CN104434882A - Pellet medicine composition containing pradaxa or salt and hydrate thereof - Google Patents
Pellet medicine composition containing pradaxa or salt and hydrate thereof Download PDFInfo
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- CN104434882A CN104434882A CN201410617261.8A CN201410617261A CN104434882A CN 104434882 A CN104434882 A CN 104434882A CN 201410617261 A CN201410617261 A CN 201410617261A CN 104434882 A CN104434882 A CN 104434882A
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- organic acid
- micropill
- active substance
- ball core
- acid
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- 150000003839 salts Chemical class 0.000 title claims abstract description 9
- 239000003814 drug Substances 0.000 title abstract description 16
- 239000000203 mixture Substances 0.000 title abstract description 8
- 239000008188 pellet Substances 0.000 title abstract 8
- 229940066336 pradaxa Drugs 0.000 title abstract 5
- 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 1
- 239000013543 active substance Substances 0.000 claims abstract description 50
- 150000007524 organic acids Chemical class 0.000 claims abstract description 49
- 238000000034 method Methods 0.000 claims abstract description 15
- 239000000945 filler Substances 0.000 claims abstract description 11
- 229960003850 dabigatran Drugs 0.000 claims description 22
- 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 20
- 238000000576 coating method Methods 0.000 claims description 18
- 238000007789 sealing Methods 0.000 claims description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims description 15
- 239000011248 coating agent Substances 0.000 claims description 13
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 11
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 11
- 239000008101 lactose Substances 0.000 claims description 11
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 11
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 11
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 11
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 11
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 11
- 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 description 10
- 235000002906 tartaric acid Nutrition 0.000 claims description 10
- 239000011975 tartaric acid Substances 0.000 claims description 10
- 239000011230 binding agent Substances 0.000 claims description 9
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 9
- -1 polyethylene ketopyrrolidine Polymers 0.000 claims description 7
- 229920002472 Starch Polymers 0.000 claims description 6
- 239000008107 starch Substances 0.000 claims description 6
- 235000019698 starch Nutrition 0.000 claims description 6
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 5
- 238000001125 extrusion Methods 0.000 claims description 5
- 239000007902 hard capsule Substances 0.000 claims description 5
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 5
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 5
- 229920000642 polymer Polymers 0.000 claims description 5
- 238000005563 spheronization Methods 0.000 claims description 5
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 4
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- 235000015165 citric acid Nutrition 0.000 claims description 4
- 239000004220 glutamic acid Substances 0.000 claims description 4
- 235000013922 glutamic acid Nutrition 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 3
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 3
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- 229920003091 Methocel™ Polymers 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 3
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 3
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 3
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 239000003086 colorant Substances 0.000 claims description 3
- 239000013530 defoamer Substances 0.000 claims description 3
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 3
- 229940071826 hydroxyethyl cellulose Drugs 0.000 claims description 3
- 239000004014 plasticizer Substances 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- 235000013399 edible fruits Nutrition 0.000 claims description 2
- 239000012530 fluid Substances 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 229920000609 methyl cellulose Polymers 0.000 claims description 2
- 239000001923 methylcellulose Substances 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 2
- 239000011162 core material Substances 0.000 abstract description 49
- 238000002360 preparation method Methods 0.000 abstract description 12
- 238000002955 isolation Methods 0.000 abstract description 11
- 238000004090 dissolution Methods 0.000 abstract description 6
- 238000012216 screening Methods 0.000 abstract description 3
- XETBXHPXHHOLOE-UHFFFAOYSA-N dabigatran etexilate methanesulfonate Chemical compound CS(O)(=O)=O.C1=CC(C(\N)=N/C(=O)OCCCCCC)=CC=C1NCC1=NC2=CC(C(=O)N(CCC(=O)OCC)C=3N=CC=CC=3)=CC=C2N1C XETBXHPXHHOLOE-UHFFFAOYSA-N 0.000 abstract 4
- 239000000853 adhesive Substances 0.000 abstract 2
- 230000001070 adhesive effect Effects 0.000 abstract 2
- 239000004480 active ingredient Substances 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 239000013558 reference substance Substances 0.000 description 7
- 239000002775 capsule Substances 0.000 description 6
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 5
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 5
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- 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 4
- 229940079593 drug Drugs 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000011049 filling Methods 0.000 description 4
- 229960003943 hypromellose Drugs 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000001133 acceleration Effects 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000011149 active material Substances 0.000 description 3
- 230000010100 anticoagulation Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000005243 fluidization Methods 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 229960004072 thrombin Drugs 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
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 108090000190 Thrombin Proteins 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 235000003704 aspartic acid Nutrition 0.000 description 2
- 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 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
- 230000007797 corrosion Effects 0.000 description 2
- 238000005260 corrosion Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000012738 dissolution medium Substances 0.000 description 2
- 229950003499 fibrin Drugs 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 235000011087 fumaric acid Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000002609 medium 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
- 206010013710 Drug interaction Diseases 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- 101000712605 Theromyzon tessulatum Theromin Proteins 0.000 description 1
- 229940122388 Thrombin inhibitor Drugs 0.000 description 1
- 238000013019 agitation Methods 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
- 230000002429 anti-coagulating effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000009506 drug dissolution testing Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 239000011229 interlayer Substances 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000010422 painting Methods 0.000 description 1
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
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- 238000011112 process operation Methods 0.000 description 1
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- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 1
- 229960005080 warfarin Drugs 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a medicinal combination containing pradaxa or salt and hydrate thereof. The medicinal combination comprises an active substance pellet core material containing an active ingredient pradaxa or pharmaceutically acceptable salt or hydrate thereof and filler and/or adhesive, an organic acid pellet core material containing organic acid and filler and/or adhesive, and an isolation layer which is arranged outside the active substance pellet core material and the organic acid pellet core material as shown in a figure I. By means of screening, the pradaxa active substance and organic acid are respectively prepared into pellet cores, and the pellet cores are respectively coated with the isolation layer, and the two pellets are prepared in a proportion to form the pradaxa oral medicine composition. The process is stable and controllable, and the preparation has good solubility and dissolution rate.
Description
Technical field
The present invention relates to the micropill pharmaceutical composition of a kind of dabigatran etcxilate or its salt and hydrate, belong to medical art.
Background technology
The chemical formula of dabigatran etcxilate of the present invention is 3-[(2-{ [4-(own oxygen carbonylamino-imino-methyl)-phenyl amino]-methyl }-1-methyl isophthalic acid H-benzimidazole-5-carbonyl)-pyridine-2-base-amino]-ethyl propionate and salt thereof and hydrate.Shown in the following I of structural formula.
Dabigatran etcxilate is another new oral anticoagulation medicine of FDA Food and Drug Administration's approval after warfarin, belong to the thrombin inhibitor of non-peptide class, play anticoagulant effect by specificity and the activity optionally blocking thrombin (sequestered or conjunction type).Have can oral, potent, without the need to features such as special Medication monitor, drug interaction are few, be a major progress in anticoagulation therapy field and potential lethal thrombus prevention field, there is milestone significance.Oral after gastrointestinal absorption, be converted into the dabigatran with direct anticoagulant active in vivo, by being incorporated into the fibrin specific binding site of thrombin, stoping Fibrinogen to be cracked into fibrin, thus having blocked final step and the thrombosis of blood coagulation waterfall network.Dabigatran can also dissociate from fibrin-thrombin coalition, plays reversible anticoagulation.
Because dabigatran etcxilate is almost insoluble in the medium of pH > 4.0, therefore sour environment is conducive to main active dabigatran etcxilate stripping and body absorption from pharmaceutical preparation.Patent (publication number CN101632668A) discloses the salt of this dabigatran etcxilate or the pharmaceutical composition of hydrate, bag sealing coat and active material layer in organic acid core material, wherein sour core material comprises the organic acidic material such as tartaric acid, fumaric acid, succinic acid, citric acid, glutamic acid or aspartic acid, sees Fig. 1.Be separated from each other by sealing coat between organic acid core and active material layer.This technique, by the medicine-feeding of organic acid ball wicking surface fluidisation, becomes suspension to add medicine to by medicine ordinance, and the method has the shortcomings such as medicine-feeding rate is low, drug loss amount large, complex operation, uneven, the upper dose of medicine-feeding are uncertain; During due to active substance and organic acid Long Term Contact, active substance is easily degraded, therefore need between organic acid core and active substance bag sealing coat, make operating procedure more complicated and wayward, if process operation is improper, easily occur sealing coat break or sealing coat coating thickness inadequate, organic acid and active substance are contacted because of diffusion depositing in process, cause the degraded of active substance.Patent (publication number CN103127109A), dabigatran etcxilate active substance is prepared into ball core, integration adds organic acidic material layer, applies sealing coat simultaneously, prepare dabigatran etcxilate combination of oral medication between dabigatran etcxilate active substance ball core and organic acidic material layer.Wherein organic acid is selected from tartaric acid, succinic acid, citric acid, glutamic acid, fumaric acid, malic acid or aspartic acid or its hydrate or hydrochlorate.This technique and a upper technics comparing, active substance is made ball core, avoid the defect of fluidisation medicine-feeding, but do not avoid active substance and organic acid Long Term Contact, still need at active substance ball core and organic acid interlayer bag sealing coat, complex process is wayward, and sealing coat cannot be avoided to break the contact of the medicine caused and active substance soon, causes active substance to degrade.
The present invention prepares separately active substance ball core and organic acid ball core, sees Fig. 2.Process avoids the defect of fluidisation medicine-feeding, medication amount is easily controlled, and uniformity of dosage units is good, and production technology is simple.Two kinds of ball cores bag contagion gown respectively, farthest reduces active substance and organic acid contact rate, adds the stability of medicine simultaneously.And by adjustment contagion gown thickness, better control medicine and organic acid dissolution rate, increase the dissolubility of medicine, improve bioavailability.
Summary of the invention
The object of this invention is to provide a kind of preparation technology simple, operate easy, be convenient to suitability for industrialized production, good stability, method that bioavailability is high.Active substance and organic acid are made ball core respectively, and coating sealing coat obtains micropill respectively, is filled in proportion by two kinds of micropills and obtains dabigatran etcxilate micropill pharmaceutical composition.
Object of the present invention can be reached by following measures:
A kind of pharmaceutical composition, it comprises
I) containing the active substance ball core material be made up of with filler and/or binding agent active component dabigatran etcxilate or its pharmaceutically acceptable salt or hydrate;
II) contain by organic acid or containing the ball core material be made up of this organic acid and filler and binding agent; Described organic acid is selected from tartaric acid or/and citric acid, fruit acid, glutamic acid, maleic acid or its hydrate or hydrochlorate.
In compositions of the present invention, outside active substance ball core, be provided with sealing coat or exterior coating.
In compositions of the present invention, sealing coat or exterior coating can be provided with further outside organic acid ball core.
Described active component is dabigatran etcxilate mesylate; The mass content of active component in active substance micropill is 10 ~ 60%; Active micropill size is 20 ~ 60 orders, preferably 30 ~ 40 orders.
Filler in described active substance ball core is selected from one or more in microcrystalline Cellulose, carboxymethyl starch sodium, lactose, starch, preferably microcrystalline cellulose, lactose; Binding agent in described active micropill is selected from one or more in polyvinylpyrrolidone, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, hydroxy methocel, preferably polyethylene ketopyrrolidine.
Active substance ball core can be prepared by known in pharmaceuticals industry and fixed method, is more particularly to form roughly spherical granule by extrusion spheronization machine, is then obtained containing the desired stepped diameter of active substance ball core by screening.
After active substance ball core material is made, by isolation suspension on active substance ball core, sealing coat can be formed.Undertaken by following conventional method: the coating device coating isolation suspension commonly used with fluid bed, coating groove.This research adopts multi-functional pill seed-coating machine, realizes extrusion spheronization, drying, coating three kinds of functions.Described isolation suspension consists of water miscible pharmaceutically acceptable polymer and optional plasticizer, anticaking agent, defoamer and/or coloring agent.Wherein said polymer is selected from one or more in hydroxypropyl cellulose, hydroxypropyl emthylcellulose, polyvidone or methylcellulose.
Described organic acid is tartaric acid; The mass content of tartaric acid in organic acid ball core is 20 ~ 60%; Organic acid micropill size is 20 ~ 60 orders, preferably 30 ~ 40 orders.
The preparation of organic acid micropill can adopt the preparation method of above-mentioned active substance ball core, after obtained ball core, according to above-mentioned sealing coat painting method bag sealing coat or coatings.
Finally active substance micropill and organic acid micropill are filled in proportion, use the capsule filling machine with secondary filling function to be inserted in hard capsules by the pill being equivalent to required dosage.Hard capsules can select hydroxypropyl methylcellulose capsules or other capsule materials pharmaceutically commonly used.
Detailed description of the invention
Following examples further describe the present invention, but these embodiments are only for illustration of the present invention, instead of limitation of the scope of the invention.
Embodiment 1
Active substance ball core
| Embodiment | Active substance | Microcrystalline Cellulose | Lactose | Polyvinylpyrrolidone | 50% ethanol |
| 1 | 20 | 25 | 10 | 4 | 36 |
The isolation of active substance ball core
| Embodiment | Containing the ball core of active substance | Pulvis Talci | Hypromellose | 80% ethanol |
| 1 | 66 | 4 | 1 | 50 |
The preparation of organic acid ball core
| Embodiment | Organic acid | Microcrystalline Cellulose | Lactose | Polyvinylpyrrolidone | 50% ethanol |
| 1 | 20 | 25 | 10 | 4 | 36 |
The isolation of organic acid ball core
| Embodiment | Containing organic acid ball core | Pulvis Talci | Hypromellose | 80% ethanol |
| 1 | 66 | 4 | 1 | 50 |
Take 4g polyvinylpyrrolidone, be dissolved in the alcoholic solution of 50% of 36ml.By the methanesulfonic acid dabigatran etcxilate of 20g and the microcrystalline Cellulose of 25g and 10g lactose mechanical agitation mix homogeneously, then add containing 4g polyvinylpyrrolidone 50% alcoholic solution in, be mixed into suitable soft material, form roughly spherical granule by extrusion spheronization machine.Then by spheric active material ball core at 30 ~ 35 DEG C of temperature, dry, obtain active substance ball core.
Use the active ball core material of screen cloth screening 30 ~ 40 object with nominal mesh.Be used between the active ball core of 30 ~ 40 objects in all the other steps of method.In blender, place 80% ethanol of 50ml, then under the mixing speed of about 400rpm, add 1g hypromellose, make it dissolve, then add 4g Pulvis Talci under the same conditions, preparation isolation suspension is for subsequent use.In multi-functional pill seed-coating machine, coating is carried out to the ball core containing active substance of preparation.Then by the drying by circulating air machine inner drying of active substance micropill at 40 DEG C 4 hours of isolation.
The preparation of organic acid ball core and coating are with the preparation method of active substance micropill.
Active substance micropill and organic acid micropill are proportionally packed in hard capsule case, select the capsule machine with secondary filling function to fill.
Embodiment 2
Active substance ball core
| Embodiment | Active substance | Microcrystalline Cellulose | Lactose | Polyvinylpyrrolidone | 50% ethanol |
| 2 | 20 | 20 | 15 | 4 | 36 |
The isolation of active substance ball core
| Embodiment | Containing the ball core of active substance | Pulvis Talci | Hypromellose | 80% ethanol |
| 2 | 66 | 4 | 1 | 50 |
The preparation of organic acid ball core
| Embodiment | Organic acid | Microcrystalline Cellulose | Lactose | Polyvinylpyrrolidone | 50% ethanol |
| 2 | 20 | 25 | 15 | 4 | 36 |
Preparation method is identical with embodiment 1, does not only carry out isolation coat to organic acid ball core.Active substance micropill and organic acid ball core are proportionally packed in hard capsule case, select the capsule machine with secondary filling function to fill.
Stripping is tested
With reference to the dissolution determination method of FDA, select dissolution test method according to dabigatran etcxilate dosage form.The dissolution testing conditions of capsule is as follows: basket method, 100rpm, dissolution medium: 0.1N HCl (pH2.0), dissolution medium volume: 900ml, sample time is as following table.Measure the stripping of the dabigatran ester formulation of embodiment 1 and embodiment 2 preparation, and measure the dissolution of commercially available prod dabigatran etcxilate.According to gained stripping data, compared.Stripping curve is shown in Fig. 3, and experimental result is as shown in the table:
As can be seen from above dissolution results, by the dissolution rate regulating organic acid sealing coat can affect medicine, the pharmaceutical composition of the embodiment of the present invention 1 is similar to reference substance dissolved corrosion, has good stripping.The non-bag sealing coat of sample tartaric acid ball core of embodiment 2, sour ball stripping is rapid, affects by acid medium, and when medicine starts, comparatively embodiment 1 and reference substance 1 are soon, variant with reference substance 1 dissolved corrosion in stripping.
Acceleration study
Embodiment 1 sample, embodiment 2 sample and reference substance 1 carries out Acceleration study.Temperature 40 DEG C ± 2 DEG C, place 6 months under the condition of relative humidity 75% ± 5%, respectively sample once 1st month, the 2nd month, the 3rd month, the 6th the end of month at duration of test, detect by stability high spot review project.Experimental data sees the following form.
As can be seen from Acceleration study data, embodiment 2 sample and reference substance 1 are all surrounded by one deck contagion gown, and two kinds of sample stabilities are similar.In embodiment 1 sample, active substance ball core and tartaric acid ball core are all surrounded by contagion gown, reduce the contact probability of two kinds of compositions, loss on drying moisture content less, and total degradation product recruitment is also relatively less, and stability is obviously better than embodiment 2 sample and reference substance 1.
Accompanying drawing explanation
Fig. 1. reference substance 1 micropill structure
Fig. 2. embodiment 1 sample micropill structure
When Fig. 3, pH=2, the stripping curve of various dabigatran ester formulation compares.
Claims (9)
1. a pharmaceutical composition, it comprises two parts ball core:
I) containing the active substance ball core be made up of with filler and binding agent active component dabigatran etcxilate or its pharmaceutically acceptable salt or hydrate;
II) contain by organic acid or containing the ball core be made up of this organic acid and filler and binding agent; Described organic acid is selected from tartaric acid, citric acid, fruit acid, glutamic acid, maleic acid or its hydrate or hydrochlorate.
2. pharmaceutical composition according to claim 1, is characterized in that described active component is dabigatran etcxilate mesylate; The mass content of active component in active substance micropill is 10 ~ 60%; Active micropill size is 20 ~ 60 orders, preferably 30 ~ 40 orders.
3. pharmaceutical composition according to claim 1, is characterized in that organic acid is tartaric acid; The mass content of tartaric acid in organic acid micropill is 20 ~ 60%; Organic acid micropill size is 20 ~ 60 orders, preferably 30 ~ 40 orders.
4. pharmaceutical composition according to claim 1, the filler that it is characterized in that in described active substance micropill is selected from one or more in microcrystalline Cellulose, carboxymethyl starch sodium, lactose, starch, preferably microcrystalline cellulose, lactose; Binding agent in described active micropill is selected from one or more in polyvinylpyrrolidone, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, hydroxy methocel, preferably polyethylene ketopyrrolidine.
5. pharmaceutical composition according to claim 1, the filler that it is characterized in that in described organic acid micropill is selected from one or more in microcrystalline Cellulose, carboxymethyl starch sodium, lactose, starch, preferably microcrystalline cellulose, lactose; Binding agent in described active micropill is selected from one or more in polyvinylpyrrolidone, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, hydroxy methocel, preferably polyethylene ketopyrrolidine.
6. pharmaceutical composition according to claim 1, is characterized in that active micropill is surrounded by sealing coat or coatings.
7. pharmaceutical composition according to claim 1, is characterized in that organic acid micropill is surrounded by sealing coat or coatings.
8. the pharmaceutical composition according to claim 6 or 7, is characterized in that described coatings is made up of water miscible pharmaceutically acceptable polymer and optional plasticizer, anticaking agent, defoamer and/or coloring agent; Wherein said water miscible pharmaceutically acceptable polymer is selected from one or more in hydroxypropyl cellulose, hydroxypropyl emthylcellulose, polyvidone or methylcellulose.
9. prepare a method for pharmaceutical composition according to claim 1, it is characterized in that comprising the steps:
I) by extrusion spheronization machine, active substance, filler, binding agent are prepared into active substance ball core; By extrusion spheronization machine, organic acid, filler, binding agent are prepared into organic acid ball core;
II) on active substance ball core, organic acid ball core, the coatings be made up of water miscible pharmaceutically acceptable polymer and optional plasticizer, anticaking agent, defoamer or coloring agent is applied with fluid bed;
III) the active substance micropill of coating obtained above, organic acid micropill are packed in hard capsules in proportion.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106999434A (en) * | 2015-04-08 | 2017-08-01 | 杭州领业医药科技有限公司 | A kind of micropill containing cysteine hydrochloride and preparation method thereof |
| CN113332256A (en) * | 2021-05-21 | 2021-09-03 | 江苏宇锐医药科技有限公司 | Dabigatran etexilate pellet combination capsule and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2722034A1 (en) * | 2012-10-19 | 2014-04-23 | Sanovel Ilac Sanayi ve Ticaret A.S. | Oral Pharmaceutical Formulations Comprising Dabigatran |
| CN104095830A (en) * | 2014-05-22 | 2014-10-15 | 万特制药(海南)有限公司 | Preparation method for mesylate dabigatran capsule |
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2014
- 2014-11-05 CN CN201410617261.8A patent/CN104434882A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2722034A1 (en) * | 2012-10-19 | 2014-04-23 | Sanovel Ilac Sanayi ve Ticaret A.S. | Oral Pharmaceutical Formulations Comprising Dabigatran |
| CN104095830A (en) * | 2014-05-22 | 2014-10-15 | 万特制药(海南)有限公司 | Preparation method for mesylate dabigatran capsule |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106999434A (en) * | 2015-04-08 | 2017-08-01 | 杭州领业医药科技有限公司 | A kind of micropill containing cysteine hydrochloride and preparation method thereof |
| CN113332256A (en) * | 2021-05-21 | 2021-09-03 | 江苏宇锐医药科技有限公司 | Dabigatran etexilate pellet combination capsule and preparation method thereof |
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