EP3551172A1 - Pharmaceutical compositions of dabigatran - Google Patents
Pharmaceutical compositions of dabigatranInfo
- Publication number
- EP3551172A1 EP3551172A1 EP17821820.2A EP17821820A EP3551172A1 EP 3551172 A1 EP3551172 A1 EP 3551172A1 EP 17821820 A EP17821820 A EP 17821820A EP 3551172 A1 EP3551172 A1 EP 3551172A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- sodium
- dabigatran etexilate
- pharmaceutical composition
- composition according
- free base
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 26
- 229960003850 dabigatran Drugs 0.000 title description 3
- YBSJFWOBGCMAKL-UHFFFAOYSA-N dabigatran Chemical group 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 description 3
- 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 claims abstract description 48
- 229960000288 dabigatran etexilate Drugs 0.000 claims abstract description 46
- 239000008185 minitablet Substances 0.000 claims abstract description 31
- 239000012458 free base Substances 0.000 claims abstract description 21
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 7
- 239000000203 mixture Substances 0.000 claims description 40
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 17
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 15
- 229920000881 Modified starch Polymers 0.000 claims description 15
- 238000009472 formulation Methods 0.000 claims description 15
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 15
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 15
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 15
- 239000000843 powder Substances 0.000 claims description 14
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 13
- 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 12
- 239000002775 capsule Substances 0.000 claims description 12
- 239000007884 disintegrant Substances 0.000 claims description 12
- 238000002156 mixing Methods 0.000 claims description 12
- 229920003109 sodium starch glycolate Polymers 0.000 claims description 12
- 239000008109 sodium starch glycolate Substances 0.000 claims description 12
- 229940079832 sodium starch glycolate Drugs 0.000 claims description 12
- 239000008101 lactose Substances 0.000 claims description 11
- 229960001375 lactose Drugs 0.000 claims description 11
- 238000007873 sieving Methods 0.000 claims description 10
- 235000019359 magnesium stearate Nutrition 0.000 claims description 9
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 8
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 7
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 7
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 6
- 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 5
- 239000000945 filler Substances 0.000 claims description 5
- 238000011049 filling Methods 0.000 claims description 5
- 239000000314 lubricant Substances 0.000 claims description 5
- -1 poloxomer Polymers 0.000 claims description 5
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 4
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 4
- 229920002472 Starch Polymers 0.000 claims description 4
- 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 4
- 235000010443 alginic acid Nutrition 0.000 claims description 4
- 229920000615 alginic acid Polymers 0.000 claims description 4
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 4
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 4
- 229940105329 carboxymethylcellulose Drugs 0.000 claims description 4
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 4
- 239000008107 starch Substances 0.000 claims description 4
- 229940032147 starch Drugs 0.000 claims description 4
- 235000019698 starch Nutrition 0.000 claims description 4
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.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 WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims description 3
- 239000004141 Sodium laurylsulphate Substances 0.000 claims description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 3
- 229960001021 lactose monohydrate Drugs 0.000 claims description 3
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 3
- 229910021653 sulphate ion Inorganic materials 0.000 claims description 3
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- 241000237858 Gastropoda Species 0.000 claims description 2
- 229920002907 Guar gum Polymers 0.000 claims description 2
- 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 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 239000000783 alginic acid Substances 0.000 claims description 2
- 229960001126 alginic acid Drugs 0.000 claims description 2
- 150000004781 alginic acids Chemical class 0.000 claims description 2
- 239000004411 aluminium Substances 0.000 claims description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 2
- 229910052782 aluminium Inorganic materials 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 235000001465 calcium Nutrition 0.000 claims description 2
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 2
- 229960000913 crospovidone Drugs 0.000 claims description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 2
- 235000019329 dioctyl sodium sulphosuccinate Nutrition 0.000 claims description 2
- RRPFCKLVOUENJB-UHFFFAOYSA-L disodium;2-aminoacetic acid;carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O.NCC(O)=O RRPFCKLVOUENJB-UHFFFAOYSA-L 0.000 claims description 2
- 229960000878 docusate sodium Drugs 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 238000000227 grinding Methods 0.000 claims description 2
- 239000000665 guar gum Substances 0.000 claims description 2
- 235000010417 guar gum Nutrition 0.000 claims description 2
- 229960002154 guar gum Drugs 0.000 claims description 2
- 239000003456 ion exchange resin Substances 0.000 claims description 2
- 229920003303 ion-exchange polymer Polymers 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 229960000502 poloxamer Drugs 0.000 claims description 2
- 229920001983 poloxamer Polymers 0.000 claims description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 229960003975 potassium Drugs 0.000 claims description 2
- 235000007686 potassium Nutrition 0.000 claims description 2
- 229940069328 povidone Drugs 0.000 claims description 2
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 claims description 2
- 238000009491 slugging Methods 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 235000010413 sodium alginate Nutrition 0.000 claims description 2
- 239000000661 sodium alginate Substances 0.000 claims description 2
- 229940005550 sodium alginate Drugs 0.000 claims description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 2
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims 3
- 239000002253 acid Substances 0.000 description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 239000005995 Aluminium silicate Substances 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 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
- 208000018522 Gastrointestinal disease Diseases 0.000 description 2
- 208000012671 Gastrointestinal haemorrhages Diseases 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 2
- 229920002774 Maltodextrin Polymers 0.000 description 2
- 239000005913 Maltodextrin Substances 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 108090000190 Thrombin Proteins 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 235000012211 aluminium silicate Nutrition 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000011162 core material Substances 0.000 description 2
- 239000008121 dextrose Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
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- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 2
- 229950003499 fibrin Drugs 0.000 description 2
- 208000030304 gastrointestinal bleeding Diseases 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 229940035034 maltodextrin Drugs 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
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- 229960004072 thrombin Drugs 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 230000001562 ulcerogenic effect Effects 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
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- BZSXEZOLBIJVQK-UHFFFAOYSA-N 2-methylsulfonylbenzoic acid Chemical compound CS(=O)(=O)C1=CC=CC=C1C(O)=O BZSXEZOLBIJVQK-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
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- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
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- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 1
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- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
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- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
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- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
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- 230000002378 acidificating effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- PZZYQPZGQPZBDN-UHFFFAOYSA-N aluminium silicate Chemical compound O=[Al]O[Si](=O)O[Al]=O PZZYQPZGQPZBDN-UHFFFAOYSA-N 0.000 description 1
- 229910000323 aluminium silicate Inorganic materials 0.000 description 1
- 230000001746 atrial effect Effects 0.000 description 1
- 230000003190 augmentative effect Effects 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- YKGMKSIHIVVYKY-UHFFFAOYSA-N dabrafenib mesylate Chemical compound CS(O)(=O)=O.S1C(C(C)(C)C)=NC(C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=CC=2)F)=C1C1=CC=NC(N)=N1 YKGMKSIHIVVYKY-UHFFFAOYSA-N 0.000 description 1
- 229940096516 dextrates Drugs 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 229940008099 dimethicone Drugs 0.000 description 1
- 239000004205 dimethyl polysiloxane Substances 0.000 description 1
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229940012444 factor xiii Drugs 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 239000005414 inactive ingredient Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- 229960000367 inositol Drugs 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000000832 lactitol Substances 0.000 description 1
- 235000010448 lactitol Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 description 1
- 229960003451 lactitol Drugs 0.000 description 1
- 229940037627 magnesium lauryl sulfate Drugs 0.000 description 1
- HBNDBUATLJAUQM-UHFFFAOYSA-L magnesium;dodecyl sulfate Chemical compound [Mg+2].CCCCCCCCCCCCOS([O-])(=O)=O.CCCCCCCCCCCCOS([O-])(=O)=O HBNDBUATLJAUQM-UHFFFAOYSA-L 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 230000014508 negative regulation of coagulation Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 229960000856 protein c Drugs 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 235000010215 titanium dioxide Nutrition 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 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
- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
-
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Definitions
- the present invention relates to a pharmaceutical composition in the form of encapsulated mini tablets comprising dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate and at least one pharmaceutically acceptable excipient.
- Dabigatran etexilate (Formula 1 ), which is already known from WO 98/37075, is a direct thrombin inhibitor indicated to reduce the risk of stroke and systemic embolism in patients with non-valcular atrial fibrilation.
- Thrombin is a multifunctional enzyme which converts fibrinogen to fibrin, cross-linking fibrin monomers via activation of factor XIII and augmenting further thrombin production via the activation of factors V and VIII. It also activates platelets, generates anticoagulant activity via activation of protein C and initiates numerous cellular processes.
- the methane sulphonic acid addition salt of dabigatran etexilate which is commercially available under the trade name PRADAXA® ® immediate release capsule (in the strength of 75, 1 10, 150mg), is disclosed in EP1870100, wherein also disclosed, pellet formulation of dabigatran etexilate methanesulphonate.
- This composition is formulated with a core material consisting of organic acid and an active layer which encloses the core.
- Each PRADAXA® capsule contains the following inactive ingredients: acacia, dimethicone, hypromellose, hydroxypropylcellulose, tartaric acid, carragenan, potassium chloride, talc, titanium dioxide, and gelatin.
- WO2012/077136 is directed to the oxalate salt of dabigatran etexilate and besides, its hydrochloride salt is identified in EP1877395. Also, it is known in the prior art that dabigatran etexilate is a weakly basic compound and therefore it has high solubility in acidic media.
- Dabigatran etexilate have been associated with gastrointestinal disorders such as ulcers and gastrointestinal bleeding.
- the administration of dabigatran etexilate may make some patients more susceptible to the ulcerogenic effects of ulcerogenic stimuli. It appears that a major factor contributing to the development of these gastrointestinal disorders is the presence of acid in the stomach and upper small intestine.
- the main object of the present invention is to provide a pharmaceutical composition in the form of encapsulated mini tablets comprising dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate and at least one pharmaceutically acceptable excipient with safe and effective dissolution profile, an easy process and reduced adverse effects.
- mini tablet refers to small tablets with a diameter equal to or less than 4 mm that are typically filled into a capsule or further compressed into larger tablets. Thickness of this mini tablets equal to or less than 3 mm.
- the mini tablets have round shape and smooth surface to ease coating process.
- Mini tablets have many advantages. Due to increased surface in relation to volume, the drug can be released more efficiently incase of mini-tablets. Some benefits of mini- tablets include excellent size uniformity, regular shape and a smooth surface. In mini tablets, smooth surface offers an excellent substrate for coating with polymeric systems. It can be concluded that pharmaceutical mini-tablets offer several advantages when compared to single unit dosage forms and are also good substitutes for granules and pellets. They have well defined size, shape, surface, low degree of porosity and high mechanical strength. Due to significant smaller dimensions of the mini tablets, when compared to normal tablets, they pass through the stomach at a more even rate. As a result, the concentration of the drug in the blood can be easily reproduced. It has been found that, dissolution and stability problems are overcome by using mini tablet form.
- dabigatran etexilate free base refers to dabigatran etexilate which is free from other forms of the active moiety, especially acid addition salts.
- dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate is present in an amount of between 10.00 and 60.00 %, preferably between 20.00 and 50.00 % and more preferably it is 30.00 to 40.00 % by weight of total formulation.
- dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran is present in an amount of between 30 to 350 mg, preferably 50 to 300 mg and more preferably it is 50 to 250 mg.
- at least one pharmaceutically acceptable excipient is disintegrant.
- the pharmaceutical composition comprises preferably at least two different disintegrants.
- the amount of total disintegrants is at least 40% by weight of total formulation.
- the amount of total disintegrants is between 40% and 60% by weight of total formulation. More preferably the amount of total disintegrants is between 40% and 50% by weight of total formulation.
- Suitable disintegants are selected from a group comprising starch, sodium starch glycolate, microcrystalline cellulose, crospovidone (cross-linked polyvinil pyrrolidone), povidone, poloxomer, cross-linked carboxymethyl cellulose (croscarmellose sodium), low-substituted hydroxypropyl cellulose, pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, low substituted hydroxypropyl cellulose, polyacryline potassium, sodium alginate, alginic acid, alginates, ion-exchange resins, magnesium aluminium silica, sodium dodesyl sulphate, poloxamer, sodium glycine carbonate, sodium lauryl sulphate or mixtures thereof.
- the disintegrants are selected from a group comprising microcrystalline cellulose, pregelatinized starch and sodium starch glycolate.
- microcrystalline cellulose is present in an amount of between 10.00% and 60.00%, preferably between 15.00% and 50.00%, more preferably between 25.00% and 40.00 by weight of total formulation
- pregelatinized starch is present in an amount of between 1 .00% and 30.00%, preferably between 5.00% and 20.00%, more preferably between 10.00% and 15.00% by weight of total formulation
- sodium starch glycolate is present in an amount of between 0.1 % and 8.00%, preferably between 0.25% and 4.00%, more preferably between 0.5% and 2.00% by weight of total formulation.
- the pharmaceutical composition further comprises lubricants, glidants, fillers or mixtures thereof.
- Suitable lubricants are selected from a group comprising sodium stearyl fumarate, magnesium stearate, calcium stearate, zinc stearate, talc, waxes, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, polyethylene glycol, stearic acid, fatty acid, fumaric acid, glyseryl palmito sulphate, sodium lauryl sulphate or mixtures thereof.
- the lubricant is selected from a group comprising magnesium stearate and sodium stearyl fumarate. According to this embodiment, the lubricant is present an amount of between 0.1 % and 10.00%, preferably 0.1 % and 5.00% and more preferably 0.1 % and 3.00% by weight of total formulation.
- Suitable glidants are selected from a group comprising colloidal silicon dioxide, talc, aluminium silicate or mixtures thereof.
- the glidant is colloidal silicon dioxide.
- the glidant is present an amount of between 0.1 % and 10.00%, 0.5% and 5.00% and more preferably 0.9% and 3.00% by weight of total formulation.
- Suitable fillers are selected from a group comprising mannitol, spray-dried mannitol, lactose, lactose monohydrate, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate, polyols, dextrose, maltitol or mixtures thereof.
- the filler is lactose.
- the filler is present an amount of between 5.00% and 50.00%, 10.00% and 40.00% and more preferably 15.00% and 30.00% by weight of total formulation.
- Suitable salts of dabigatran etexilate are selected from a group comprising mesylate, maleate, malonate, citrate, tosylate, esylate, tartrate, oxalate, camphor sulfonate.
- suitable salts of dabigatran etexilate are selected from maleate, malonate, citrate, tosylate, esylate, tartrate, oxalate, camphor sulfonate.
- the pharmaceutical composition in the form encapsulated mini tablets comprises:
- magnesium stearate 0.1 to 10.00 % magnesium stearate
- the pharmaceutical composition in the form encapsulated mini tablets comprises:
- Example 1 Capsule containing mini tablets
- Example 2 Capsule containing mini tablets
- compositions mentioned above are prepared by following these steps:
- Example 3 Capsule containing mini tablets
- compositions mentioned above are prepared by following these steps:
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- Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a pharmaceutical composition in the form of encapsulated mini tablets comprising dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate and at least one pharmaceutically acceptable excipient.
Description
PHARMACEUTICAL COMPOSITIONS OF DABIGATRAN
Technical Field
The present invention relates to a pharmaceutical composition in the form of encapsulated mini tablets comprising dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate and at least one pharmaceutically acceptable excipient.
Background of the Invention
Dabigatran etexilate (Formula 1 ), which is already known from WO 98/37075, is a direct thrombin inhibitor indicated to reduce the risk of stroke and systemic embolism in patients with non-valcular atrial fibrilation. Thrombin is a multifunctional enzyme which converts fibrinogen to fibrin, cross-linking fibrin monomers via activation of factor XIII and augmenting further thrombin production via the activation of factors V and VIII. It also activates platelets, generates anticoagulant activity via activation of protein C and initiates numerous cellular processes.
Formula 1 : Dabigatran etexilate
The methane sulphonic acid addition salt of dabigatran etexilate, which is commercially available under the trade name PRADAXA® ® immediate release capsule (in the strength of 75, 1 10, 150mg), is disclosed in EP1870100, wherein also disclosed, pellet formulation of dabigatran etexilate methanesulphonate. This composition is formulated with a core material consisting of organic acid and an active layer which encloses the
core. Each PRADAXA® capsule contains the following inactive ingredients: acacia, dimethicone, hypromellose, hydroxypropylcellulose, tartaric acid, carragenan, potassium chloride, talc, titanium dioxide, and gelatin. Apart from the methanesulfonate salt of dabigatran etexilate, other acid addition salts of the compound are provided in prior art. For exemple, WO2012/077136 is directed to the oxalate salt of dabigatran etexilate and besides, its hydrochloride salt is identified in EP1877395. Also, it is known in the prior art that dabigatran etexilate is a weakly basic compound and therefore it has high solubility in acidic media.
Dabigatran etexilate have been associated with gastrointestinal disorders such as ulcers and gastrointestinal bleeding. In addition, the administration of dabigatran etexilate, may make some patients more susceptible to the ulcerogenic effects of ulcerogenic stimuli. It appears that a major factor contributing to the development of these gastrointestinal disorders is the presence of acid in the stomach and upper small intestine.
But also, in prior art, most of formulations are formulated with an acid excipient. This acidity may partly explain increased risk of dyspeptic symptoms and gastrointestinal bleeding.
Thus, there is still a need in the art to develop stable and bioavailable pharmaceutical formulations comprising dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate by an easy process. By this need, the formulation has been developed to overcome the solubility and stability problems of dabigatran etexilate in a safe manner disclosed above.
Detailed description of the Invention
The main object of the present invention is to provide a pharmaceutical composition in the form of encapsulated mini tablets comprising dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate and at least one pharmaceutically acceptable excipient with safe and effective dissolution profile, an easy process and reduced adverse effects.
The term "mini tablet", as used herein, refers to small tablets with a diameter equal to or less than 4 mm that are typically filled into a capsule or further compressed into larger tablets. Thickness of this mini tablets equal to or less than 3 mm. The mini tablets have round shape and smooth surface to ease coating process.
Mini tablets have many advantages. Due to increased surface in relation to volume, the drug can be released more efficiently incase of mini-tablets. Some benefits of mini- tablets include excellent size uniformity, regular shape and a smooth surface. In mini tablets, smooth surface offers an excellent substrate for coating with polymeric systems. It can be concluded that pharmaceutical mini-tablets offer several advantages when compared to single unit dosage forms and are also good substitutes for granules and pellets. They have well defined size, shape, surface, low degree of porosity and high mechanical strength. Due to significant smaller dimensions of the mini tablets, when compared to normal tablets, they pass through the stomach at a more even rate. As a result, the concentration of the drug in the blood can be easily reproduced. It has been found that, dissolution and stability problems are overcome by using mini tablet form.
As used herein, the term "dabigatran etexilate free base" refers to dabigatran etexilate which is free from other forms of the active moiety, especially acid addition salts.
According to one embodiment, dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate is present in an amount of between 10.00 and 60.00 %, preferably between 20.00 and 50.00 % and more preferably it is 30.00 to 40.00 % by weight of total formulation.
According to another embodiment, dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran is present in an amount of between 30 to 350 mg, preferably 50 to 300 mg and more preferably it is 50 to 250 mg. According to another embodiment of this present invention, wherein at least one pharmaceutically acceptable excipient is disintegrant. During the development study of the present invention, it has been observed that, dissolution and stability problems are overcome by using particularly at least two different disintegrants in a specific amount. According to one embodiment, the pharmaceutical composition comprises preferably at least two different disintegrants.
According to another embodiment, the amount of total disintegrants is at least 40% by weight of total formulation. Preferably the amount of total disintegrants is between 40% and 60% by weight of total formulation. More preferably the amount of total disintegrants is between 40% and 50% by weight of total formulation.
Suitable disintegants are selected from a group comprising starch, sodium starch glycolate, microcrystalline cellulose, crospovidone (cross-linked polyvinil pyrrolidone), povidone, poloxomer, cross-linked carboxymethyl cellulose (croscarmellose sodium), low-substituted hydroxypropyl cellulose, pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, low substituted hydroxypropyl cellulose, polyacryline potassium, sodium alginate, alginic acid, alginates, ion-exchange resins, magnesium aluminium silica, sodium dodesyl sulphate, poloxamer, sodium glycine carbonate, sodium lauryl sulphate or mixtures thereof.
In a preferred embodiment, the disintegrants are selected from a group comprising microcrystalline cellulose, pregelatinized starch and sodium starch glycolate. According to this embodiment, microcrystalline cellulose is present in an amount of between 10.00% and 60.00%, preferably between 15.00% and 50.00%, more preferably between 25.00% and 40.00 by weight of total formulation, pregelatinized starch is present in an amount of between 1 .00% and 30.00%, preferably between 5.00% and 20.00%, more preferably between 10.00% and 15.00% by weight of total formulation, sodium starch glycolate is present in an amount of between 0.1 % and 8.00%, preferably between 0.25% and 4.00%, more preferably between 0.5% and 2.00% by weight of total formulation.
According to another embodiment of the present invention, the pharmaceutical composition further comprises lubricants, glidants, fillers or mixtures thereof.
Suitable lubricants are selected from a group comprising sodium stearyl fumarate, magnesium stearate, calcium stearate, zinc stearate, talc, waxes, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, polyethylene glycol, stearic acid, fatty acid, fumaric acid, glyseryl palmito sulphate, sodium lauryl sulphate or mixtures thereof.
In a preferred embodiment, the lubricant is selected from a group comprising magnesium stearate and sodium stearyl fumarate. According to this embodiment, the lubricant is present an amount of between 0.1 % and 10.00%, preferably 0.1 % and 5.00% and more preferably 0.1 % and 3.00% by weight of total formulation.
Suitable glidants are selected from a group comprising colloidal silicon dioxide, talc, aluminium silicate or mixtures thereof.
In a preferred embodiment, the glidant is colloidal silicon dioxide.
According to this embodiment, the glidant is present an amount of between 0.1 % and 10.00%, 0.5% and 5.00% and more preferably 0.9% and 3.00% by weight of total formulation.
Suitable fillers are selected from a group comprising mannitol, spray-dried mannitol, lactose, lactose monohydrate, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate, polyols, dextrose, maltitol or mixtures thereof. In a preferred embodiment, the filler is lactose.
According to this embodiment, the filler is present an amount of between 5.00% and 50.00%, 10.00% and 40.00% and more preferably 15.00% and 30.00% by weight of total formulation.
Suitable salts of dabigatran etexilate are selected from a group comprising mesylate, maleate, malonate, citrate, tosylate, esylate, tartrate, oxalate, camphor sulfonate.
Preferably suitable salts of dabigatran etexilate are selected from maleate, malonate, citrate, tosylate, esylate, tartrate, oxalate, camphor sulfonate.
In one embodiment, the pharmaceutical composition in the form encapsulated mini tablets comprises:
10.00 to 60.00 % dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate
10.00 to 60.00 % microcrystalline cellulose
5.00 to 50.00 % lactose
0.1 to 10.00 % colloidal silicon dioxide
1 .0 to 30.00 % pregelatinized starch
0.1 to 8.00 % sodium starch glycolate
0.1 to 10.00 % magnesium stearate
In one embodiment, the pharmaceutical composition in the form encapsulated mini tablets comprises:
10.00 to 60.00 % dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate
10.00 to 60.00 % microcrystalline cellulose
5.00 to 50.00 % lactose
0.1 to 10.00 % colloidal silicon dioxide
1 .0 to 30.00 % pregelatinized starch
0.1 to 10.00 % sodium stearyl fumarate
Example 1 : Capsule containing mini tablets
Ingredients (%) amount (w/w)
Dabigatran etexilate free base 10-60
Microcrystalline celluose 10-60
Lactose 5-50
Colloidal silicon dioxide 0.1 -10
Starch, pregelatinize 1 -30
Sodium starch glycolate 0.1 -8
Magnesium stearate 0.1 -10
Total 100
The pharmaceutical compositions mentioned above are prepared by following these steps:
• Sieving and mixing dabigatran etexilate free base, sodium starch glycolate, microcrystalline cellulose, colloidal silicon dioxide, pregelatinized starch and lactose monohydrate
• Adding magnesium stearate to the powder mixture and mixing for 1 -2 more minutes
• Compressing the powder mixture into mini tablets
· Filling the mini tablets into HPMC capsules.
Example 2: Capsule containing mini tablets
The pharmaceutical compositions mentioned above are prepared by following these steps:
• Sieving and mixing dabigatran etexilate free base, microcrystalline cellulose, lactose, colloidal silicon dioxide, pregelatinized starch, sodium starch glycolate.
• Granulating the powder mixture with water and drying in an oven at 50°C.
• Adding magnesium stearate and mixing 1 -2 more minutes.
• Compressing the powder mixture into mini tablets
• Filling the mini tablets into HPMC capsules.
Example 3: Capsule containing mini tablets
The pharmaceutical compositions mentioned above are prepared by following these steps:
• Sieving and mixing dabigatran etexilate free base, microcrystalline cellulose, lactose, colloidal silicon dioxide, pregelatinized starch, and half of sodium stearyl fumarate.
• Passing the powder mixture through the compactor or slugging
• Sieving the powder which passed through the compactor or grinding the slugs and sieving
• Adding the other half of sodium stearyl fumarate to the mixture and mixing for 1 - 2 more minutes
• Compressing the powder mixture into mini tablets
• Filling the mini tablets into HPMC capsules.
Claims
A pharmaceutical composition in the form of encapsulated mini tablets comprising dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate and at least one pharmaceutically acceptable excipient.
The pharmaceutical composition according to claim 1 , wherein the composition comprising dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate in an amount of 10.00% to 60.00% by weight of total formulation.
The pharmaceutical composition according to claim 1 , wherein the amount of dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate is between 30 to 350 mg.
The pharmaceutical composition according to claim 1 , wherein at least one pharmaceutically acceptable excipient is disintegrant.
The pharmaceutical composition according to claim 4, wherein the composition comprising preferably at least two different disintegrants.
The pharmaceutical composition according to claim 5, wherein the amount of total disintegrants is at least 40% by weight of total formulation.
The pharmaceutical composition according to claim 4, wherein the disintegrants are selected from a group comprising starch, sodium starch glycolate, microcrystalline cellulose, crospovidone (cross-linked polyvinil pyrrolidone), povidone, poloxomer, cross-linked carboxymethyl cellulose (croscarmellose sodium), low-substituted hydroxypropyl cellulose, pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, low substituted hydroxypropyl cellulose, polyacryline potassium, sodium alginate, alginic acid, alginates, ion-exchange resins, magnesium aluminium silica, sodium dodesyl sulphate, poloxamer, sodium glycine carbonate, sodium lauryl sulphate or mixtures thereof, preferably the disintegrants are microcrystalline cellulose, sodium starch glycolate and pregelatinized starch.
8. The pharmaceutical composition according to claim 1 , further comprising lubricants, glidants, fillers or mixtures thereof.
9. The pharmaceutical composition according to any of the preceding claims, comprising:
10.00 to 60.00 % dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate
10.00 to 60.00 % microcrystalline cellulose
5.00 to 50.00 % lactose
0.1 to 10.00 % colloidal silicon dioxide
1 .0 to 30.00 % pregelatinized starch
0.1 to 8.00 % sodium starch glycolate
0.1 to 10.00 % magnesium stearate 10. The pharmaceutical composition according to any of the preceding claims, comprising:
10.00 to 60.00 % dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate
10.00 to 60.00 % microcrystalline cellulose
5.00 to 50.00 % lactose
0.1 to 10.00 % colloidal silicon dioxide
1 .0 to 30.00 % pregelatinized starch
0.1 to 10.00 % sodium stearyl fumarate
1 1 . The process for preparation of the pharmaceutical composition according to claim 9, wherein the process comprising the following steps:
a. Sieving and mixing dabigatran etexilate free base, sodium starch glycolate, microcrystalline cellulose, colloidal silicon dioxide, pregelatinized starch and lactose monohydrate
b. Adding magnesium stearate to the powder mixture and mixing for 1 -2 more minutes
c. Compressing the powder mixture into mini tablets
d. Filing the mini tablets into HPMC capsules.
12. The process for preparation of the pharmaceutical composition according to claim 9, wherein the process comprising the following steps:
Sieving and mixing dabigatran etexilate free base, microcrystalline cellulose, lactose, colloidal silicon dioxide, pregelatinized starch, sodium starch glycolate.
Granulating the powder mixture with water and drying in an oven at 50°C. Adding magnesium stearate and mixing 1 -2 more minutes.
Compressing the powder mixture into mini tablets
Filling the mini tablets into HPMC capsules.
13. The process for preparation of the pharmaceutical composition according to claim 10, wherein the process comprising the following steps: a. Sieving and mixing dabigatran etexilate free base, microcrystalline cellulose, lactose, colloidal silicon dioxide, pregelatinized starch, and half of sodium stearyl fumarate.
b. Passing the powder mixture through the compactor or slugging c. Sieving the powder which passed through the compactor or grinding the slugs and sieving
d. Adding the other half of sodium stearyl fumarate to the mixture and mixing for 1 -2 more minutes
e. Compressing the powder mixture into mini tablets
f. Filling the mini tablets into HPMC capsules.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2016/17984A TR201617984A2 (en) | 2016-12-07 | 2016-12-07 | PHARMACEUTICAL COMPOSITIONS OF DABIGATRAN |
| PCT/EP2017/081639 WO2018104370A1 (en) | 2016-12-07 | 2017-12-06 | Pharmaceutical compositions of dabigatran |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP3551172A1 true EP3551172A1 (en) | 2019-10-16 |
Family
ID=60582497
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP17821820.2A Withdrawn EP3551172A1 (en) | 2016-12-07 | 2017-12-06 | Pharmaceutical compositions of dabigatran |
| EP17205599.8A Withdrawn EP3332770A1 (en) | 2016-12-07 | 2017-12-06 | Pharmaceutical compositions of dabigatran |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP17205599.8A Withdrawn EP3332770A1 (en) | 2016-12-07 | 2017-12-06 | Pharmaceutical compositions of dabigatran |
Country Status (4)
| Country | Link |
|---|---|
| EP (2) | EP3551172A1 (en) |
| EA (1) | EA201991288A1 (en) |
| TR (2) | TR201617984A2 (en) |
| WO (1) | WO2018104370A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113933400B (en) * | 2020-06-29 | 2024-01-12 | 石药集团恩必普药业有限公司 | Detection method of genotoxic impurities in dabigatran etexilate bulk drug or preparation |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130052262A1 (en) * | 2010-03-01 | 2013-02-28 | Sandra Brueck | Dabigatran etexilate-containing oral pharmaceutical composition |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PE121699A1 (en) | 1997-02-18 | 1999-12-08 | Boehringer Ingelheim Pharma | BICYCLE HETERO CYCLES DISSTITUTED AS INHIBITORS OF THROMBIN |
| CA2476054C (en) | 2002-03-07 | 2011-11-08 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Pharmaceutical composition for the oral administration of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino)-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino)-propionic acid ethyl ester and the salts thereof |
| DE102005020002A1 (en) | 2005-04-27 | 2006-11-02 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Physiologically acceptable salts of 3 - [(2 - {[4- (hexyloxycarbonylamino-imino-methyl) -phenyl-amino] -methyl} -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino] - propionate |
| US9006448B2 (en) | 2010-12-06 | 2015-04-14 | Msn Laboratories Private Limited | Process for the preparation of benzimidazole derivatives and its salts |
| IN2013CH05441A (en) * | 2013-11-26 | 2015-05-29 | Aurobindo Pharma Ltd | |
| IN2014MU01042A (en) * | 2014-03-26 | 2015-10-02 | Cadila Healthcare Ltd |
-
2016
- 2016-12-07 TR TR2016/17984A patent/TR201617984A2/en unknown
- 2016-12-28 TR TR2016/19828A patent/TR201619828A2/en unknown
-
2017
- 2017-12-06 EP EP17821820.2A patent/EP3551172A1/en not_active Withdrawn
- 2017-12-06 WO PCT/EP2017/081639 patent/WO2018104370A1/en not_active Ceased
- 2017-12-06 EA EA201991288A patent/EA201991288A1/en unknown
- 2017-12-06 EP EP17205599.8A patent/EP3332770A1/en not_active Withdrawn
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130052262A1 (en) * | 2010-03-01 | 2013-02-28 | Sandra Brueck | Dabigatran etexilate-containing oral pharmaceutical composition |
Also Published As
| Publication number | Publication date |
|---|---|
| EP3332770A1 (en) | 2018-06-13 |
| TR201617984A2 (en) | 2018-06-21 |
| TR201619828A2 (en) | 2018-06-21 |
| EA201991288A1 (en) | 2019-10-31 |
| WO2018104370A1 (en) | 2018-06-14 |
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