A kind of dabigatran etexilate methanesulfonate pharmaceutical capsules composition and preparation method thereof
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.