CN104784147A - A dabigatran etexilate mesylate capsule pharmaceutical composition and a preparing method thereof - Google Patents
A dabigatran etexilate mesylate capsule pharmaceutical composition and a preparing method thereof Download PDFInfo
- Publication number
- CN104784147A CN104784147A CN201510024276.8A CN201510024276A CN104784147A CN 104784147 A CN104784147 A CN 104784147A CN 201510024276 A CN201510024276 A CN 201510024276A CN 104784147 A CN104784147 A CN 104784147A
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- China
- Prior art keywords
- granulate
- methanesulfonic acid
- dabigatran etcxilate
- binding agent
- granule
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- Granted
Links
- 239000002775 capsule Substances 0.000 title claims abstract description 97
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 16
- 238000000034 method Methods 0.000 title abstract description 10
- 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 abstract 3
- 229960004951 dabigatran etexilate mesylate Drugs 0.000 title abstract 3
- 239000008187 granular material Substances 0.000 claims abstract description 248
- 239000000203 mixture Substances 0.000 claims abstract description 84
- 239000007931 coated granule Substances 0.000 claims abstract description 77
- 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 62
- 239000011975 tartaric acid Substances 0.000 claims abstract description 56
- 235000002906 tartaric acid Nutrition 0.000 claims abstract description 56
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 240
- 229960003850 dabigatran Drugs 0.000 claims description 124
- 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 claims description 124
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 120
- 239000011230 binding agent Substances 0.000 claims description 109
- 239000011248 coating agent Substances 0.000 claims description 97
- 238000000576 coating method Methods 0.000 claims description 97
- 238000002360 preparation method Methods 0.000 claims description 92
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 43
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 43
- 229950005770 hyprolose Drugs 0.000 claims description 43
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 22
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 22
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 22
- 229960003943 hypromellose Drugs 0.000 claims description 22
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 22
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 22
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 22
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 16
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 16
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 16
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 16
- 229920000609 methyl cellulose Polymers 0.000 claims description 12
- 239000001923 methylcellulose Substances 0.000 claims description 12
- 235000010981 methylcellulose Nutrition 0.000 claims description 12
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 claims description 6
- 229940105329 carboxymethylcellulose Drugs 0.000 claims description 2
- 229960002900 methylcellulose Drugs 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims 1
- 238000004090 dissolution Methods 0.000 abstract description 9
- 150000001875 compounds Chemical class 0.000 abstract 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 138
- 239000012467 final product Substances 0.000 description 69
- 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 description 56
- 238000001035 drying Methods 0.000 description 46
- 239000012530 fluid Substances 0.000 description 46
- 238000003756 stirring Methods 0.000 description 46
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 46
- 238000005516 engineering process Methods 0.000 description 28
- 230000000052 comparative effect Effects 0.000 description 17
- 238000009472 formulation Methods 0.000 description 17
- 238000012360 testing method Methods 0.000 description 6
- 239000011162 core material Substances 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 150000007524 organic acids Chemical group 0.000 description 5
- 230000004308 accommodation Effects 0.000 description 3
- 239000013543 active substance 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
- 239000003814 drug Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000007789 sealing Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 102000009123 Fibrin Human genes 0.000 description 2
- 108010073385 Fibrin Proteins 0.000 description 2
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 230000001133 acceleration Effects 0.000 description 2
- 239000012738 dissolution medium Substances 0.000 description 2
- 229950003499 fibrin Drugs 0.000 description 2
- 239000008203 oral pharmaceutical composition Substances 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 239000000047 product Substances 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
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-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
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- 208000001435 Thromboembolism Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000011149 active material 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
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 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
- 238000010586 diagram Methods 0.000 description 1
- 238000009506 drug dissolution testing Methods 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 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
- 229960004072 thrombin 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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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
A dabigatran etexilate mesylate capsule pharmaceutical composition is provided. The composition comprises following two parts: coated granules of dabigatran etexilate mesylate and coated granules of tartaric acid. The granules of the two parts are mixed uniformly and filled into capsules. Capsules prepared by a prescription and a process are small in size and low in weight, have dissolution effects superior to that of the prior art, and have advantages of less related compounds, better stability and better quality.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to a kind of methanesulfonic acid dabigatran etcxilate pharmaceutical capsules composition and method of making the same.
Background technology
Dabigatran etcxilate is a kind of novel IIa factor direct thrombin inhibitor, is the prodrug of dabigatran, is mainly used in for acute and Prevention and Curation that is chronic thromboembolic disease.Oral after gastrointestinal absorption, be converted into the dabigatran with direct anticoagulant active in vivo.Dabigatran is incorporated into the fibrin specific binding site of thrombin, stops Fibrinogen to be cracked into fibrin, thus has blocked final step and the thrombosis of blood coagulation waterfall network.
The patent No. is that ZL03805473.6 patent discloses the oral pharmaceutical composition of a kind of methanesulfonic acid dabigatran etcxilate, wherein compositions can be prepared into capsule, each granule in capsule is a complete pill, from inside outwards be respectively containing organic acid core material layer, sealing coat, active material layer, coating, finally the pill of acquisition incapsulated.Its organic acid is selected from tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid or aspartic acid or a kind of its hydrate or hydrochlorate etc., its Figure of description 1 can find out in its each granule all have complete layering, because this patent adopts the medicine-feeding of ball core, in existence, dose is difficult to control, medicine accommodation layer is uneven, between batch, repeatability is poor, the problems such as product yield is lower.
Application number is that 201310047056.8 patents also disclose the oral pharmaceutical composition of a kind of methanesulfonic acid dabigatran etcxilate, capsule can be prepared into, but disclose another kind of grain structure, from inside outwards be respectively active substance ball core material, sealing coat, organic acid layer, sealing coat, in its each granule, all have complete layering.Owing to need add a large amount of filleies and/or binding agent when active substance to be prepared into ball core by this patent preparation technology, make the volume and weight of granule comparatively large, need select the capsule compared with large gauge during filling, compliance when causing patient to take is poor.And active substance is prepared into ball core and also exists and be not easy stripping defect completely, also there is upper organic acid content and be difficult to control in this preparation technology, and organic acid layer is uneven, and between batch, repeatability is poor, the problems such as product yield is lower simultaneously.
Above-mentioned two patents all exist to be needed by successively applying, thus causes complex process, consuming time longer, therefore, this area still needs a kind of preparation technology simple, fully can ensure again new recipe and the preparation technology of the stripping of methanesulfonic acid dabigatran etcxilate, and the present invention meets such demand simultaneously.
Summary of the invention
For the problems referred to above, the object of this invention is to provide one does not need successively to apply, and technique is simple, fully can ensure again new pharmaceutical compositions and the preparation method of the stripping of methanesulfonic acid dabigatran etcxilate simultaneously.
An object of the present invention is to disclose a kind of new methanesulfonic acid dabigatran etcxilate pharmaceutical capsules compositions, this pharmaceutical composition comprises following two parts: Part I: the coated granule containing methanesulfonic acid dabigatran etcxilate; Part II: containing tartaric coated granule; Described Part I granule and Part II granule filled capsules after mixing homogeneously.
Further, in methanesulfonic acid dabigatran etcxilate pharmaceutical capsules compositions of the present invention Part I and Part II all containing binding agent.
Wherein, in Part I, the mass ratio of methanesulfonic acid dabigatran etcxilate and binding agent is (50 ~ 200): (4 ~ 18); Preferably, in Part I, the mass ratio of methanesulfonic acid dabigatran etcxilate and binding agent is (86 ~ 173): (7 ~ 16); Preferred, in Part I, the mass ratio of methanesulfonic acid dabigatran etcxilate and hyprolose is 86:7 or 127:11 or 173:16.
Wherein, the mass ratio of Part II mesotartaric acid and binding agent is (50 ~ 200): (5 ~ 22); Preferably, the mass ratio of Part II mesotartaric acid and binding agent is (86 ~ 173): (9 ~ 19); Preferred, the mass ratio of Part II mesotartaric acid and binding agent is 86:9 or 127:14 or 173:19.
Binding agent of the present invention is polyvinylpyrrolidone, hyprolose, hypromellose, methylcellulose or carboxymethyl cellulose; Preferred hyprolose.
Further, the pharmaceutical composition of the present invention of per unit preparation contains following component: Part I: methanesulfonic acid dabigatran etcxilate 86.0mg, hyprolose 7.0mg, Pulvis Talci 2.2mg; Part II: tartaric acid 86.0mg, hyprolose 9.0mg, Pulvis Talci 4.3mg.
Or the pharmaceutical composition of the present invention of per unit preparation contains following component: Part I: methanesulfonic acid dabigatran etcxilate 127.0mg, hyprolose 11.0mg, Pulvis Talci 3.2mg; Part II: tartaric acid 127.0mg, hyprolose 14.0mg, Pulvis Talci 6.3mg.
Or the pharmaceutical composition of the present invention of per unit preparation contains following component: Part I: methanesulfonic acid dabigatran etcxilate 173.0mg, hyprolose 16.0mg, Pulvis Talci 4.3mg; Part II: tartaric acid 173.0mg, hyprolose 19.0mg, Pulvis Talci 8.6mg.
Or the pharmaceutical composition of the present invention of per unit preparation contains following component: Part I: methanesulfonic acid dabigatran etcxilate 126.8mg, hyprolose 11.3mg, Pulvis Talci 3.2mg; Part II: tartaric acid 126.0mg, hyprolose 13.6mg, Pulvis Talci 6.3mg.
Or the pharmaceutical composition of the present invention of per unit preparation contains following component: Part I: methanesulfonic acid dabigatran etcxilate 86.5mg, hyprolose 7.0mg, Pulvis Talci 2.1mg; Part II: tartaric acid 86.0mg, hyprolose 9.0mg, Pulvis Talci 4.3mg.
Another object of the present invention there are provided a kind of preparation method of methanesulfonic acid dabigatran etcxilate pharmaceutical capsules compositions, and it comprises following steps:
1) methanesulfonic acid dabigatran etcxilate granule is prepared, coating;
2) tartaric acid granulate is prepared, coating;
3) filled capsules after granule mix homogeneously step 1 and step 2 obtained.
Methanesulfonic acid dabigatran etcxilate capsule prepared by the present invention has the following advantages:
1, compared with prior art, the present invention is direct filled capsules after preparing granule, technique is more simple, do not need successively to apply, in stripping contrast test, embodiment of the present invention sample is when 10min and 15min, the RSD% of 12 sample dissolutions is starkly lower than Comparative formulation sample, illustrate that the uniformity of sample prepared by the present invention is obviously better than Comparative formulation, overcome the upper more difficult control of dose in prior art, the problems such as medicine accommodation layer is uneven; And owing to not needing extra absorb fillers, the volume and weight of granule prepared by the present invention is less, without the need to selecting the capsule compared with large gauge, thus improves the compliance of patient.
2, the capsule stripping prepared of the present invention is very fast, dissolution when 10min, 15min, 20min is all higher than the Comparative formulation sample under the same terms, when 45min, the stripping of Comparative formulation, still lower than sample prepared by the present invention, illustrates that capsule result of extraction prepared by the present invention is better.
3, after 6 months, total impurities is lower than 1% in acceleration for the capsule prepared of the present invention, and it is lower to be starkly lower than Comparative formulation related substance, and stability is better, and quality is melancholy more.
Accompanying drawing explanation
Fig. 1 methanesulfonic acid dabigatran etcxilate capsule overall structure schematic diagram
Fig. 2 methanesulfonic acid dabigatran etcxilate coated granule structural representation
Fig. 3 tartaric acid coated granule structural representation
Detailed description of the invention
The preparation of embodiment 1 ~ 3 methanesulfonic acid dabigatran etcxilate capsule
Prescription: the prescription preparing 1000 methanesulfonic acid dabigatran etcxilate capsules
Preparation technology:
Part I: the preparation of methanesulfonic acid dabigatran etcxilate coated granule
(1) granulate: the hypromellose getting recipe quantity 40%, adds the solution that appropriate isopropyl alcohol is mixed with 2%, for subsequent use as binding agent; Binding agent is added in methanesulfonic acid dabigatran etcxilate, granulate; By granulate after wet grain drying;
(2) coating: get remaining hypromellose, adds the solution that appropriate isopropyl alcohol is mixed with 2%, adds the Pulvis Talci of Part I prescription total amount 2.2%, stirs, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Part II: the preparation of tartaric acid coated granule
(1) granulate: the hypromellose getting recipe quantity 10%, adds the solution that suitable quantity of water is mixed with 4%, for subsequent use as binding agent; Binding agent is added in tartaric acid, granulate; By granulate after wet grain drying;
(2) coating: get remaining hypromellose, adds the solution that suitable quantity of water is mixed with 4%, adds the Pulvis Talci of Part II prescription total amount 4.3%, stirs, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Get above-mentioned two parts coated granule to mix, obtain homodisperse mixture, by said mixture filled capsules, to obtain final product.
The preparation of embodiment 4 ~ 6 methanesulfonic acid dabigatran etcxilate capsule
Prescription: the prescription preparing 1000 methanesulfonic acid dabigatran etcxilate capsules
Preparation technology:
Part I: the preparation of methanesulfonic acid dabigatran etcxilate coated granule
(1) granulate: the polyvinylpyrrolidone getting recipe quantity 40%, adds the solution that appropriate isopropyl alcohol is mixed with 3%, for subsequent use as binding agent; Binding agent is added in methanesulfonic acid dabigatran etcxilate, granulate; By granulate after wet grain drying;
(2) coating: get remaining polyvinylpyrrolidone, adds the solution that appropriate isopropyl alcohol is mixed with 3%, adds the Pulvis Talci of Part I prescription total amount 2.2%, stirs, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Part II: the preparation of tartaric acid coated granule
(1) granulate: the polyvinylpyrrolidone getting recipe quantity 10%, adds the solution that suitable quantity of water is mixed with 5%, for subsequent use as binding agent; Binding agent is added in tartaric acid, granulate; By granulate after wet grain drying;
(2) coating: get remaining polyvinylpyrrolidone, adds the solution that suitable quantity of water is mixed with 5%, adds the Pulvis Talci of Part II prescription total amount 4.3%, stirs, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Get above-mentioned two parts coated granule to mix, obtain homodisperse mixture, by said mixture filled capsules, to obtain final product.
The preparation of embodiment 7 methanesulfonic acid dabigatran etcxilate capsule
Prescription: the prescription preparing 1000 methanesulfonic acid dabigatran etcxilate capsules
Preparation technology:
Part I: the preparation of methanesulfonic acid dabigatran etcxilate coated granule
(1) granulate: get 2.8g hyprolose, add the solution that appropriate isopropyl alcohol is mixed with 3%, for subsequent use as binding agent; Binding agent is added in methanesulfonic acid dabigatran etcxilate, granulate; By granulate after wet grain drying;
(2) coating: get remaining hyprolose, adds the solution that appropriate isopropyl alcohol is mixed with 3%, adds 2.2g Pulvis Talci, stir, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Part II: the preparation of tartaric acid coated granule
(1) granulate: get 0.9g hyprolose, add the solution that suitable quantity of water is mixed with 5%, for subsequent use as binding agent; Binding agent is added in tartaric acid, granulate; By granulate after wet grain drying;
(2) coating: get remaining hyprolose, adds the solution that suitable quantity of water is mixed with 5%, adds 4.3g Pulvis Talci, stir, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Get above-mentioned two parts coated granule to mix, obtain homodisperse mixture, by said mixture filled capsules, to obtain final product.
The preparation of embodiment 8 methanesulfonic acid dabigatran etcxilate capsule
Prescription: the prescription preparing 1000 methanesulfonic acid dabigatran etcxilate capsules
Preparation technology:
Part I: the preparation of methanesulfonic acid dabigatran etcxilate coated granule
(1) granulate: get 4.4g hyprolose, add the solution that appropriate isopropyl alcohol is mixed with 3%, for subsequent use as binding agent; Binding agent is added in methanesulfonic acid dabigatran etcxilate, granulate; By granulate after wet grain drying;
(2) coating: get remaining hyprolose, adds the solution that appropriate isopropyl alcohol is mixed with 3%, adds 3.2g Pulvis Talci, stir, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Part II: the preparation of tartaric acid coated granule
(1) granulate: get 1.4g hyprolose, add the solution that suitable quantity of water is mixed with 5%, for subsequent use as binding agent; Binding agent is added in tartaric acid, granulate; By granulate after wet grain drying;
(2) coating: get remaining hyprolose, adds the solution that suitable quantity of water is mixed with 5%, adds 6.3g Pulvis Talci, stir, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Get above-mentioned two parts coated granule to mix, obtain homodisperse mixture, by said mixture filled capsules, to obtain final product.
The preparation of embodiment 9 methanesulfonic acid dabigatran etcxilate capsule
Prescription: the prescription preparing 1000 methanesulfonic acid dabigatran etcxilate capsules
Preparation technology:
Part I: the preparation of methanesulfonic acid dabigatran etcxilate coated granule
(1) granulate: get 4.5g hyprolose, add the solution that appropriate isopropyl alcohol is mixed with 3%, for subsequent use as binding agent; Binding agent is added in methanesulfonic acid dabigatran etcxilate, granulate; By granulate after wet grain drying;
(2) coating: get remaining hyprolose, adds the solution that appropriate isopropyl alcohol is mixed with 3%, adds 3.2g Pulvis Talci, stir, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Part II: the preparation of tartaric acid coated granule
(1) granulate: get 1.4g hyprolose, add the solution that suitable quantity of water is mixed with 5%, for subsequent use as binding agent; Binding agent is added in tartaric acid, granulate; By granulate after wet grain drying;
(2) coating: get remaining hyprolose, adds the solution that suitable quantity of water is mixed with 5%, adds 6.3g Pulvis Talci, stir, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Get above-mentioned two parts coated granule to mix, obtain homodisperse mixture, by said mixture filled capsules, to obtain final product.
The preparation of embodiment 10 methanesulfonic acid dabigatran etcxilate capsule
Prescription: the prescription preparing 1000 methanesulfonic acid dabigatran etcxilate capsules
Preparation technology:
Part I: the preparation of methanesulfonic acid dabigatran etcxilate coated granule
(1) granulate: get 6.4g hyprolose, add the solution that appropriate isopropyl alcohol is mixed with 3%, for subsequent use as binding agent; Binding agent is added in methanesulfonic acid dabigatran etcxilate, granulate; By granulate after wet grain drying;
(2) coating: get remaining hyprolose, adds the solution that appropriate isopropyl alcohol is mixed with 3%, adds 4.3g Pulvis Talci, stir, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Part II: the preparation of tartaric acid coated granule
(1) granulate: get 1.9g hyprolose, add the solution that suitable quantity of water is mixed with 5%, for subsequent use as binding agent; Binding agent is added in tartaric acid, granulate; By granulate after wet grain drying;
(2) coating: get remaining hyprolose, adds the solution that suitable quantity of water is mixed with 5%, adds 8.6g Pulvis Talci, stir, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Get above-mentioned two parts coated granule to mix, obtain homodisperse mixture, by said mixture filled capsules, to obtain final product.
The preparation of embodiment 11 ~ 15 methanesulfonic acid dabigatran etcxilate capsule
Prescription: the prescription preparing 1000 methanesulfonic acid dabigatran etcxilate capsules
Preparation technology:
Part I: the preparation of methanesulfonic acid dabigatran etcxilate coated granule
(1) granulate: the hyprolose getting recipe quantity 40%, adds the solution that appropriate isopropyl alcohol is mixed with 2%, for subsequent use as binding agent; Binding agent is added in methanesulfonic acid dabigatran etcxilate, granulate; By granulate after wet grain drying;
(2) coating: get remaining hyprolose, adds the solution that appropriate isopropyl alcohol is mixed with 2%, adds the Pulvis Talci of Part I prescription total amount 2.2%, stirs, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Part II: the preparation of tartaric acid coated granule
(1) granulate: the methylcellulose getting recipe quantity 10%, adds the solution that suitable quantity of water is mixed with 5%, for subsequent use as binding agent; Binding agent is added in tartaric acid, granulate; By granulate after wet grain drying;
(2) coating: get remaining methylcellulose, adds the solution that suitable quantity of water is mixed with 5%, adds the Pulvis Talci of Part II prescription total amount 4.3%, stirs, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.Get above-mentioned two parts coated granule to mix, obtain homodisperse mixture, by said mixture filled capsules, to obtain final product.
The preparation of embodiment 16 ~ 20 methanesulfonic acid dabigatran etcxilate capsule
Prescription: the prescription preparing 1000 methanesulfonic acid dabigatran etcxilate capsules
Preparation technology:
Part I: the preparation of methanesulfonic acid dabigatran etcxilate coated granule
(1) granulate: the hyprolose getting recipe quantity 40%, adds the solution that appropriate isopropyl alcohol is mixed with 4%, for subsequent use as binding agent; Binding agent is added in methanesulfonic acid dabigatran etcxilate, granulate; By granulate after wet grain drying;
(2) coating: get remaining hyprolose, adds the solution that appropriate isopropyl alcohol is mixed with 4%, adds the Pulvis Talci of Part I prescription total amount 2.2%, stirs, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Part II: the preparation of tartaric acid coated granule
(1) granulate: the carboxymethyl cellulose getting recipe quantity 10%, adds the solution that suitable quantity of water is mixed with 5%, for subsequent use as binding agent; Binding agent is added in tartaric acid, granulate; By granulate after wet grain drying;
(2) coating: get remaining carboxymethyl cellulose, adds the solution that suitable quantity of water is mixed with 5%, adds the Pulvis Talci of Part II prescription total amount 4.3%, stirs, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Get above-mentioned two parts coated granule to mix, obtain homodisperse mixture, by said mixture filled capsules, to obtain final product.
Embodiment 21
Prescription: the prescription preparing 1000 methanesulfonic acid dabigatran etcxilate capsules
Preparation technology:
Part I: the preparation of methanesulfonic acid dabigatran etcxilate coated granule
(1) granulate: get 1.6g hyprolose, add the solution that appropriate isopropyl alcohol is mixed with 3%, for subsequent use as binding agent; Binding agent is added in methanesulfonic acid dabigatran etcxilate, granulate; By granulate after wet grain drying;
(2) coating: get remaining hyprolose, adds the solution that appropriate isopropyl alcohol is mixed with 4%, adds 1.2g Pulvis Talci, stir, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Part II: the preparation of tartaric acid coated granule
(1) granulate: get 0.5g polyvinylpyrrolidone, add the solution that suitable quantity of water is mixed with 4%, for subsequent use as binding agent; Binding agent is added in tartaric acid, granulate; By granulate after wet grain drying;
(2) coating: get remaining polyvinylpyrrolidone, adds the solution that suitable quantity of water is mixed with 4%, adds 9.2g Pulvis Talci, stir, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Get above-mentioned two parts coated granule to mix, obtain homodisperse mixture, by said mixture filled capsules, to obtain final product.
Embodiment 22
Prescription: the prescription preparing 1000 methanesulfonic acid dabigatran etcxilate capsules
Preparation technology:
Part I: the preparation of methanesulfonic acid dabigatran etcxilate coated granule
(1) granulate: get 7.2g polyvinylpyrrolidone, add the solution that appropriate isopropyl alcohol is mixed with 3%, for subsequent use as binding agent; Binding agent is added in methanesulfonic acid dabigatran etcxilate, granulate; By granulate after wet grain drying;
(2) coating: get remaining polyvinylpyrrolidone, adds the solution that appropriate isopropyl alcohol is mixed with 3%, adds 1.5g Pulvis Talci, stir, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Part II: the preparation of tartaric acid coated granule
(1) granulate: get 0.5g hyprolose, add the solution that suitable quantity of water is mixed with 6%, for subsequent use as binding agent; Binding agent is added in tartaric acid, granulate; By granulate after wet grain drying;
(2) coating: get remaining hyprolose, adds the solution that suitable quantity of water is mixed with 5%, adds 9.2g Pulvis Talci, stir, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Get above-mentioned two parts coated granule to mix, obtain homodisperse mixture, by said mixture filled capsules, to obtain final product.
Embodiment 23
Prescription: the prescription preparing 1000 methanesulfonic acid dabigatran etcxilate capsules
Preparation technology:
Part I: the preparation of methanesulfonic acid dabigatran etcxilate coated granule
(1) granulate: get 1.7g hypromellose, add the solution that appropriate isopropyl alcohol is mixed with 2%, for subsequent use as binding agent; Binding agent is added in methanesulfonic acid dabigatran etcxilate, granulate; By granulate after wet grain drying;
(2) coating: get remaining hypromellose, adds the solution that appropriate isopropyl alcohol is mixed with 3%, adds 4.6g Pulvis Talci, stir, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Part II: the preparation of tartaric acid coated granule
(1) granulate: get 0.5g methylcellulose, add the solution that suitable quantity of water is mixed with 5%, for subsequent use as binding agent; Binding agent is added in tartaric acid, granulate; By granulate after wet grain drying;
(2) coating: get remaining methylcellulose, adds the solution that suitable quantity of water is mixed with 5%, adds 9.2g Pulvis Talci, stir, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Get above-mentioned two parts coated granule to mix, obtain homodisperse mixture, by said mixture filled capsules, to obtain final product.
Embodiment 24
Prescription: the prescription preparing 1000 methanesulfonic acid dabigatran etcxilate capsules
Preparation technology:
Part I: the preparation of methanesulfonic acid dabigatran etcxilate coated granule
(1) granulate: get 7.2g hypromellose, add the solution that appropriate isopropyl alcohol is mixed with 2%, for subsequent use as binding agent; Binding agent is added in methanesulfonic acid dabigatran etcxilate, granulate; By granulate after wet grain drying;
(2) coating: get remaining hypromellose, adds the solution that appropriate isopropyl alcohol is mixed with 3%, adds 4.9g Pulvis Talci, stir, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Part II: the preparation of tartaric acid coated granule
(1) granulate: get 0.5g methylcellulose, add the solution that suitable quantity of water is mixed with 4%, for subsequent use as binding agent; Binding agent is added in tartaric acid, granulate; By granulate after wet grain drying;
(2) coating: get remaining methylcellulose, adds the solution that suitable quantity of water is mixed with 4%, adds 9.2g Pulvis Talci, stir, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Get above-mentioned two parts coated granule to mix, obtain homodisperse mixture, by said mixture filled capsules, to obtain final product.
Embodiment 25
Prescription: the prescription preparing 1000 methanesulfonic acid dabigatran etcxilate capsules
Preparation technology:
Part I: the preparation of methanesulfonic acid dabigatran etcxilate coated granule
(1) granulate: get 1.6g polyvinylpyrrolidone, add the solution that appropriate isopropyl alcohol is mixed with 3%, for subsequent use as binding agent; Binding agent is added in methanesulfonic acid dabigatran etcxilate, granulate; By granulate after wet grain drying;
(2) coating: get remaining polyvinylpyrrolidone, adds the solution that appropriate isopropyl alcohol is mixed with 4%, adds 4.6g Pulvis Talci, stir, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Part II: the preparation of tartaric acid coated granule
(1) granulate: get 2.2g methylcellulose, add the solution that suitable quantity of water is mixed with 3%, for subsequent use as binding agent; Binding agent is added in tartaric acid, granulate; By granulate after wet grain drying;
(2) coating: get remaining methylcellulose, adds the solution that suitable quantity of water is mixed with 5%, adds 10.0g Pulvis Talci, stir, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Get above-mentioned two parts coated granule to mix, obtain homodisperse mixture, by said mixture filled capsules, to obtain final product.
Embodiment 26
Prescription: the prescription preparing 1000 methanesulfonic acid dabigatran etcxilate capsules
Preparation technology:
Part I: the preparation of methanesulfonic acid dabigatran etcxilate coated granule
(1) granulate: get 7.2g polyvinylpyrrolidone, add the solution that appropriate isopropyl alcohol is mixed with 3%, for subsequent use as binding agent; Binding agent is added in methanesulfonic acid dabigatran etcxilate, granulate; By granulate after wet grain drying;
(2) coating: get remaining polyvinylpyrrolidone, adds the solution that appropriate isopropyl alcohol is mixed with 4%, adds 4.9g Pulvis Talci, stir, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Part II: the preparation of tartaric acid coated granule
(1) granulate: get 2.2g methylcellulose, add the solution that suitable quantity of water is mixed with 5%, for subsequent use as binding agent; Binding agent is added in tartaric acid, granulate; By granulate after wet grain drying;
(2) coating: get remaining methylcellulose, adds the solution that suitable quantity of water is mixed with 4%, adds 10.0g Pulvis Talci, stir, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Get above-mentioned two parts coated granule to mix, obtain homodisperse mixture, by said mixture filled capsules, to obtain final product.
Embodiment 27
Prescription: the prescription preparing 1000 methanesulfonic acid dabigatran etcxilate capsules
Preparation technology:
Part I: the preparation of methanesulfonic acid dabigatran etcxilate coated granule
(1) granulate: get 2.8g polyvinylpyrrolidone, add the solution that appropriate isopropyl alcohol is mixed with 2%, for subsequent use as binding agent; Binding agent is added in methanesulfonic acid dabigatran etcxilate, granulate; By granulate after wet grain drying;
(2) coating: get remaining polyvinylpyrrolidone, adds the solution that appropriate isopropyl alcohol is mixed with 2%, adds 2.1g Pulvis Talci, stir, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Part II: the preparation of tartaric acid coated granule
(1) granulate: get 1.9g carboxymethyl cellulose, add the solution that suitable quantity of water is mixed with 4%, for subsequent use as binding agent; Binding agent is added in tartaric acid, granulate; By granulate after wet grain drying;
(2) coating: get remaining carboxymethyl cellulose, adds the solution that suitable quantity of water is mixed with 4%, adds 4.7g Pulvis Talci, stir, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Get above-mentioned two parts coated granule to mix, obtain homodisperse mixture, by said mixture filled capsules, to obtain final product.
Embodiment 28
Prescription: the prescription preparing 1000 methanesulfonic acid dabigatran etcxilate capsules
Preparation technology:
Part I: the preparation of methanesulfonic acid dabigatran etcxilate coated granule
(1) granulate: get 6.4g polyvinylpyrrolidone, add the solution that appropriate isopropyl alcohol is mixed with 4%, for subsequent use as binding agent; Binding agent is added in methanesulfonic acid dabigatran etcxilate, granulate; By granulate after wet grain drying;
(2) coating: get remaining polyvinylpyrrolidone, adds the solution that appropriate isopropyl alcohol is mixed with 3%, adds 2.3g Pulvis Talci, stir, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Part II: the preparation of tartaric acid coated granule
(1) granulate: get 1.9g carboxymethyl cellulose, add the solution that suitable quantity of water is mixed with 5%, for subsequent use as binding agent; Binding agent is added in tartaric acid, granulate; By granulate after wet grain drying;
(2) coating: get remaining carboxymethyl cellulose, adds the solution that suitable quantity of water is mixed with 4%, adds 4.7g Pulvis Talci, stir, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Get above-mentioned two parts coated granule to mix, obtain homodisperse mixture, by said mixture filled capsules, to obtain final product.
Embodiment 29
Prescription: the prescription preparing 1000 methanesulfonic acid dabigatran etcxilate capsules
Preparation technology:
Part I: the preparation of methanesulfonic acid dabigatran etcxilate coated granule
(1) granulate: get 2.8g hypromellose, add the solution that appropriate isopropyl alcohol is mixed with 2%, for subsequent use as binding agent; Binding agent is added in methanesulfonic acid dabigatran etcxilate, granulate; By granulate after wet grain drying;
(2) coating: get remaining hypromellose, adds the solution that appropriate isopropyl alcohol is mixed with 4%, adds 4.0g Pulvis Talci, stir, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Part II: the preparation of tartaric acid coated granule
(1) granulate: get 1.9g carboxymethyl cellulose, add the solution that suitable quantity of water is mixed with 5%, for subsequent use as binding agent; Binding agent is added in tartaric acid, granulate; By granulate after wet grain drying;
(2) coating: get remaining carboxymethyl cellulose, adds the solution that suitable quantity of water is mixed with 5%, adds 4.7g Pulvis Talci, stir, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Get above-mentioned two parts coated granule to mix, obtain homodisperse mixture, by said mixture filled capsules, to obtain final product.
Embodiment 30
Prescription: the prescription preparing 1000 methanesulfonic acid dabigatran etcxilate capsules
Preparation technology:
Part I: the preparation of methanesulfonic acid dabigatran etcxilate coated granule
(1) granulate: get 6.4g hypromellose, add the solution that appropriate isopropyl alcohol is mixed with 3%, for subsequent use as binding agent; Binding agent is added in methanesulfonic acid dabigatran etcxilate, granulate; By granulate after wet grain drying;
(2) coating: get remaining hypromellose, adds the solution that appropriate isopropyl alcohol is mixed with 3%, adds 4.3g Pulvis Talci, stir, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Part II: the preparation of tartaric acid coated granule
(1) granulate: get 1.9g carboxymethyl cellulose, add the solution that suitable quantity of water is mixed with 5%, for subsequent use as binding agent; Binding agent is added in tartaric acid, granulate; By granulate after wet grain drying;
(2) coating: get remaining carboxymethyl cellulose, adds the solution that suitable quantity of water is mixed with 4%, adds 4.7g Pulvis Talci, stir, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Get above-mentioned two parts coated granule to mix, obtain homodisperse mixture, by said mixture filled capsules, to obtain final product.
Embodiment 31
Prescription: the prescription preparing 1000 methanesulfonic acid dabigatran etcxilate capsules
Preparation technology:
Part I: the preparation of methanesulfonic acid dabigatran etcxilate coated granule
(1) granulate: get 6.3g hypromellose, add the solution that appropriate isopropyl alcohol is mixed with 3%, for subsequent use as binding agent; Binding agent is added in methanesulfonic acid dabigatran etcxilate, granulate; By granulate after wet grain drying;
(2) coating: get remaining hypromellose, adds the solution that appropriate isopropyl alcohol is mixed with 5%, adds 2.3g Pulvis Talci, stir, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Part II: the preparation of tartaric acid coated granule
(1) granulate: get 0.9g polyvinylpyrrolidone, add the solution that suitable quantity of water is mixed with 5%, for subsequent use as binding agent; Binding agent is added in tartaric acid, granulate; By granulate after wet grain drying;
(2) coating: get remaining polyvinylpyrrolidone, adds the solution that suitable quantity of water is mixed with 4%, adds 8.2g Pulvis Talci, stir, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Get above-mentioned two parts coated granule to mix, obtain homodisperse mixture, by said mixture filled capsules, to obtain final product.
Embodiment 32
Prescription: the prescription preparing 1000 methanesulfonic acid dabigatran etcxilate capsules
Preparation technology:
Part I: the preparation of methanesulfonic acid dabigatran etcxilate coated granule
(1) granulate: get 2.8g polyvinylpyrrolidone, add the solution that appropriate isopropyl alcohol is mixed with 3%, for subsequent use as binding agent; Binding agent is added in methanesulfonic acid dabigatran etcxilate, granulate; By granulate after wet grain drying;
(2) coating: get remaining polyvinylpyrrolidone, adds the solution that appropriate isopropyl alcohol is mixed with 3%, adds 4.0g Pulvis Talci, stir, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Part II: the preparation of tartaric acid coated granule
(1) granulate: get 0.9g hypromellose, add the solution that suitable quantity of water is mixed with 4%, for subsequent use as binding agent; Binding agent is added in tartaric acid, granulate; By granulate after wet grain drying;
(2) coating: get remaining hypromellose, adds the solution that suitable quantity of water is mixed with 5%, adds 8.2g Pulvis Talci, stir, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Get above-mentioned two parts coated granule to mix, obtain homodisperse mixture, by said mixture filled capsules, to obtain final product.
Embodiment 33
Prescription: the prescription preparing 1000 methanesulfonic acid dabigatran etcxilate capsules
Preparation technology:
Part I: the preparation of methanesulfonic acid dabigatran etcxilate coated granule
(1) granulate: get 1.7g hypromellose, add the solution that appropriate isopropyl alcohol is mixed with 3%, for subsequent use as binding agent; Binding agent is added in methanesulfonic acid dabigatran etcxilate, granulate; By granulate after wet grain drying;
(2) coating: get remaining hypromellose, adds the solution that appropriate isopropyl alcohol is mixed with 3%, adds 1.2g Pulvis Talci, stir, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Part II: the preparation of tartaric acid coated granule
(1) granulate: get 2.2g carboxymethyl cellulose, add the solution that suitable quantity of water is mixed with 5%, for subsequent use as binding agent; Binding agent is added in tartaric acid, granulate; By granulate after wet grain drying;
(2) coating: get remaining carboxymethyl cellulose, adds the solution that suitable quantity of water is mixed with 5%, adds 10.0g Pulvis Talci, stir, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Get above-mentioned two parts coated granule to mix, obtain homodisperse mixture, by said mixture filled capsules, to obtain final product.
Embodiment 34
Prescription: the prescription preparing 1000 methanesulfonic acid dabigatran etcxilate capsules
Preparation technology:
Part I: the preparation of methanesulfonic acid dabigatran etcxilate coated granule
(1) granulate: get 7.0g hypromellose, add the solution that appropriate isopropyl alcohol is mixed with 3%, for subsequent use as binding agent; Binding agent is added in methanesulfonic acid dabigatran etcxilate, granulate; By granulate after wet grain drying;
(2) coating: get remaining hypromellose, adds the solution that appropriate isopropyl alcohol is mixed with 3%, adds 1.5g Pulvis Talci, stir, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Part II: the preparation of tartaric acid coated granule
(1) granulate: get 2.2g carboxymethyl cellulose, add the solution that suitable quantity of water is mixed with 5%, for subsequent use as binding agent; Binding agent is added in tartaric acid, granulate; By granulate after wet grain drying;
(2) coating: get remaining carboxymethyl cellulose, adds the solution that suitable quantity of water is mixed with 5%, adds 10.0g Pulvis Talci, stir, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Get above-mentioned two parts coated granule to mix, obtain homodisperse mixture, by said mixture filled capsules, to obtain final product.
The preparation of embodiment 35 methanesulfonic acid dabigatran etcxilate capsule
Prescription: the prescription preparing 1000 methanesulfonic acid dabigatran etcxilate capsules
Preparation technology:
Part I: the preparation of methanesulfonic acid dabigatran etcxilate coated granule
(1) granulate: get 2.8g hyprolose, add the solution that appropriate isopropyl alcohol is mixed with 3%, for subsequent use as binding agent; Binding agent is added in methanesulfonic acid dabigatran etcxilate, granulate; By granulate after wet grain drying;
(2) coating: get remaining hyprolose, adds the solution that appropriate isopropyl alcohol is mixed with 3%, adds 2.1g Pulvis Talci, stir, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Part II: the preparation of tartaric acid coated granule
(1) granulate: get 0.9g hyprolose, add the solution that suitable quantity of water is mixed with 5%, for subsequent use as binding agent; Binding agent is added in tartaric acid, granulate; By granulate after wet grain drying;
(2) coating: get remaining hyprolose, adds the solution that suitable quantity of water is mixed with 5%, adds 4.3g Pulvis Talci, stir, for subsequent use; Granule after granulate in step (1) is placed in fluid bed, carries out coating, to obtain final product.
Get above-mentioned two parts coated granule to mix, obtain homodisperse mixture, by said mixture filled capsules, to obtain final product.Comparative formulation 1: methanesulfonic acid dabigatran etcxilate capsule, specification: 110mg, lot number: 303398, manufacturer: BoehringerIngelheim
Comparative formulation 2: embodiment 35 capsule preparation method thereof in reference 201310047056.8, is prepared into the capsule that specification is 110mg methanesulfonic acid dabigatran etcxilate.
Stripping contrast test:
Get Comparative formulation sample and embodiment of the present invention sample carries out stripping contrast test, dissolution testing conditions is as follows: basket method, 100rpm, dissolution medium: 0.01NHCl (pH2.0), dissolution medium volume: 900ml, sample time: 10,15,20,30,45 minutes.According to gained stripping data, compared, result is as shown in table 1.
Table 1 each sample dissolution results compares
Remarks: above test result is meansigma methods, testing time n=12.
Conclusion: as can be seen from above-mentioned table 1 measurement result, dissolution Comparative formulation 1 ~ 2 sample all apparently higher than the same terms under of capsule when 10min, 15min, 20min prepared by the embodiment of the present invention 1,7,9,10,16,22,26; When 45min, the stripping of Comparative formulation is still lower than sample prepared by the present invention.Illustrate that pharmaceutical composition of the present invention is compared with Comparative formulation 1 ~ 2, result of extraction is better; And when 10min, the RSD% of Comparative formulation dissolution is greater than 40%, when 15min, the RSD% of Comparative formulation dissolution, close to 20%, apparently higher than the embodiment of the present invention sample at same time point place, illustrates that embodiment of the present invention sample is more even.
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, place 6 months under RH70 ± 5% condition, detect character, dissolution, related substance and content sampling in 0,3,6 month respectively, the results are shown in Table 2.
Table 2 each sample accelerated stability test result
As can be seen from Table 2, after pharmaceutical composition of the present invention places 6 months under acceleration conditions, all there is not significant change in character, dissolution, content, maximum single impurity all presents growth trend, but be significantly less than the maximum single impurity of Comparative formulation 1 ~ 2, total impurities is all less than 1%, is starkly lower than the total impurities of Comparative formulation 1 ~ 2.Therefore, the result of extraction of pharmaceutical composition of the present invention is better, and stability is better, and quality is more excellent compared with Comparative formulation.
In sum, adopt technique of the present invention to prepare methanesulfonic acid dabigatran etcxilate pharmaceutical capsules compositions, technique is more simple, directly prepares filled capsules after granule, does not need successively to apply, and overcomes the shortcomings such as the more difficult control of dose, medicine accommodation layer be uneven; The methanesulfonic acid dabigatran etcxilate pharmaceutical capsules compositions stripping adopting prescription of the present invention and technique to prepare is very fast, and uniformity is better, and related substance is lower, and stability is better, and compared with prior art quality is more excellent, is more suitable for industrialized great production.
Claims (11)
1. a methanesulfonic acid dabigatran etcxilate pharmaceutical capsules compositions, is characterized in that, this pharmaceutical composition comprises following two parts:
Part I: the coated granule containing methanesulfonic acid dabigatran etcxilate;
Part II: containing tartaric coated granule;
Described Part I granule and Part II granule filled capsules after mixing homogeneously.
2. methanesulfonic acid dabigatran etcxilate pharmaceutical capsules compositions according to claim 1, it is characterized in that, in this pharmaceutical composition, Part I and Part II are all containing binding agent.
3. methanesulfonic acid dabigatran etcxilate pharmaceutical capsules compositions according to claim 2, it is characterized in that, in Part I, the mass ratio of methanesulfonic acid dabigatran etcxilate and binding agent is (50 ~ 200): (4 ~ 18).
4. methanesulfonic acid dabigatran etcxilate pharmaceutical capsules compositions according to claim 3, it is characterized in that, in Part I, the mass ratio of methanesulfonic acid dabigatran etcxilate and binding agent is (86 ~ 173): (7 ~ 16).
5. the methanesulfonic acid dabigatran etcxilate pharmaceutical capsules compositions according to claim 3 or 4, it is characterized in that, in this pharmaceutical composition Part I, the mass ratio of methanesulfonic acid dabigatran etcxilate and binding agent is 86:7 or 127:11 or 173:16.
6. methanesulfonic acid dabigatran etcxilate pharmaceutical capsules compositions according to claim 2, is characterized in that the mass ratio of Part II mesotartaric acid and binding agent is for (50 ~ 200): (5 ~ 22).
7. methanesulfonic acid dabigatran etcxilate pharmaceutical capsules compositions according to claim 6, is characterized in that the mass ratio of Part II mesotartaric acid and binding agent is for (86 ~ 173): (9 ~ 19).
8. the methanesulfonic acid dabigatran etcxilate pharmaceutical capsules compositions according to claim 6 or 7, is characterized in that the mass ratio of Part II mesotartaric acid and binding agent is 86:9 or 127:14 or 173:19.
9. the methanesulfonic acid dabigatran etcxilate pharmaceutical capsules compositions according to any one of claim 1 ~ 8, it is characterized in that, described binding agent is polyvinylpyrrolidone, hyprolose, hypromellose, methylcellulose or carboxymethyl cellulose.
10. methanesulfonic acid dabigatran etcxilate pharmaceutical capsules compositions according to claim 9, it is characterized in that, described binding agent is hyprolose.
The preparation method of 11. 1 kinds of methanesulfonic acid dabigatran etcxilate pharmaceutical capsules compositionss, it is characterized in that, the preparation of this pharmaceutical composition comprises following steps:
1) methanesulfonic acid dabigatran etcxilate granule is prepared, coating;
2) tartaric acid granulate is prepared, coating;
3) filled capsules after granule mix homogeneously step 1 and step 2 obtained.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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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| CN201410024112 | 2014-01-20 | ||
| CN2014100241120 | 2014-01-20 | ||
| 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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| CN104784147A true CN104784147A (en) | 2015-07-22 |
| CN104784147B CN104784147B (en) | 2018-01-23 |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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| WO2019004980A3 (en) * | 2017-05-10 | 2019-04-11 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Solid oral pharmaceutical compositions of dabigatran etexilate |
| WO2019004979A3 (en) * | 2017-05-10 | 2019-04-11 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Solid oral pharmaceutical compositions of dabigatran etexilate |
| EP3787624A4 (en) * | 2018-05-04 | 2022-03-30 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Capsule-in-capsule compositions of dabigatran etexilate |
| CN115227663A (en) * | 2021-04-22 | 2022-10-25 | 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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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106727414A (en) * | 2016-12-27 | 2017-05-31 | 哈药集团技术中心 | A kind of dabigatran etexilate methanesulfonate micropill and preparation method |
| 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 |
| WO2019004980A3 (en) * | 2017-05-10 | 2019-04-11 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Solid oral pharmaceutical compositions of dabigatran etexilate |
| WO2019004979A3 (en) * | 2017-05-10 | 2019-04-11 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Solid oral pharmaceutical compositions of dabigatran etexilate |
| AU2018293361B2 (en) * | 2017-05-10 | 2021-09-16 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Solid oral pharmaceutical compositions of dabigatran etexilate |
| EP3787624A4 (en) * | 2018-05-04 | 2022-03-30 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Capsule-in-capsule compositions of dabigatran etexilate |
| CN115227663A (en) * | 2021-04-22 | 2022-10-25 | 石药集团恩必普药业有限公司 | Dabigatran etexilate mesylate capsule and preparation method thereof |
| 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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| CN104784147B (en) | 2018-01-23 |
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