CN108261409A - A kind of combination of oral medication of dabigatran etcxilate and preparation method thereof - Google Patents
A kind of combination of oral medication of dabigatran etcxilate and preparation method thereof Download PDFInfo
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- CN108261409A CN108261409A CN201710000211.9A CN201710000211A CN108261409A CN 108261409 A CN108261409 A CN 108261409A CN 201710000211 A CN201710000211 A CN 201710000211A CN 108261409 A CN108261409 A CN 108261409A
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- 229960003850 dabigatran Drugs 0.000 title claims abstract description 23
- 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 title claims abstract description 22
- 229940126701 oral medication Drugs 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 239000002775 capsule Substances 0.000 claims abstract description 60
- 239000013078 crystal Substances 0.000 claims abstract description 41
- 239000003814 drug Substances 0.000 claims abstract description 33
- 150000007524 organic acids Chemical class 0.000 claims abstract description 30
- 239000000463 material Substances 0.000 claims abstract description 27
- 239000002245 particle Substances 0.000 claims abstract description 27
- 239000011149 active material Substances 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 18
- 239000004615 ingredient Substances 0.000 claims abstract description 17
- 229940079593 drug Drugs 0.000 claims abstract description 12
- 229920002678 cellulose Polymers 0.000 claims abstract description 11
- 239000001913 cellulose Substances 0.000 claims abstract description 11
- 238000002955 isolation Methods 0.000 claims abstract description 10
- 239000000853 adhesive Substances 0.000 claims abstract description 8
- 230000001070 adhesive effect Effects 0.000 claims abstract description 8
- 238000000926 separation method Methods 0.000 claims abstract description 8
- 239000007884 disintegrant Substances 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 17
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 15
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 15
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 15
- 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 claims description 14
- 239000002253 acid Substances 0.000 claims description 13
- 229920000159 gelatin Polymers 0.000 claims description 13
- 235000019322 gelatine Nutrition 0.000 claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 108010010803 Gelatin Proteins 0.000 claims description 10
- 235000010980 cellulose Nutrition 0.000 claims description 10
- 235000011852 gelatine desserts Nutrition 0.000 claims description 10
- 238000005469 granulation Methods 0.000 claims description 10
- 230000003179 granulation Effects 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 10
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 239000008273 gelatin Substances 0.000 claims description 9
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 9
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 9
- 238000005550 wet granulation Methods 0.000 claims description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 8
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 8
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 8
- 239000000080 wetting agent Substances 0.000 claims description 8
- 238000005453 pelletization Methods 0.000 claims description 7
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 6
- 235000020985 whole grains Nutrition 0.000 claims description 6
- 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 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 5
- 239000011975 tartaric acid Substances 0.000 claims description 5
- 235000002906 tartaric acid Nutrition 0.000 claims description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- 238000007908 dry granulation Methods 0.000 claims description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 claims description 3
- -1 hydroxyl Propyl Chemical group 0.000 claims description 3
- 229920000609 methyl cellulose Polymers 0.000 claims description 3
- 239000001923 methylcellulose Substances 0.000 claims description 3
- 235000010981 methylcellulose Nutrition 0.000 claims description 3
- 239000004014 plasticizer Substances 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 239000001069 triethyl citrate Substances 0.000 claims description 3
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 claims description 3
- 235000013769 triethyl citrate Nutrition 0.000 claims description 3
- 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 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 2
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 0.000 claims description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 2
- 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 2
- 239000001856 Ethyl cellulose Substances 0.000 claims description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 2
- 229920000881 Modified starch Polymers 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 235000003704 aspartic acid Nutrition 0.000 claims 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 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 229960005069 calcium Drugs 0.000 claims description 2
- 235000001465 calcium Nutrition 0.000 claims description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 2
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 2
- 238000004132 cross linking Methods 0.000 claims description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 229920001249 ethyl cellulose Polymers 0.000 claims description 2
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 239000004220 glutamic acid Substances 0.000 claims description 2
- 235000013922 glutamic acid Nutrition 0.000 claims description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 2
- 239000001630 malic acid Substances 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 2
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- 235000005979 Citrus limon Nutrition 0.000 claims 1
- 244000131522 Citrus pyriformis Species 0.000 claims 1
- 240000008042 Zea mays Species 0.000 claims 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 claims 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 claims 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims 1
- 235000005822 corn Nutrition 0.000 claims 1
- 235000011087 fumaric acid Nutrition 0.000 claims 1
- 229960003943 hypromellose Drugs 0.000 claims 1
- 150000002576 ketones Chemical class 0.000 claims 1
- 229940098779 methanesulfonic acid Drugs 0.000 claims 1
- 239000000843 powder Substances 0.000 claims 1
- 239000013049 sediment Substances 0.000 claims 1
- 235000021419 vinegar Nutrition 0.000 claims 1
- 239000000052 vinegar Substances 0.000 claims 1
- 238000004090 dissolution Methods 0.000 abstract description 7
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 7
- 239000011162 core material Substances 0.000 description 6
- 239000012530 fluid Substances 0.000 description 6
- 239000008188 pellet Substances 0.000 description 6
- 230000002378 acidificating effect Effects 0.000 description 4
- 239000011248 coating agent Substances 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 102000009123 Fibrin Human genes 0.000 description 3
- 108010073385 Fibrin Proteins 0.000 description 3
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 3
- 239000001828 Gelatine Substances 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000003146 anticoagulant agent Substances 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 229960000288 dabigatran etexilate Drugs 0.000 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 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 229950003499 fibrin Drugs 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 206010003658 Atrial Fibrillation Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229940127219 anticoagulant drug Drugs 0.000 description 2
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 235000013339 cereals Nutrition 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 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 2
- 229960005080 warfarin Drugs 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 1
- 229940123900 Direct thrombin inhibitor Drugs 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
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 230000004308 accommodation Effects 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 239000004855 amber Substances 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- JYZIHLWOWKMNNX-UHFFFAOYSA-N benzimidazole Chemical compound C1=C[CH]C2=NC=NC2=C1 JYZIHLWOWKMNNX-UHFFFAOYSA-N 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000005253 cladding Methods 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 210000000629 knee joint Anatomy 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229940100691 oral capsule Drugs 0.000 description 1
- 239000008203 oral pharmaceutical composition Substances 0.000 description 1
- 238000009522 phase III clinical trial Methods 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000009861 stroke prevention Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Entitled a kind of oral drug preparation of dabigatran etcxilate of the present invention and preparation method thereof.Belong to field of pharmaceutical preparations.The purpose is to provide it is a kind of it is simple for process, be easily achieved, cost is relatively low, active material dissolution preferably, be easy to absorb dabigatran etcxilate oral preparation and said preparation preparation method.A kind of combination of oral medication of the present invention, it includes：A) by the medicine-containing particle formed containing active material ingredients and adhesive, disintegrant, glidant, wherein active material ingredients are dabigatran etcxilate or its pharmaceutically acceptable salt；B) by the organic acid crystal of isolation, separation layer is for Capsules I or selected from the isolated material for including pharmaceutically acceptable cellulose family auxiliary material；Layer is preferably isolated as Capsules I；Medicine-containing particle is filled with after the organic acid crystal being isolated mixes in proportion into Capsules II.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, are related to a kind of active material for N- [2- [4- [N- (own oxygen carbonyl) amidino groups] benzene
Amino methyl] -1- methyl-1 H benzimidazole -5- bases carbonyl]-N- (2- pyridyl groups)-Beta-alanine ethyl ester is (i.e.：Dabigatran
Ester) or its pharmaceutically-acceptable salts combination of oral medication.The invention further relates to the preparation methods of the pharmaceutical composition.
Background technology
Dabigatran etcxilate, chemical name are N- [2- [4- [N- (own oxygen carbonyl) amidino groups] phenylaminomethyl] -1- methyl-1s H
Benzimidazole -5- bases carbonyl]-N- (2- pyridyl groups)-Beta-alanine ethyl ester, the chemical structural formula of mesylate is as follows：
Dabigatran etcxilate is first disclosed as WO 98/37075, by German Boehringer Ingelheim (Boehringer
Ingelheim) company develop, be a kind of novel direct thrombin inhibitor, have it is orally available, potent, without special medication supervise
The features such as survey, few drug interaction.It is listed for the first time in Britain in April, 2008, in 36 Europe including Germany
The non-european countries such as continent country and Canada, New Zealand, Brazil, Hong-Kong and area listing.For complete knee joint or full hip
The prevention of the postoperative venous thronbosis of joint replacement takes orally the main administration route for dabigatran etcxilate, after gastrointestinal absorption,
It is converted into the dabigatran with direct anticoagulant active in vivo.The fibrin that dabigatran is incorporated into fibrin ferment is special
Different binding site prevents fibrinogen from cracking fibrin, so as to block the final step and thrombus of blood coagulation waterfall network
It is formed.In addition, the medicine shows for the polycentric phase III clinical trial result in the whole world of patients with atrial fibrillation stroke prevention：Da Bijia
Group's ester significantly reduces the risk of patients with atrial fibrillation apoplectic seizure, good security compared with standard anticoagulant warfarin.September 28 in 2010
Day, the U.S. FDA approved indication.Foreign countries predict the market share that the medicine will seize warfarin 50% after listing 5 years, quickly
Antithrombotic field weight pound grade drug will be become.
Dabigatran etcxilate dissolution has pH dependences, and dissolution rate is higher in acid medium, in pH>It is several in 4.0 medium
It is insoluble, therefore acidic environment is conducive to the dissolution and absorption of main active.
Chinese patent CN1638771A discloses a kind of dabigatran etcxilate oral pharmaceutical compositions, wherein comprising adhesive with appointing
Interleaving agent is selected to be applied in organic acid core material around the active material layer of core material.Organic acid core material and active material
Layer is separated by separation layer.Active medicine suspension is coated in organic acid capsule core by the technique using capsule core medicine-feeding method.
This method complex process, product yield is relatively low, there is separation layer cladding it is imperfect, main ingredient degradation risk it is big, the upper more difficult control of dose
The problems such as system, medicine accommodation layer is uneven, poor repeatability.
Chinese patent CN103127109 A disclose a kind of containing dabigatran etcxilate or the pharmaceutical compositions of its salt and hydrate.
Active material is prepared into capsule core by it, is then coated with organic acidic material layer, obtains dabigatran etcxilate pharmaceutical composition, this method will be active
In substance is coated on, it is impossible to be released effectively, and equally exist that technology difficulty is big, more difficult the problem of repeating.
104274444 A of Chinese patent CN disclose a kind of dabigatran etcxilate or double pellet pharmaceutical compositions of its salt.It will
Active material prepares pellet, and be isolated respectively with organic acid.The method is related to the preparation of multistep pellet and isolation technology, technique are multiple
Miscellaneous, processing step is more so that the quality control of multicomponent pellet is relatively difficult, and production cost is higher.
Invention content
The object of the present invention is to provide it is a kind of it is simple for process, easy realize, at low cost, active material dissolution is preferable, be easy to inhale
The dabigatran etcxilate oral capsule preparation of receipts.
The present invention provides a kind of combination of oral medication, it includes
A) by the medicine-containing particle formed containing active material ingredients and adhesive, disintegrant, glidant, wherein active material
Ingredient is dabigatran etcxilate or its pharmaceutically acceptable salt；
B) by the organic acid crystal of isolation, separation layer is for Capsules I or selected from including pharmaceutically acceptable fibre
The isolated material of the plain class auxiliary material of dimension；Layer is preferably isolated as Capsules I；
Medicine-containing particle is filled with after the organic acid crystal being isolated mixes in proportion into Capsules II.
In the present invention, since acidic materials and active material dabigatran etcxilate or its pharmaceutically acceptable salt cannot be direct
Otherwise contact can cause degradation occurs and fails, therefore organic acid crystal need to be isolated during drug storage, Ke Yixuan
It selects directly to fill the organic acid crystal of crystalline state using capsule filling machine and be isolated into Capsules；Can also have
Machine acid crystal external demand coats isolated material as separation layer, and isolated material is mainly made of cellulose family auxiliary material, while according to work
Skill needs, and can add suitable plasticizer, antitackiness agent, such as triethyl citrate, polyethylene glycol, talcum powder etc..
The combination of oral medication of the present invention, wherein the organic acid crystal is selected from tartaric acid, fumaric acid, citric acid, amber
Amber acid, malic acid, glutamic acid or aspartic acid crystal；It is preferred that winestone acid crystal.
The combination of oral medication of the present invention, wherein the Capsules I be selected from gelatin or hydroxypropyl methylcellulose into
The Capsules of the Capsules, preferably gelatin that divide；The pharmaceutically acceptable cellulose family auxiliary material is selected from hydroxypropyl
Cellulose, hydroxypropyl methylcellulose, methylcellulose, ethyl cellulose, hydroxyethyl cellulose, polyvinylpyrrolidone and acetic acid are fine
Tie up one of element or its arbitrary combination；The Capsules II is selected from the Capsules or gelatin of hydroxypropyl methylcellulose ingredient
Capsules, preferably hydroxypropyl methylcellulose ingredient Capsules.
The Capsules of the preferred gelatins of Capsules I of the present invention, disintegration are very fast.The Capsules II of the present invention is excellent
The Capsules of hydroxypropyl methylcellulose ingredient are selected, can effectively reduce the moisture of pharmaceutical composition, and are ensured good after placing for a long time
Good appearance.Plant origin is also safer simultaneously.
The combination of oral medication of the present invention, wherein described adhesive are selected from hydroxypropyl cellulose, microcrystalline cellulose, hydroxypropyl
One of methylcellulose, polyvinylpyrrolidone and cornstarch or its arbitrary combination；It is preferred that hydroxypropyl cellulose；
The disintegrant is selected from low-substituted hydroxypropyl cellulose, croscarmellose sodium, calcium carboxymethylcellulose, crosslinking
One of povidone and partially pregelatinized starch or its arbitrary combination；It is preferred that low-substituted hydroxypropyl cellulose；
The glidant is selected from colloidal silicon dioxide or talcum powder, preferably colloidal silicon dioxide.
The combination of oral medication of the present invention, wherein the active material ingredients are dabigatran etexilate methanesulfonate, content is
20-60%；It is preferred that 40-55%.
The combination of oral medication of the present invention, the wherein content of organic acid crystal described in pharmaceutical composition are 20-90%；
It is preferred that 30-50%.
The combination of oral medication of the present invention, the wherein content of glidant described in pharmaceutical composition are 0.2-10%；It is excellent
Select 0.2-1.0%
The combination of oral medication of the present invention, wherein the medicine-containing particle is obtained for wet granulation or dry granulation, it is described
Glidant is adds in after granulation；
When the medicine-containing particle is obtained for wet granulation, wherein also containing granulation wetting agent, the granulation wetting agent is
Isopropanol.
The pharmaceutical composition of the present invention, according to wet granulation technology, then preferred isopropanol is as granulation wetting agent, purpose
It is that raw material is made, in insoluble state, to be unlikely to degradation or solution modeling in wetting agent of pelletizing and change crystal form.Using certain
The glidant of amount be in order to enable medicine-containing particle fill capsule when sticking and medicine-containing particle adhesion will not occur, ensure fill it is suitable
Profit progress and the qualified grain method of double differences are different, while can promote drug-eluting.
The present invention also provides the preparation methods of aforementioned pharmaceutical compositions, include the following steps：
A) active material ingredients, adhesive, disintegrant are pelletized by wet granulation or dry granulation, are sieved after granulation whole
Grain adds in glidant, medicine-containing particle is made；
When using wet granulation, isopropanol is added in pelletization as wetting agent；
B) organic acid crystal is filled into Capsules I and be isolated；Or
Isolated material is coated outside organic acid crystal as separation layer, the isolated material includes one or more medicines
Acceptable cellulose family auxiliary material on；
C) by the organic acid crystal after being isolated obtained by medicine-containing particle obtained by step a) and step b) by 1：9 to 4：1 ratio
Range is filled after mixing into Capsules II.
The above-mentioned preparation method of the present invention, isolated material described in step b) is also comprising plasticizer and antitackiness agent, the increasing
It moulds agent and is selected from triethyl citrate or polyethylene glycol, the antitackiness agent is selected from talcum powder；The dosage of isolated material is organic acid crystals
The 15-20% of the 10-30% of body weight, preferably organic acid crystal weight.
In the above-mentioned preparation method of the present invention, the mode of isolated material is coated in step b) outside organic acid crystal, preferably
It is carried out using fluid bed, specially：, into aqueous solution, antitackiness agent is added, so using as the cellulose family auxiliaries of isolated material
Organic acid crystal is coated by fluidized bed coating technique afterwards.
The preparation method of the present invention simplifies technical process, is commonly used using pharmacy and the wet method or dry method system that repeatability is good
Grain technique, and pass through and organic acid crystal is directly subjected to capsule isolation/or the isolation of cellulose family auxiliary material, medicated pellet system is omitted
The step of preparing pellet again after the standby crushing with organic acid crystal, simplifies numerous and diverse artificial processing, reduces the influence to auxiliary material, carry
The high yield of finished product, while can ensure that active material is in an acidic environment, promote the dissolution and absorption of drug.
Description of the drawings
The dabigatran etcxilate capsule of Fig. 1 embodiment of the present invention 1-4 and the stripping curve comparison diagram of commercially available product " safe Bi Quan ".
Specific embodiment
It is further illustrated the present invention below by embodiment.It should be understood to：The embodiment of the present invention is only used for
Illustrate the present invention and provide rather than limitation of the present invention, to the simple of the present invention under the premise of technical solution of the present invention
Improvement all belongs to the scope of protection of the present invention.
It is wet granulator for the embodiment of the present invention major process unit, capsule filling machine, fluid bed.
Embodiment 1
A) preparation of medicine-containing particle
Composition：
The active material, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose of recipe quantity are added in mixer-granulator, mixing
5 minutes, after mixing, continue in stirring, add in recipe quantity isopropanol, stir 2min, particle is made and adds in fluid bed and dries
It does to moisture below 0.7%.Cross 30 mesh sieve or pelletizing machine whole grain.
Additional colloidal silicon dioxide is uniformly mixed.
B) isolation of winestone acid crystal
Composition：
129.9 parts by weight of tartaric acid
No. 4 capsules of gelatin hollow capsule
The winestone acid crystal of recipe quantity is filled into No. 4 capsules.
C) capsule is filled
Medicine-containing particle and tartrated gelatine capsule are fitted into No. 1 hydroxypropyl methylcellulose Capsules.
Embodiment 2
A) preparation of medicine-containing particle
Composition：
The active material, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose of recipe quantity are added in mixer-granulator, mixing
5 minutes, after mixing, continue in stirring, add in recipe quantity isopropanol, stir 2min, particle is made and adds in fluid bed and dries
It does to moisture below 0.7%.Cross 30 mesh sieve or pelletizing machine whole grain.
Additional colloidal silicon dioxide is uniformly mixed.
B) isolation of winestone acid crystal
Composition：
110 parts by weight of tartaric acid
No. 5 capsules of gelatin hollow capsule
The winestone acid crystal of recipe quantity is filled into No. 5 capsules.
C) capsule is filled
Medicine-containing particle and tartrated gelatine capsule are fitted into No. 1 hydroxypropyl methylcellulose Capsules.
Embodiment 3
A) preparation of medicine-containing particle
Composition：
The active material, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose of recipe quantity are added in hopper mixing machine,
15rpm is mixed 10 minutes, after mixing, is added in dry granulating machine and is pelletized, granulation mesh size selection 2.0mm, after
Whole grain is carried out using pelletizing machine 1.2mm apertures.
Additional colloidal silicon dioxide is uniformly mixed.
B) isolation of Citric acid crystal
Composition：
110 parts by weight of tartaric acid
No. 5 capsules of gelatin hollow capsule
The Citric acid crystal of recipe quantity is filled into No. 5 capsules.
C) capsule is filled
Medicine-containing particle and the gelatine capsule containing citric acid are fitted into No. 1 hydroxypropyl methylcellulose Capsules.
Embodiment 4
A) preparation of medicine-containing particle
Composition：
The active material, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose of recipe quantity are added in mixer-granulator, mixing
5 minutes, after mixing, continue in stirring, add in recipe quantity isopropanol, stir 2min, particle is made and adds in fluid bed and dries
It does to moisture below 0.7%.Cross 30 mesh sieve or pelletizing machine whole grain.
Additional colloidal silicon dioxide is uniformly mixed.
B) isolation of winestone acid crystal
Composition：
The hydroxypropyl methylcellulose E5 of recipe quantity is made to be dissolved in the pure water of recipe quantity, the talcum powder for then adding in recipe quantity is held
Continuous stirring, makes to be uniformly dispersed, be sieved with 100 mesh sieve before use.
Winestone acid crystal is put in fluid bed, be preheated to 38 DEG C of product temperature, carried out under the conditions of 50-60 DEG C of inlet air temperature
Coating, 35-40 DEG C of product temperature, when coating to the end of, under the conditions of 60 DEG C of inlet air temperature with fluidized bed drying to moisture 0.7% with
Under.
C) capsule is filled
Medicine-containing particle and the winestone acid crystal after coating are fitted into No. 1 hydroxypropyl methylcellulose Capsules.
Dissolution determination
Using dabigatran etexilate methanesulfonate preparation made from 1-4 of the embodiment of the present invention, according to dissolution method (Chinese Pharmacopoeia
Four general rules of version in 2015,0,931 first method), using 0.01mol/L hydrochloric acid solutions 900ml as dissolution medium, rotating speed per minute 100
Turn, operate in accordance with the law, during through 15,20,30,45 minutes, stripping curve is measured by sampling.Reference substance is (following for commercially available product " safe Bi Quan "
Referred to as " commercially available product "), it the results are shown in Table 1 and attached drawing 1.
The stripping curve of the dabigatran etcxilate composition of 1 embodiment 1-4 of table measures
| Time (min) | 15 | 20 | 30 | 45 |
| Commercially available product | 71.3 | 89.5 | 94.4 | 97.4 |
| Embodiment 1 | 72.7 | 87.3 | 93.3 | 92.4 |
| Embodiment 2 | 74.7 | 81.6 | 91.5 | 93.7 |
| Embodiment 3 | 69.8 | 79.6 | 92.8 | 94.9 |
| Embodiment 4 | 62.5 | 72.5 | 92.2 | 97.3 |
Stability experiment
It is steady with reference to Chinese Pharmacopoeia version in 2015 using dabigatran etexilate methanesulfonate preparation made from 1-4 of the embodiment of the present invention
Qualitative test guideline carries out study on the stability, and self-control sample and listing sample are placed on 40 DEG C ± 2 DEG C of temperature, phase respectively
To carrying out accelerated test under 75% ± 5% environment of humidity, stability is measured by sampling 0 day, 1 month, 2 months, 3 months respectively.
It the results are shown in Table 2.
The study on the stability of the dabigatran etcxilate composition of 2 embodiment 1-4 of table
Claims (10)
1. a kind of combination of oral medication, it includes：
A) by the medicine-containing particle formed containing active material ingredients and adhesive, disintegrant, glidant, wherein active material ingredients
For dabigatran etcxilate or its pharmaceutically acceptable salt；
B) by the organic acid crystal of isolation, separation layer is for Capsules I or selected from including pharmaceutically acceptable cellulose
The isolated material of class auxiliary material；Layer is preferably isolated as Capsules I；
Medicine-containing particle is filled with after the organic acid crystal being isolated mixes in proportion into Capsules II.
2. combination of oral medication according to claim 1, the organic acid crystal is selected from tartaric acid, fumaric acid, lemon
Acid, succinic acid, malic acid, glutamic acid or aspartic acid crystal；It is preferred that winestone acid crystal.
3. combination of oral medication according to claim 1, the Capsules I is selected from gelatin or hypromellose
The Capsules of the Capsules of plain ingredient, preferably gelatin；The pharmaceutically acceptable cellulose family auxiliary material is selected from hydroxyl
Propyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethyl cellulose, hydroxyethyl cellulose, polyvinylpyrrolidone and vinegar
One of acid cellulose or its arbitrary combination；The Capsules II is selected from the Capsules or gelatin of hydroxypropyl methylcellulose ingredient
The Capsules of the Capsules of ingredient, preferably hydroxypropyl methylcellulose ingredient.
4. combination of oral medication according to claim 1, wherein：
Described adhesive is selected from hydroxypropyl cellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone and corn and forms sediment
One of powder or its arbitrary combination；It is preferred that hydroxypropyl cellulose；
The disintegrant is selected from low-substituted hydroxypropyl cellulose, croscarmellose sodium, calcium carboxymethylcellulose, the poly- dimension of crosslinking
One of ketone and partially pregelatinized starch or its arbitrary combination；It is preferred that low-substituted hydroxypropyl cellulose；
The glidant is selected from colloidal silicon dioxide or talcum powder, preferably colloidal silicon dioxide.
5. according to the combination of oral medication described in any one of claim 1-4, the active material ingredients are reached for methanesulfonic acid
Than adding group ester, content 20-60%；It is preferred that 40-55%.
6. according to the combination of oral medication described in any one of claim 1-4, organic acid crystal described in pharmaceutical composition
Content be 20-90%；It is preferred that 30-50%.
7. according to the combination of oral medication described in any one of claim 1-4, glidant described in pharmaceutical composition contains
It measures as 0.2-10%；It is preferred that 0.2-1.0%.
8. combination of oral medication according to claim 1, the medicine-containing particle is obtained for wet granulation or dry granulation,
The glidant is adds in after granulation；
When the medicine-containing particle is obtained for wet granulation, wherein also containing granulation wetting agent, the granulation wetting agent is isopropyl
Alcohol.
9. a kind of method for preparing any one of claim 1-8 combination of oral medication, includes the following steps：
A) active material ingredients, adhesive, disintegrant are pelletized by wet granulation or dry granulation, whole grain of being sieved after granulation,
Glidant is added in, medicine-containing particle is made；
When using wet granulation, isopropanol is added in pelletization as wetting agent；
B) organic acid crystal is filled into Capsules I and be isolated；Or
Isolated material is coated outside organic acid crystal as separation layer, the isolated material include it is one or more described in pharmaceutically
Acceptable cellulose family auxiliary material；
C) by the organic acid crystal after being isolated obtained by medicine-containing particle obtained by step a) and step b) by 1：9 to 4：1 proportional region
It is filled after mixing into Capsules II.
10. preparation method according to claim 9, which is characterized in that isolated material described in step b) is also comprising plasticising
Agent and antitackiness agent, the plasticizer are selected from triethyl citrate or polyethylene glycol, and the antitackiness agent is selected from talcum powder；Isolated material
Dosage for organic acid crystal weight 10-30%, preferably organic acid crystal weight 15-20%.
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Cited By (2)
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| CN113577067A (en) * | 2021-06-03 | 2021-11-02 | 北京福元医药股份有限公司 | Dabigatran etexilate mesylate pharmaceutical preparation |
| CN113768883A (en) * | 2021-08-25 | 2021-12-10 | 海南海神同洲制药有限公司 | Preparation method of high-stability clindamycin palmitate hydrochloride particles |
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| CN113768883A (en) * | 2021-08-25 | 2021-12-10 | 海南海神同洲制药有限公司 | Preparation method of high-stability clindamycin palmitate hydrochloride particles |
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