extraction Methods 0.000 abstract description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 abstract description 2
- XETBXHPXHHOLOE-UHFFFAOYSA-N dabigatran etexilate methanesulfonate Chemical compound CS(O)(=O)=O.C1=CC(C(\N)=N/C(=O)OCCCCCC)=CC=C1NCC1=NC2=CC(C(=O)N(CCC(=O)OCC)C=3N=CC=CC=3)=CC=C2N1C XETBXHPXHHOLOE-UHFFFAOYSA-N 0.000 description 99
- 239000003292 glue Substances 0.000 description 23
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 21
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 21
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 21
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 21
- 238000004090 dissolution Methods 0.000 description 19
- 230000000052 comparative effect Effects 0.000 description 17
- 238000009472 formulation Methods 0.000 description 17
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 15
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 15
- 239000000843 powder Substances 0.000 description 15
- 235000012222 talc Nutrition 0.000 description 15
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 13
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 13
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 13
- 229920000609 methyl cellulose Polymers 0.000 description 11
- 239000001923 methylcellulose Substances 0.000 description 11
- 235000010981 methylcellulose Nutrition 0.000 description 11
- 239000001768 carboxy methyl cellulose Substances 0.000 description 9
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 9
- 229960003850 dabigatran Drugs 0.000 description 8
- 239000004575 stone Substances 0.000 description 8
- 235000013312 flour Nutrition 0.000 description 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 239000011248 coating agent Substances 0.000 description 5
- 238000000576 coating method Methods 0.000 description 5
- 239000011162 core material Substances 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 229940098779 methanesulfonic acid Drugs 0.000 description 5
- 150000007524 organic acids Chemical class 0.000 description 5
- -1 Methanesulfonic acid dabigatran Ester Chemical class 0.000 description 4
- 239000011149 active material Substances 0.000 description 4
- YBSJFWOBGCMAKL-UHFFFAOYSA-N dabigatran Chemical compound N=1C2=CC(C(=O)N(CCC(O)=O)C=3N=CC=CC=3)=CC=C2N(C)C=1CNC1=CC=C(C(N)=N)C=C1 YBSJFWOBGCMAKL-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 102000009123 Fibrin Human genes 0.000 description 3
- 108010073385 Fibrin Proteins 0.000 description 3
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 3
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 3
- 230000004308 accommodation Effects 0.000 description 3
- 239000007767 bonding agent Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229950003499 fibrin Drugs 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- 239000012738 dissolution medium Substances 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- 229940123900 Direct thrombin inhibitor Drugs 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000009506 drug dissolution testing Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 239000008203 oral pharmaceutical composition Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 229960005137 succinic acid Drugs 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides coated granule two parts of a kind of dabigatran etexilate methanesulfonate pharmaceutical capsules composition, including the coated granule of dabigatran etexilate methanesulfonate, tartaric acid, two parts particle fills capsule afterwards by evenly mixing；The volume and weight of the capsule particle prepared by prescription of the present invention and technique is smaller, and result of extraction is substantially better than prior art, while has the advantages of relevant material is lower, and stability is more preferable, quality more sorrow.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, and in particular to a kind of dabigatran etexilate methanesulfonate pharmaceutical capsules composition and its
Preparation method.
Background technology
Dabigatran etcxilate is a kind of new IIa factor direct thrombin inhibitors, is the pro-drug of dabigatran, main
It is used for the prevention and treatment for acute and chronic thrombotic disease.Orally after gastrointestinal absorption, it is converted into vivo
Dabigatran with direct anticoagulant active.Dabigatran is incorporated into the fibrin specific binding site of fibrin ferment, prevents
Fibrinogen is cracked into fibrin, so as to block the final step and thrombosis of blood coagulation waterfall network.
Patent No. ZL03805473.6 patents disclose a kind of oral pharmaceutical composition of dabigatran etexilate methanesulfonate, its
Middle composition can be prepared into capsule, and each particle in capsule is a complete pill, be respectively from inside outwards to contain
There are core material layer, separation layer, active material layer, the coating of organic acid, the pill of acquisition is finally loaded into capsule.Its organic acid selects
From tartaric acid, fumaric acid, butanedioic acid, citric acid, malic acid, glutamic acid or aspartic acid or its a kind of hydrate or hydrochlorate
Deng, its Figure of description 1 it can be seen that having complete layering in each of which particle, because the patent is using capsule core medicine-feeding,
There is upper dose to be difficult to control, medicine accommodation layer is uneven, and reappearance is poor between batch, the problems such as product yield is relatively low.
The patent of Application No. 201310047056.8 also discloses that a kind of oral drug regimen of dabigatran etexilate methanesulfonate
Thing, capsule can be prepared into, but disclose another grain structure, from inside outwards respectively active material capsule core material, isolation
Layer, organic acid layer, separation layer, there is complete layering in each of which particle.Because patent preparation technology is by active material
Substantial amounts of filler and/or adhesive need to be added when being prepared into capsule core so that the volume and weight of particle is larger, needs to select during filling
With the capsule of larger specification, compliance when causing the patient to take is poor.Moreover, active material is prepared into capsule core, there is also not
The defects of easily dissolution is complete, while upper organic acid content also be present and be difficult to control in the preparation technology, organic acid layer is uneven, between batch
The problems such as reappearance is poor, and product yield is relatively low.
Above-mentioned two patents pass through in the presence of needs successively to be coated, time-consuming longer so as to cause complex process, therefore, this
Field still needs that a kind of preparation technology is simple, at the same and can fully ensure that the dissolution of dabigatran etexilate methanesulfonate new recipe and
Preparation technology, and the present invention meets such demand.
The content of the invention
Need not successively it be coated in view of the above-mentioned problems, it is an object of the invention to provide one kind, technique is simple, while can fill again
Code insurance demonstrate,proves the new pharmaceutical compositions and preparation method of dabigatran etexilate methanesulfonate dissolution.
It is an object of the invention to disclose a kind of new dabigatran etexilate methanesulfonate pharmaceutical capsules composition, the medicine
Composition includes following two parts：Part I：Coated granule containing dabigatran etexilate methanesulfonate；Part II：Contain wine
The coated granule of stone acid；The Part I particle fills capsule afterwards by evenly mixing with Part II particle.
Further, Part I and Part II contain in dabigatran etexilate methanesulfonate pharmaceutical capsules composition of the present invention
There is adhesive.
Wherein, the mass ratio of dabigatran etexilate methanesulfonate and adhesive is (50~200) in Part I：(4~18)；
Preferably, the mass ratio of dabigatran etexilate methanesulfonate and adhesive is (86~173) in Part I：(7~16)；More preferably
, the mass ratio of dabigatran etexilate methanesulfonate and hydroxypropylcellulose is 86 in Part I：7 or 127：11 or 173：16.
Wherein, the mass ratio of Part II mesotartaric acid and adhesive is (50~200)：(5~22)；Preferably,
The mass ratio of two part mesotartaric acid and adhesive is (86~173)：(9~19)；It is furthermore preferred that Part II mesotartaric acid
Mass ratio with adhesive is 86：9 or 127：14 or 173：19.
Adhesive of the present invention is polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropyl methylcellulose, methylcellulose
Or carboxymethyl cellulose；It is preferred that hydroxypropylcellulose.
Further, the pharmaceutical composition of the present invention of per unit preparation contains following components：Part I：Methanesulfonic acid reach than
Add crowd ester 86.0mg, hydroxypropylcellulose 7.0mg, talcum powder 2.2mg；Part II：Tartaric acid 86.0mg, hydroxypropylcellulose
9.0mg, talcum powder 4.3mg.
Or the pharmaceutical composition of the present invention of per unit preparation contains following components：Part I：Methanesulfonic acid dabigatran
Ester 127.0mg, hydroxypropylcellulose 11.0mg, talcum powder 3.2mg；Part II：Tartaric acid 127.0mg, hydroxypropylcellulose
14.0mg, talcum powder 6.3mg.
Or the pharmaceutical composition of the present invention of per unit preparation contains following components：Part I：Methanesulfonic acid dabigatran
Ester 173.0mg, hydroxypropylcellulose 16.0mg, talcum powder 4.3mg；Part II：Tartaric acid 173.0mg, hydroxypropylcellulose
19.0mg, talcum powder 8.6mg.
Or the pharmaceutical composition of the present invention of per unit preparation contains following components：Part I：Methanesulfonic acid dabigatran
Ester 126.8mg, hydroxypropylcellulose 11.3mg, talcum powder 3.2mg；Part II：Tartaric acid 126.0mg, hydroxypropylcellulose
13.6mg, talcum powder 6.3mg.
Or the pharmaceutical composition of the present invention of per unit preparation contains following components：Part I：Methanesulfonic acid dabigatran
Ester 86.5mg, hydroxypropylcellulose 7.0mg, talcum powder 2.1mg；Part II：Tartaric acid 86.0mg, hydroxypropylcellulose 9.0mg are sliding
Stone flour 4.3mg.
It is another object of the present invention to provide a kind of preparation of dabigatran etexilate methanesulfonate pharmaceutical capsules composition
Method, it is comprised the steps of：
1) dabigatran etexilate methanesulfonate particle is prepared, is coated；
2) tartaric acid granulate, coating are prepared；
3) capsule is filled after particle made from step 1 and step 2 is well mixed.
Dabigatran etexilate methanesulfonate capsule prepared by the present invention has advantages below：
1st, compared with prior art, directly filling capsule, technique is more simple after the present invention prepares particle, it is not necessary to successively
Coating, in dissolution contrast test, sample of the embodiment of the present invention is in 10min and 15min, the RSD% of 12 sample dissolution rates
Significantly lower than Comparative formulation sample, illustrate that the uniformity of sample prepared by the present invention is substantially better than Comparative formulation, overcome existing
The upper more difficult control of dose in technology, the problems such as medicine accommodation layer is uneven；Filler need not additionally be added by being additionally, since, the present invention
The volume and weight of the particle of preparation is smaller, without the capsule from larger specification, so as to improve the compliance of patient.
2nd, the capsule dissolution that prepared by the present invention is very fast, and the dissolution rate in 10min, 15min, 20min is above identical bar
Comparative formulation sample under part, in 45min, the dissolution of Comparative formulation is still below sample prepared by the present invention, illustrates the present invention
The capsule result of extraction of preparation is more preferable.
3rd, capsule prepared by the present invention total impurities after accelerating 6 months is less than 1%, hence it is evident that material relevant less than Comparative formulation
Lower, stability is more preferable, quality more sorrow.
Brief description of the drawings
Fig. 1 dabigatran etexilate methanesulfonate capsule overall structure diagrams
Fig. 2 dabigatran etexilate methanesulfonate coated granule structural representations
Fig. 3 tartaric acid coated granule structural representations
Embodiment
The preparation of the dabigatran etexilate methanesulfonate capsule of embodiment 1~3
Prescription：Prepare the prescription of 1000 dabigatran etexilate methanesulfonate capsules
Preparation technology：
Part I：The preparation of dabigatran etexilate methanesulfonate coated granule
(1) pelletize：The hydroxypropyl methylcellulose of recipe quantity 40% is taken, adds appropriate isopropanol to be configured to 2% solution, as viscous
Mixture is standby；Adhesive is added in dabigatran etexilate methanesulfonate, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining hydroxypropyl methylcellulose is taken, adds appropriate isopropanol to be configured to 2% solution, adds Part I
The talcum powder of prescription total amount 2.2%, stirs, standby；Particle after whole grain in step (1) is placed in fluid bed, carried out
Coating, is produced.
Part II：The preparation of tartaric acid coated granule
(1) pelletize：The hydroxypropyl methylcellulose of recipe quantity 10% is taken, adds suitable quantity of water to be configured to 4% solution, as adhesive
It is standby；Adhesive is added in tartaric acid, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining hydroxypropyl methylcellulose is taken, adds suitable quantity of water to be configured to 4% solution, adds Part II prescription
The talcum powder of total amount 4.3%, stirs, standby；Particle after whole grain in step (1) is placed in fluid bed, is coated,
Produce.
Take above-mentioned two parts coated granule to be mixed, obtain dispersed mixture, said mixture is filled into glue
Capsule, produce.
The preparation of the dabigatran etexilate methanesulfonate capsule of embodiment 4~6
Prescription：Prepare the prescription of 1000 dabigatran etexilate methanesulfonate capsules
Preparation technology：
Part I：The preparation of dabigatran etexilate methanesulfonate coated granule
(1) pelletize：The polyvinylpyrrolidone of recipe quantity 40% is taken, adds appropriate isopropanol to be configured to 3% solution, as
Adhesive is standby；Adhesive is added in dabigatran etexilate methanesulfonate, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining polyvinylpyrrolidone is taken, adds appropriate isopropanol to be configured to 3% solution, adds first
The talcum powder of office side's total amount 2.2%, stirs, standby；Particle after whole grain in step (1) is placed in fluid bed, entered
Row coating, is produced.
Part II：The preparation of tartaric acid coated granule
(1) pelletize：The polyvinylpyrrolidone of recipe quantity 10% is taken, adds suitable quantity of water to be configured to 5% solution, as bonding
Agent is standby；Adhesive is added in tartaric acid, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining polyvinylpyrrolidone is taken, adds suitable quantity of water to be configured to 5% solution, is added at Part II
The talcum powder of square total amount 4.3%, stirs, standby；Particle after whole grain in step (1) is placed in fluid bed, wrapped
Clothing, produce.
Take above-mentioned two parts coated granule to be mixed, obtain dispersed mixture, said mixture is filled into glue
Capsule, produce.
The preparation of the dabigatran etexilate methanesulfonate capsule of embodiment 7
Prescription：Prepare the prescription of 1000 dabigatran etexilate methanesulfonate capsules
Preparation technology：
Part I：The preparation of dabigatran etexilate methanesulfonate coated granule
(1) pelletize：2.8g hydroxypropylcelluloses are taken, add appropriate isopropanol to be configured to 3% solution, it is standby as adhesive；
Adhesive is added in dabigatran etexilate methanesulfonate, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining hydroxypropylcellulose is taken, adds appropriate isopropanol to be configured to 3% solution, adds 2.2g talcums
Powder, stir, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces.
Part II：The preparation of tartaric acid coated granule
(1) pelletize：0.9g hydroxypropylcelluloses are taken, add suitable quantity of water to be configured to 5% solution, it is standby as adhesive；Will be viscous
Mixture is added in tartaric acid, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining hydroxypropylcellulose is taken, adds suitable quantity of water to be configured to 5% solution, 4.3g talcum powder is added, stirs
Mix uniformly, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces.
Take above-mentioned two parts coated granule to be mixed, obtain dispersed mixture, said mixture is filled into glue
Capsule, produce.
The preparation of the dabigatran etexilate methanesulfonate capsule of embodiment 8
Prescription：Prepare the prescription of 1000 dabigatran etexilate methanesulfonate capsules
Preparation technology：
Part I：The preparation of dabigatran etexilate methanesulfonate coated granule
(1) pelletize：4.4g hydroxypropylcelluloses are taken, add appropriate isopropanol to be configured to 3% solution, it is standby as adhesive；
Adhesive is added in dabigatran etexilate methanesulfonate, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining hydroxypropylcellulose is taken, adds appropriate isopropanol to be configured to 3% solution, adds 3.2g talcums
Powder, stir, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces.
Part II：The preparation of tartaric acid coated granule
(1) pelletize：1.4g hydroxypropylcelluloses are taken, add suitable quantity of water to be configured to 5% solution, it is standby as adhesive；Will be viscous
Mixture is added in tartaric acid, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining hydroxypropylcellulose is taken, adds suitable quantity of water to be configured to 5% solution, 6.3g talcum powder is added, stirs
Mix uniformly, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces.
Take above-mentioned two parts coated granule to be mixed, obtain dispersed mixture, said mixture is filled into glue
Capsule, produce.
The preparation of the dabigatran etexilate methanesulfonate capsule of embodiment 9
Prescription：Prepare the prescription of 1000 dabigatran etexilate methanesulfonate capsules
Preparation technology：
Part I：The preparation of dabigatran etexilate methanesulfonate coated granule
(1) pelletize：4.5g hydroxypropylcelluloses are taken, add appropriate isopropanol to be configured to 3% solution, it is standby as adhesive；
Adhesive is added in dabigatran etexilate methanesulfonate, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining hydroxypropylcellulose is taken, adds appropriate isopropanol to be configured to 3% solution, adds 3.2g talcums
Powder, stir, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces.
Part II：The preparation of tartaric acid coated granule
(1) pelletize：1.4g hydroxypropylcelluloses are taken, add suitable quantity of water to be configured to 5% solution, it is standby as adhesive；Will be viscous
Mixture is added in tartaric acid, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining hydroxypropylcellulose is taken, adds suitable quantity of water to be configured to 5% solution, 6.3g talcum powder is added, stirs
Mix uniformly, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces.
Take above-mentioned two parts coated granule to be mixed, obtain dispersed mixture, said mixture is filled into glue
Capsule, produce.
The preparation of the dabigatran etexilate methanesulfonate capsule of embodiment 10
Prescription：Prepare the prescription of 1000 dabigatran etexilate methanesulfonate capsules
Preparation technology：
Part I：The preparation of dabigatran etexilate methanesulfonate coated granule
(1) pelletize：6.4g hydroxypropylcelluloses are taken, add appropriate isopropanol to be configured to 3% solution, it is standby as adhesive；
Adhesive is added in dabigatran etexilate methanesulfonate, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining hydroxypropylcellulose is taken, adds appropriate isopropanol to be configured to 3% solution, adds 4.3g talcums
Powder, stir, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces.
Part II：The preparation of tartaric acid coated granule
(1) pelletize：1.9g hydroxypropylcelluloses are taken, add suitable quantity of water to be configured to 5% solution, it is standby as adhesive；Will be viscous
Mixture is added in tartaric acid, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining hydroxypropylcellulose is taken, adds suitable quantity of water to be configured to 5% solution, 8.6g talcum powder is added, stirs
Mix uniformly, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces.
Take above-mentioned two parts coated granule to be mixed, obtain dispersed mixture, said mixture is filled into glue
Capsule, produce.
The preparation of the dabigatran etexilate methanesulfonate capsule of embodiment 11~15
Prescription：Prepare the prescription of 1000 dabigatran etexilate methanesulfonate capsules
Preparation technology：
Part I：The preparation of dabigatran etexilate methanesulfonate coated granule
(1) pelletize：The hydroxypropylcellulose of recipe quantity 40% is taken, adds appropriate isopropanol to be configured to 2% solution, as bonding
Agent is standby；Adhesive is added in dabigatran etexilate methanesulfonate, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining hydroxypropylcellulose is taken, adds appropriate isopropanol to be configured to 2% solution, is added at Part I
The talcum powder of square total amount 2.2%, stirs, standby；Particle after whole grain in step (1) is placed in fluid bed, wrapped
Clothing, produce.
Part II：The preparation of tartaric acid coated granule
(1) pelletize：The methylcellulose of recipe quantity 10% is taken, adds suitable quantity of water to be configured to 5% solution, it is standby as adhesive
With；Adhesive is added in tartaric acid, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining methylcellulose is taken, adds suitable quantity of water to be configured to 5% solution, it is total to add Part II prescription
The talcum powder of amount 4.3%, stirs, standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, i.e.,
.Take above-mentioned two parts coated granule to be mixed, obtain dispersed mixture, said mixture is filled into capsule, i.e.,
.
The preparation of the dabigatran etexilate methanesulfonate capsule of embodiment 16~20
Prescription：Prepare the prescription of 1000 dabigatran etexilate methanesulfonate capsules
Preparation technology：
Part I：The preparation of dabigatran etexilate methanesulfonate coated granule
(1) pelletize：The hydroxypropylcellulose of recipe quantity 40% is taken, adds appropriate isopropanol to be configured to 4% solution, as bonding
Agent is standby；Adhesive is added in dabigatran etexilate methanesulfonate, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining hydroxypropylcellulose is taken, adds appropriate isopropanol to be configured to 4% solution, is added at Part I
The talcum powder of square total amount 2.2%, stirs, standby；Particle after whole grain in step (1) is placed in fluid bed, wrapped
Clothing, produce.
Part II：The preparation of tartaric acid coated granule
(1) pelletize：The carboxymethyl cellulose of recipe quantity 10% is taken, adds suitable quantity of water to be configured to 5% solution, as adhesive
It is standby；Adhesive is added in tartaric acid, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining carboxymethyl cellulose is taken, adds suitable quantity of water to be configured to 5% solution, adds Part II prescription
The talcum powder of total amount 4.3%, stirs, standby；Particle after whole grain in step (1) is placed in fluid bed, is coated,
Produce.
Take above-mentioned two parts coated granule to be mixed, obtain dispersed mixture, said mixture is filled into glue
Capsule, produce.
Embodiment 21
Prescription：Prepare the prescription of 1000 dabigatran etexilate methanesulfonate capsules
Preparation technology：
Part I：The preparation of dabigatran etexilate methanesulfonate coated granule
(1) pelletize：1.6g hydroxypropylcelluloses are taken, add appropriate isopropanol to be configured to 3% solution, it is standby as adhesive；
Adhesive is added in dabigatran etexilate methanesulfonate, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining hydroxypropylcellulose is taken, adds appropriate isopropanol to be configured to 4% solution, adds 1.2g talcums
Powder, stir, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces.
Part II：The preparation of tartaric acid coated granule
(1) pelletize：0.5g polyvinylpyrrolidones are taken, add suitable quantity of water to be configured to 4% solution, it is standby as adhesive；
Adhesive is added in tartaric acid, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining polyvinylpyrrolidone is taken, adds suitable quantity of water to be configured to 4% solution, adds 9.2g talcums
Powder, stir, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces.
Take above-mentioned two parts coated granule to be mixed, obtain dispersed mixture, said mixture is filled into glue
Capsule, produce.
Embodiment 22
Prescription：Prepare the prescription of 1000 dabigatran etexilate methanesulfonate capsules
Preparation technology：
Part I：The preparation of dabigatran etexilate methanesulfonate coated granule
(1) pelletize：7.2g polyvinylpyrrolidones are taken, add appropriate isopropanol to be configured to 3% solution, it is standby as adhesive
With；Adhesive is added in dabigatran etexilate methanesulfonate, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining polyvinylpyrrolidone is taken, adds appropriate isopropanol to be configured to 3% solution, 1.5g is added and slides
Stone flour, stir, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces.
Part II：The preparation of tartaric acid coated granule
(1) pelletize：0.5g hydroxypropylcelluloses are taken, add suitable quantity of water to be configured to 6% solution, it is standby as adhesive；Will be viscous
Mixture is added in tartaric acid, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining hydroxypropylcellulose is taken, adds suitable quantity of water to be configured to 5% solution, 9.2g talcum powder is added, stirs
Mix uniformly, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces.
Take above-mentioned two parts coated granule to be mixed, obtain dispersed mixture, said mixture is filled into glue
Capsule, produce.
Embodiment 23
Prescription：Prepare the prescription of 1000 dabigatran etexilate methanesulfonate capsules
Preparation technology：
Part I：The preparation of dabigatran etexilate methanesulfonate coated granule
(1) pelletize：1.7g hydroxypropyl methylcelluloses are taken, add appropriate isopropanol to be configured to 2% solution, it is standby as adhesive
With；Adhesive is added in dabigatran etexilate methanesulfonate, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining hydroxypropyl methylcellulose is taken, adds appropriate isopropanol to be configured to 3% solution, adds 4.6g talcums
Powder, stir, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces.
Part II：The preparation of tartaric acid coated granule
(1) pelletize：0.5g methylcellulose is taken, adds suitable quantity of water to be configured to 5% solution, it is standby as adhesive；Will be viscous
Mixture is added in tartaric acid, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining methylcellulose is taken, adds suitable quantity of water to be configured to 5% solution, 9.2g talcum powder is added, stirs
Mix uniformly, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces.
Take above-mentioned two parts coated granule to be mixed, obtain dispersed mixture, said mixture is filled into glue
Capsule, produce.
Embodiment 24
Prescription：Prepare the prescription of 1000 dabigatran etexilate methanesulfonate capsules
Preparation technology：
Part I：The preparation of dabigatran etexilate methanesulfonate coated granule
(1) pelletize：7.2g hydroxypropyl methylcelluloses are taken, add appropriate isopropanol to be configured to 2% solution, it is standby as adhesive
With；Adhesive is added in dabigatran etexilate methanesulfonate, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining hydroxypropyl methylcellulose is taken, adds appropriate isopropanol to be configured to 3% solution, adds 4.9g talcums
Powder, stir, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces.
Part II：The preparation of tartaric acid coated granule
(1) pelletize：0.5g methylcellulose is taken, adds suitable quantity of water to be configured to 4% solution, it is standby as adhesive；Will be viscous
Mixture is added in tartaric acid, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining methylcellulose is taken, adds suitable quantity of water to be configured to 4% solution, 9.2g talcum powder is added, stirs
Mix uniformly, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces.
Take above-mentioned two parts coated granule to be mixed, obtain dispersed mixture, said mixture is filled into glue
Capsule, produce.
Embodiment 25
Prescription：Prepare the prescription of 1000 dabigatran etexilate methanesulfonate capsules
Preparation technology：
Part I：The preparation of dabigatran etexilate methanesulfonate coated granule
(1) pelletize：1.6g polyvinylpyrrolidones are taken, add appropriate isopropanol to be configured to 3% solution, it is standby as adhesive
With；Adhesive is added in dabigatran etexilate methanesulfonate, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining polyvinylpyrrolidone is taken, adds appropriate isopropanol to be configured to 4% solution, 4.6g is added and slides
Stone flour, stir, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces.
Part II：The preparation of tartaric acid coated granule
(1) pelletize：2.2g methylcellulose is taken, adds suitable quantity of water to be configured to 3% solution, it is standby as adhesive；Will be viscous
Mixture is added in tartaric acid, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining methylcellulose is taken, adds suitable quantity of water to be configured to 5% solution, 10.0g talcum powder is added, stirs
Mix uniformly, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces.
Take above-mentioned two parts coated granule to be mixed, obtain dispersed mixture, said mixture is filled into glue
Capsule, produce.
Embodiment 26
Prescription：Prepare the prescription of 1000 dabigatran etexilate methanesulfonate capsules
Preparation technology：
Part I：The preparation of dabigatran etexilate methanesulfonate coated granule
(1) pelletize：7.2g polyvinylpyrrolidones are taken, add appropriate isopropanol to be configured to 3% solution, it is standby as adhesive
With；Adhesive is added in dabigatran etexilate methanesulfonate, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining polyvinylpyrrolidone is taken, adds appropriate isopropanol to be configured to 4% solution, 4.9g is added and slides
Stone flour, stir, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces.
Part II：The preparation of tartaric acid coated granule
(1) pelletize：2.2g methylcellulose is taken, adds suitable quantity of water to be configured to 5% solution, it is standby as adhesive；Will be viscous
Mixture is added in tartaric acid, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining methylcellulose is taken, adds suitable quantity of water to be configured to 4% solution, 10.0g talcum powder is added, stirs
Mix uniformly, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces.
Take above-mentioned two parts coated granule to be mixed, obtain dispersed mixture, said mixture is filled into glue
Capsule, produce.
Embodiment 27
Prescription：Prepare the prescription of 1000 dabigatran etexilate methanesulfonate capsules
Preparation technology：
Part I：The preparation of dabigatran etexilate methanesulfonate coated granule
(1) pelletize：2.8g polyvinylpyrrolidones are taken, add appropriate isopropanol to be configured to 2% solution, it is standby as adhesive
With；Adhesive is added in dabigatran etexilate methanesulfonate, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining polyvinylpyrrolidone is taken, adds appropriate isopropanol to be configured to 2% solution, 2.1g is added and slides
Stone flour, stir, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces.
Part II：The preparation of tartaric acid coated granule
(1) pelletize：1.9g carboxymethyl celluloses are taken, add suitable quantity of water to be configured to 4% solution, it is standby as adhesive；Will
Adhesive is added in tartaric acid, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining carboxymethyl cellulose is taken, adds suitable quantity of water to be configured to 4% solution, adds 4.7g talcum powder,
Stir, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces.
Take above-mentioned two parts coated granule to be mixed, obtain dispersed mixture, said mixture is filled into glue
Capsule, produce.
Embodiment 28
Prescription：Prepare the prescription of 1000 dabigatran etexilate methanesulfonate capsules
Preparation technology：
Part I：The preparation of dabigatran etexilate methanesulfonate coated granule
(1) pelletize：6.4g polyvinylpyrrolidones are taken, add appropriate isopropanol to be configured to 4% solution, it is standby as adhesive
With；Adhesive is added in dabigatran etexilate methanesulfonate, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining polyvinylpyrrolidone is taken, adds appropriate isopropanol to be configured to 3% solution, 2.3g is added and slides
Stone flour, stir, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces.
Part II：The preparation of tartaric acid coated granule
(1) pelletize：1.9g carboxymethyl celluloses are taken, add suitable quantity of water to be configured to 5% solution, it is standby as adhesive；Will
Adhesive is added in tartaric acid, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining carboxymethyl cellulose is taken, adds suitable quantity of water to be configured to 4% solution, adds 4.7g talcum powder,
Stir, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces.
Take above-mentioned two parts coated granule to be mixed, obtain dispersed mixture, said mixture is filled into glue
Capsule, produce.
Embodiment 29
Prescription：Prepare the prescription of 1000 dabigatran etexilate methanesulfonate capsules
Preparation technology：
Part I：The preparation of dabigatran etexilate methanesulfonate coated granule
(1) pelletize：2.8g hydroxypropyl methylcelluloses are taken, add appropriate isopropanol to be configured to 2% solution, it is standby as adhesive
With；Adhesive is added in dabigatran etexilate methanesulfonate, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining hydroxypropyl methylcellulose is taken, adds appropriate isopropanol to be configured to 4% solution, adds 4.0g talcums
Powder, stir, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces.
Part II：The preparation of tartaric acid coated granule
(1) pelletize：1.9g carboxymethyl celluloses are taken, add suitable quantity of water to be configured to 5% solution, it is standby as adhesive；Will
Adhesive is added in tartaric acid, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining carboxymethyl cellulose is taken, adds suitable quantity of water to be configured to 5% solution, adds 4.7g talcum powder,
Stir, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces.
Take above-mentioned two parts coated granule to be mixed, obtain dispersed mixture, said mixture is filled into glue
Capsule, produce.
Embodiment 30
Prescription：Prepare the prescription of 1000 dabigatran etexilate methanesulfonate capsules
Preparation technology：
Part I：The preparation of dabigatran etexilate methanesulfonate coated granule
(1) pelletize：6.4g hydroxypropyl methylcelluloses are taken, add appropriate isopropanol to be configured to 3% solution, it is standby as adhesive
With；Adhesive is added in dabigatran etexilate methanesulfonate, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining hydroxypropyl methylcellulose is taken, adds appropriate isopropanol to be configured to 3% solution, adds 4.3g talcums
Powder, stir, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces.
Part II：The preparation of tartaric acid coated granule
(1) pelletize：1.9g carboxymethyl celluloses are taken, add suitable quantity of water to be configured to 5% solution, it is standby as adhesive；Will
Adhesive is added in tartaric acid, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining carboxymethyl cellulose is taken, adds suitable quantity of water to be configured to 4% solution, adds 4.7g talcum powder,
Stir, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces.
Take above-mentioned two parts coated granule to be mixed, obtain dispersed mixture, said mixture is filled into glue
Capsule, produce.
Embodiment 31
Prescription：Prepare the prescription of 1000 dabigatran etexilate methanesulfonate capsules
Preparation technology：
Part I：The preparation of dabigatran etexilate methanesulfonate coated granule
(1) pelletize：6.3g hydroxypropyl methylcelluloses are taken, add appropriate isopropanol to be configured to 3% solution, it is standby as adhesive
With；Adhesive is added in dabigatran etexilate methanesulfonate, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining hydroxypropyl methylcellulose is taken, adds appropriate isopropanol to be configured to 5% solution, adds 2.3g talcums
Powder, stir, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces.
Part II：The preparation of tartaric acid coated granule
(1) pelletize：0.9g polyvinylpyrrolidones are taken, add suitable quantity of water to be configured to 5% solution, it is standby as adhesive；
Adhesive is added in tartaric acid, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining polyvinylpyrrolidone is taken, adds suitable quantity of water to be configured to 4% solution, adds 8.2g talcums
Powder, stir, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces.
Take above-mentioned two parts coated granule to be mixed, obtain dispersed mixture, said mixture is filled into glue
Capsule, produce.
Embodiment 32
Prescription：Prepare the prescription of 1000 dabigatran etexilate methanesulfonate capsules
Preparation technology：
Part I：The preparation of dabigatran etexilate methanesulfonate coated granule
(1) pelletize：2.8g polyvinylpyrrolidones are taken, add appropriate isopropanol to be configured to 3% solution, it is standby as adhesive
With；Adhesive is added in dabigatran etexilate methanesulfonate, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining polyvinylpyrrolidone is taken, adds appropriate isopropanol to be configured to 3% solution, 4.0g is added and slides
Stone flour, stir, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces.
Part II：The preparation of tartaric acid coated granule
(1) pelletize：0.9g hydroxypropyl methylcelluloses are taken, add suitable quantity of water to be configured to 4% solution, it is standby as adhesive；Will
Adhesive is added in tartaric acid, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining hydroxypropyl methylcellulose is taken, adds suitable quantity of water to be configured to 5% solution, adds 8.2g talcum powder,
Stir, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces.
Take above-mentioned two parts coated granule to be mixed, obtain dispersed mixture, said mixture is filled into glue
Capsule, produce.
Embodiment 33
Prescription：Prepare the prescription of 1000 dabigatran etexilate methanesulfonate capsules
Preparation technology：
Part I：The preparation of dabigatran etexilate methanesulfonate coated granule
(1) pelletize：1.7g hydroxypropyl methylcelluloses are taken, add appropriate isopropanol to be configured to 3% solution, it is standby as adhesive
With；Adhesive is added in dabigatran etexilate methanesulfonate, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining hydroxypropyl methylcellulose is taken, adds appropriate isopropanol to be configured to 3% solution, adds 1.2g talcums
Powder, stir, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces.
Part II：The preparation of tartaric acid coated granule
(1) pelletize：2.2g carboxymethyl celluloses are taken, add suitable quantity of water to be configured to 5% solution, it is standby as adhesive；Will
Adhesive is added in tartaric acid, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining carboxymethyl cellulose is taken, adds suitable quantity of water to be configured to 5% solution, adds 10.0g talcum powder,
Stir, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces.
Take above-mentioned two parts coated granule to be mixed, obtain dispersed mixture, said mixture is filled into glue
Capsule, produce.
Embodiment 34
Prescription：Prepare the prescription of 1000 dabigatran etexilate methanesulfonate capsules
Preparation technology：
Part I：The preparation of dabigatran etexilate methanesulfonate coated granule
(1) pelletize：7.0g hydroxypropyl methylcelluloses are taken, add appropriate isopropanol to be configured to 3% solution, it is standby as adhesive
With；Adhesive is added in dabigatran etexilate methanesulfonate, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining hydroxypropyl methylcellulose is taken, adds appropriate isopropanol to be configured to 3% solution, adds 1.5g talcums
Powder, stir, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces.
Part II：The preparation of tartaric acid coated granule
(1) pelletize：2.2g carboxymethyl celluloses are taken, add suitable quantity of water to be configured to 5% solution, it is standby as adhesive；Will
Adhesive is added in tartaric acid, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining carboxymethyl cellulose is taken, adds suitable quantity of water to be configured to 5% solution, adds 10.0g talcum powder,
Stir, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces.
Take above-mentioned two parts coated granule to be mixed, obtain dispersed mixture, said mixture is filled into glue
Capsule, produce.
The preparation of the dabigatran etexilate methanesulfonate capsule of embodiment 35
Prescription：Prepare the prescription of 1000 dabigatran etexilate methanesulfonate capsules
Preparation technology：
Part I：The preparation of dabigatran etexilate methanesulfonate coated granule
(1) pelletize：2.8g hydroxypropylcelluloses are taken, add appropriate isopropanol to be configured to 3% solution, it is standby as adhesive；
Adhesive is added in dabigatran etexilate methanesulfonate, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining hydroxypropylcellulose is taken, adds appropriate isopropanol to be configured to 3% solution, adds 2.1g talcums
Powder, stir, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces.
Part II：The preparation of tartaric acid coated granule
(1) pelletize：0.9g hydroxypropylcelluloses are taken, add suitable quantity of water to be configured to 5% solution, it is standby as adhesive；Will be viscous
Mixture is added in tartaric acid, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining hydroxypropylcellulose is taken, adds suitable quantity of water to be configured to 5% solution, 4.3g talcum powder is added, stirs
Mix uniformly, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces.
Take above-mentioned two parts coated granule to be mixed, obtain dispersed mixture, said mixture is filled into glue
Capsule, produce.Comparative formulation 1：Dabigatran etexilate methanesulfonate capsule, specification：110mg, lot number：303398, manufacturer：
Boehringer Ingelheim
Comparative formulation 2：With reference to the capsule preparation method thereof of embodiment 35 in 201310047056.8, it is 110mg to be prepared into specification
The capsule of dabigatran etexilate methanesulfonate.
Dissolution contrast test：
Comparative formulation sample and sample of the embodiment of the present invention is taken to carry out dissolution contrast test, dissolution testing conditions are as follows：Basket
Method, 100rpm, dissolution medium：0.01NHCl (pH2.0), dissolution medium volume：900ml, sample time：10、15、20、30、45
Minute.According to gained dissolution data, compared, as a result as shown in table 1.
The each sample dissolution results of table 1 compare
Remarks：Above test result is average value, testing time n=12.
Conclusion：The glue of the preparation of the embodiment of the present invention 1,7,9,10,16,22,26 is can be seen that from the above-mentioned measurement result of table 1
Dissolution rate of the capsule in 10min, 15min, 20min is obviously higher than the sample of Comparative formulation 1~2 under the same terms；In 45min
When, the dissolution of Comparative formulation is still below sample prepared by the present invention.Illustrate pharmaceutical composition of the present invention and the phase of Comparative formulation 1~2
Than result of extraction is more preferable；And in 10min, the RSD% of Comparative formulation dissolution rate is more than 40%, in 15min, Comparative formulation
The RSD% of dissolution rate is close to 20%, hence it is evident that higher than the sample of the embodiment of the present invention at same time point, illustrates the embodiment of the present invention
Sample is more uniformly distributed.
Stability contrast test
The embodiment of the present invention 1,7,9,10,16,22,26 and Comparative formulation 1~2 are placed in 40 DEG C, under the conditions of RH70 ± 5%
Place 6 months, respectively in 0,3,6 month sampling detection character, dissolution rate, about material and content, the results are shown in Table 2.
The each sample accelerated stability test result of table 2
From table 2 it can be seen that after pharmaceutical composition of the present invention places 6 months under acceleration conditions, character, dissolution rate, contain
Significant change does not occur for amount, and growth trend is presented in maximum single impurity, but the maximum for being significantly less than Comparative formulation 1~2 is single
Individual impurity, total impurities are respectively less than 1%, hence it is evident that less than the total impurities of Comparative formulation 1~2.Therefore, pharmaceutical composition of the present invention is molten
It is preferable to go out effect, stability is more preferable, and quality is more excellent compared with Comparative formulation.
In summary, dabigatran etexilate methanesulfonate pharmaceutical capsules composition is prepared using the technique of the present invention, technique is more
Simply, fill capsule after directly preparing particle, it is not necessary to successively coat, overcome dose it is more difficult control, medicine accommodation layer it is uneven
The shortcomings of；The dabigatran etexilate methanesulfonate pharmaceutical capsules composition dissolution prepared using the prescription and technique of the present invention is very fast,
Even property is preferable, and relevant material is relatively low, and stability is more preferable, and quality is more excellent compared with prior art, is more suitable for industrialized production.
Claims (2)
1. a kind of dabigatran etexilate methanesulfonate pharmaceutical capsules composition, it is characterised in that every 1000 pharmaceutical compositions are under
State two parts composition：
Part I：Coated granule containing dabigatran etexilate methanesulfonate；
Part II：Coated granule containing tartaric acid；
The Part I particle fills capsule afterwards by evenly mixing with Part II particle；
Wherein, dabigatran etexilate methanesulfonate 86.0g, hydroxypropyl cellulose 7.0g, talcum powder 2.2g are contained in Part I；
Contain tartaric acid 86.0g, hydroxypropylcellulose 9.0g, talcum powder 4.3g in Part II；
The preparation of Part I dabigatran etexilate methanesulfonate coated granule comprises the following steps:
(1) pelletize：2.8g hydroxypropylcelluloses are taken, add appropriate isopropanol to be configured to 3% solution, it is standby as adhesive；Will be viscous
Mixture is added in dabigatran etexilate methanesulfonate, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining hydroxypropylcellulose is taken, adds appropriate isopropanol to be configured to 3% solution, 2.2g talcum powder is added, stirs
Mix uniformly, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces；
The preparation of Part II tartaric acid coated granule comprises the following steps:
(1) pelletize：0.9g hydroxypropylcelluloses are taken, add suitable quantity of water to be configured to 5% solution, it is standby as adhesive；By adhesive
Add in tartaric acid, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining hydroxypropylcellulose is taken, adds suitable quantity of water to be configured to 5% solution, adds 4.3g talcum powder, stirring is equal
It is even, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces；
Take above-mentioned two parts coated granule to be mixed, obtain dispersed mixture, said mixture is filled into capsule, i.e.,
.
2. a kind of dabigatran etexilate methanesulfonate pharmaceutical capsules composition, it is characterised in that every 1000 pharmaceutical compositions are under
State two parts composition：
Part I：Coated granule containing dabigatran etexilate methanesulfonate；
Part II：Coated granule containing tartaric acid；
The Part I particle fills capsule afterwards by evenly mixing with Part II particle；
Wherein, dabigatran etexilate methanesulfonate 173.0g, hydroxypropylcellulose 16.0g, talcum powder 4.3g are contained in Part I；
Contain tartaric acid 173.0g, hydroxypropylcellulose 19.0g, talcum powder 8.6g in Part II；
The preparation of Part I dabigatran etexilate methanesulfonate coated granule comprises the following steps:
(1) pelletize：6.4g hydroxypropylcelluloses are taken, add appropriate isopropanol to be configured to 3% solution, it is standby as adhesive；Will be viscous
Mixture is added in dabigatran etexilate methanesulfonate, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining hydroxypropylcellulose is taken, adds appropriate isopropanol to be configured to 3% solution, 4.3g talcum powder is added, stirs
Mix uniformly, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces；
The preparation of Part II tartaric acid coated granule comprises the following steps:
(1) pelletize：1.9g hydroxypropylcelluloses are taken, add suitable quantity of water to be configured to 5% solution, it is standby as adhesive；By adhesive
Add in tartaric acid, granulation；Whole grain after wet granular is dried；
(2) it is coated：Remaining hydroxypropylcellulose is taken, adds suitable quantity of water to be configured to 5% solution, adds 8.6g talcum powder, stirring is equal
It is even, it is standby；Particle after whole grain in step (1) is placed in fluid bed, is coated, produces；
Take above-mentioned two parts coated granule to be mixed, obtain dispersed mixture, said mixture is filled into capsule, i.e.,
.
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| CN201510024276.8A CN104784147B (en) | 2014-01-20 | 2015-01-19 | A kind of dabigatran etexilate methanesulfonate pharmaceutical capsules composition and preparation method thereof |
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| CN106727414B (en) * | 2016-12-27 | 2019-06-07 | 哈药集团技术中心 | A kind of dabigatran etexilate methanesulfonate pellet and preparation method |
| WO2019004980A2 (en) * | 2017-05-10 | 2019-01-03 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Solid oral pharmaceutical compositions of dabigatran etexilate |
| TR201706848A2 (en) * | 2017-05-10 | 2018-11-21 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | SOLID ORAL PHARMACEUTICAL COMPOSITIONS CONTAINING DABIGATRAN ETEXCLATE |
| EP3787624A4 (en) * | 2018-05-04 | 2022-03-30 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Capsule-in-capsule compositions of dabigatran etexilate |
| CN115227663B (en) * | 2021-04-22 | 2023-12-12 | 石药集团恩必普药业有限公司 | Dabigatran etexilate mesylate capsule and preparation method thereof |
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| CN102793699A (en) * | 2012-08-06 | 2012-11-28 | 严轶东 | Medicinal composition containing dabigatran etexilate |
| CN103127109A (en) * | 2013-02-05 | 2013-06-05 | 南京华威医药科技开发有限公司 | Pharmaceutical composition containing dabigatran etexilate or salt and hydrate thereof |
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| DE10337697A1 (en) * | 2003-08-16 | 2005-03-24 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Tablet containing 3 - [(2 - {[4- (hexyloxycarbonylamino-iminomethyl) -phenyl-amino] -methyl} -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino] - propionic acid ethyl ester or its salts |
| EP3858337A3 (en) * | 2012-02-21 | 2021-09-29 | Towa Pharmaceutical Europe, S.L. | Oral pharmaceutical compositions of dabigatran etexilate |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102793699A (en) * | 2012-08-06 | 2012-11-28 | 严轶东 | Medicinal composition containing dabigatran etexilate |
| CN103127109A (en) * | 2013-02-05 | 2013-06-05 | 南京华威医药科技开发有限公司 | Pharmaceutical composition containing dabigatran etexilate or salt and hydrate thereof |
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