EP4054566A1 - Kapsel mit eltrombopag olamin - Google Patents
Kapsel mit eltrombopag olaminInfo
- Publication number
- EP4054566A1 EP4054566A1 EP20884244.3A EP20884244A EP4054566A1 EP 4054566 A1 EP4054566 A1 EP 4054566A1 EP 20884244 A EP20884244 A EP 20884244A EP 4054566 A1 EP4054566 A1 EP 4054566A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- weight
- sodium
- composition according
- pharmaceutical capsule
- capsule composition
- 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.)
- Pending
Links
- DJMJHIKGMVJYCW-UHFFFAOYSA-N 2-aminoethanol 3-[3-[[2-(3,4-dimethylphenyl)-5-methyl-3-oxo-1H-pyrazol-4-yl]diazenyl]-2-hydroxyphenyl]benzoic acid Chemical compound CC1=C(C=C(C=C1)N2C(=O)C(=C(N2)C)N=NC3=CC=CC(=C3O)C4=CC(=CC=C4)C(=O)O)C.C(CO)N.C(CO)N DJMJHIKGMVJYCW-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 229960001827 eltrombopag olamine Drugs 0.000 title claims abstract description 27
- 239000002775 capsule Substances 0.000 title description 6
- 239000007963 capsule composition Substances 0.000 claims abstract description 24
- 239000011230 binding agent Substances 0.000 claims abstract description 8
- 239000000203 mixture Substances 0.000 claims description 43
- 239000002202 Polyethylene glycol Substances 0.000 claims description 20
- 229920001223 polyethylene glycol Polymers 0.000 claims description 20
- 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 claims description 9
- 229930195725 Mannitol Natural products 0.000 claims description 9
- 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 9
- 239000000594 mannitol Substances 0.000 claims description 9
- 235000010355 mannitol Nutrition 0.000 claims description 9
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 8
- 239000003085 diluting agent Substances 0.000 claims description 8
- 239000007884 disintegrant Substances 0.000 claims description 8
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 7
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 7
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 7
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 7
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 7
- 229920002472 Starch Polymers 0.000 claims description 6
- 235000010443 alginic acid Nutrition 0.000 claims description 6
- 229920000615 alginic acid Polymers 0.000 claims description 6
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 6
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 6
- -1 glidants Substances 0.000 claims description 6
- 239000000314 lubricant Substances 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 239000008107 starch Substances 0.000 claims description 6
- 229940032147 starch Drugs 0.000 claims description 6
- 235000019698 starch Nutrition 0.000 claims description 6
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 5
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 5
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 5
- 239000008109 sodium starch glycolate Substances 0.000 claims description 5
- 229920003109 sodium starch glycolate Polymers 0.000 claims description 5
- 229940079832 sodium starch glycolate Drugs 0.000 claims description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 4
- 239000005913 Maltodextrin Substances 0.000 claims description 4
- 229920002774 Maltodextrin 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
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 235000021355 Stearic acid Nutrition 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
- 229940096516 dextrates Drugs 0.000 claims description 4
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 4
- 229940035034 maltodextrin Drugs 0.000 claims description 4
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 4
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 4
- 229960000502 poloxamer Drugs 0.000 claims description 4
- 229920001983 poloxamer Polymers 0.000 claims description 4
- 229940069328 povidone Drugs 0.000 claims description 4
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 4
- 239000008117 stearic acid Substances 0.000 claims description 4
- 238000005550 wet granulation Methods 0.000 claims description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 3
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 claims description 2
- 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
- 229920001817 Agar Polymers 0.000 claims description 2
- 239000005995 Aluminium silicate Substances 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- 229920000623 Cellulose acetate phthalate Polymers 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- 235000019739 Dicalciumphosphate Nutrition 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
- 229920002907 Guar gum Polymers 0.000 claims description 2
- 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 claims description 2
- 229920000715 Mucilage Polymers 0.000 claims description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 2
- 229920000148 Polycarbophil calcium Polymers 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 239000004373 Pullulan Substances 0.000 claims description 2
- 229920001218 Pullulan Polymers 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 2
- 229920002125 Sokalan® Polymers 0.000 claims description 2
- 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 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 2
- 239000000853 adhesive Substances 0.000 claims description 2
- 239000008272 agar Substances 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
- 235000012211 aluminium silicate Nutrition 0.000 claims description 2
- PZZYQPZGQPZBDN-UHFFFAOYSA-N aluminium silicate Chemical compound O=[Al]O[Si](=O)O[Al]=O PZZYQPZGQPZBDN-UHFFFAOYSA-N 0.000 claims description 2
- 229910000323 aluminium silicate Inorganic materials 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
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- 239000001506 calcium phosphate Substances 0.000 claims description 2
- 159000000007 calcium salts Chemical class 0.000 claims description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 2
- 235000013539 calcium stearate Nutrition 0.000 claims description 2
- 239000008116 calcium stearate Substances 0.000 claims description 2
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 claims description 2
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 claims description 2
- 239000004359 castor oil Substances 0.000 claims description 2
- 235000019438 castor oil Nutrition 0.000 claims description 2
- 229940081734 cellulose acetate phthalate Drugs 0.000 claims description 2
- 229940082500 cetostearyl alcohol Drugs 0.000 claims description 2
- 239000008119 colloidal silica Substances 0.000 claims description 2
- 229920001531 copovidone Polymers 0.000 claims description 2
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 claims description 2
- 229940038472 dicalcium phosphate Drugs 0.000 claims description 2
- 229910000390 dicalcium phosphate Inorganic materials 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
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 2
- 229920001249 ethyl cellulose Polymers 0.000 claims description 2
- 229960004667 ethyl cellulose Drugs 0.000 claims description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 2
- 229940049654 glyceryl behenate Drugs 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
- 239000008172 hydrogenated vegetable oil Substances 0.000 claims description 2
- 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 claims description 2
- 229960000367 inositol 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
- 239000000832 lactitol Substances 0.000 claims description 2
- 235000010448 lactitol Nutrition 0.000 claims description 2
- 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 claims description 2
- 229960003451 lactitol Drugs 0.000 claims description 2
- 229940059904 light mineral oil Drugs 0.000 claims description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 2
- 239000000395 magnesium oxide Substances 0.000 claims description 2
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 claims description 2
- 235000012245 magnesium oxide Nutrition 0.000 claims description 2
- 239000000391 magnesium silicate Substances 0.000 claims description 2
- 229910052919 magnesium silicate Inorganic materials 0.000 claims description 2
- 235000019792 magnesium silicate Nutrition 0.000 claims description 2
- 235000019359 magnesium stearate Nutrition 0.000 claims description 2
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 claims description 2
- 229960001855 mannitol Drugs 0.000 claims description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 2
- 229920000609 methyl cellulose Polymers 0.000 claims description 2
- 239000001923 methylcellulose Substances 0.000 claims description 2
- 229960002900 methylcellulose Drugs 0.000 claims description 2
- 239000002480 mineral oil Substances 0.000 claims description 2
- 235000010446 mineral oil Nutrition 0.000 claims description 2
- 229920001206 natural gum Polymers 0.000 claims description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 claims description 2
- 229950005134 polycarbophil Drugs 0.000 claims description 2
- 229920000193 polymethacrylate Polymers 0.000 claims description 2
- 229920001282 polysaccharide Polymers 0.000 claims description 2
- 239000005017 polysaccharide Substances 0.000 claims description 2
- 150000004804 polysaccharides Chemical class 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
- 235000019423 pullulan Nutrition 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 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
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 2
- 239000004299 sodium benzoate Substances 0.000 claims description 2
- 235000010234 sodium benzoate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 229960002668 sodium chloride Drugs 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
- 239000000600 sorbitol Substances 0.000 claims description 2
- 229960002920 sorbitol Drugs 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 229960004793 sucrose Drugs 0.000 claims description 2
- 239000000454 talc Substances 0.000 claims description 2
- 229910052623 talc Inorganic materials 0.000 claims description 2
- 235000012222 talc Nutrition 0.000 claims description 2
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 claims description 2
- 239000000811 xylitol Substances 0.000 claims description 2
- 235000010447 xylitol Nutrition 0.000 claims description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 2
- 229960002675 xylitol Drugs 0.000 claims description 2
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 claims description 2
- ZADYMNAVLSWLEQ-UHFFFAOYSA-N magnesium;oxygen(2-);silicon(4+) Chemical compound [O-2].[O-2].[O-2].[Mg+2].[Si+4] ZADYMNAVLSWLEQ-UHFFFAOYSA-N 0.000 claims 1
- 206010043554 thrombocytopenia Diseases 0.000 abstract description 4
- 238000004090 dissolution Methods 0.000 description 13
- 206010021245 Idiopathic thrombocytopenic purpura Diseases 0.000 description 7
- 208000031981 Thrombocytopenic Idiopathic Purpura Diseases 0.000 description 7
- 102000036693 Thrombopoietin Human genes 0.000 description 7
- 108010041111 Thrombopoietin Proteins 0.000 description 7
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 5
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 102000005763 Thrombopoietin Receptors Human genes 0.000 description 3
- 108010070774 Thrombopoietin Receptors Proteins 0.000 description 3
- 229940127323 Thrombopoietin Receptor Agonists Drugs 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229960001069 eltrombopag Drugs 0.000 description 2
- XDXWLKQMMKQXPV-QYQHSDTDSA-N eltrombopag Chemical compound CC1=NN(C=2C=C(C)C(C)=CC=2)C(=O)\C1=N/NC(C=1O)=CC=CC=1C1=CC=CC(C(O)=O)=C1 XDXWLKQMMKQXPV-QYQHSDTDSA-N 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 210000003593 megakaryocyte Anatomy 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000003582 thrombocytopenic effect Effects 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- 208000032467 Aplastic anaemia Diseases 0.000 description 1
- 208000006154 Chronic hepatitis C Diseases 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 101150116986 THPO gene Proteins 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 238000005189 flocculation Methods 0.000 description 1
- 230000016615 flocculation Effects 0.000 description 1
- 208000010710 hepatitis C virus infection Diseases 0.000 description 1
- 238000009474 hot melt extrusion Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- HCWCAKKEBCNQJP-UHFFFAOYSA-N magnesium orthosilicate Chemical compound [Mg+2].[Mg+2].[O-][Si]([O-])([O-])[O-] HCWCAKKEBCNQJP-UHFFFAOYSA-N 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 229950004864 olamine Drugs 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 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
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
Definitions
- the present invention relates to a pharmaceutical capsule composition
- a pharmaceutical capsule composition comprising eltrombopag olamine and at least one binder for use in the treatment of thrombocytopenia.
- THPO Thrombopoietin
- MGDF megakaryocyte growth and development factor
- thrombopoietin receptor agonists mimic the action of thrombopoietin on its receptor and stimulate the activation, proliferation and maturation of megakaryocytes, resulting in an increase in circulating platelet counts.
- Thrombopoietin itself acts in this manner, but when recombinant thrombopoietins were used clinically, they were found to cause rebound thrombocytopenia, probably due to induction of anti-thrombopoietin antibodies. For this reason, direct administration of thrombopoietin was abandoned as an approach to treating thrombocytopenia and other approaches for activating the thrombopoietin receptor were sought.
- thrombopoietin receptor agonists Two thrombopoietin receptor agonists were subsequently developed and are now in clinical use for chronic idiopathic thrombocytopenic purpura (ITP) and for other thrombocytopenic conditions.
- Eltrombopag olamine is a peptide-like, small molecular weight agonist of the thrombopoietin receptor. This agent is given by mouth and result in significant increases in platelet counts in normal persons as well as patients with idiopathic thrombocytopenic purpura (ITP).
- ITP idiopathic thrombocytopenic purpura
- Eltrombopag olamine is a small molecular weight peptide-like molecule that binds to the transmembrane domain of the thrombopoietin receptor and causes its activation and the proliferation and differentiation of megakaryocytes, with a resultant increase in synthesis and release of platelets.
- eltrombopag olamine was shown to raise the platelet count in patients with idiopathic thrombocytopenic purpura (ITP), aplastic anemia and cirrhosis due to chronic hepatitis C during interferon therapy.
- ITP idiopathic thrombocytopenic purpura
- Eltrombopag olamine was approved for use in the United States in 2008 for the treatment of ITP and its indications have subsequently been expanded to other thrombocytopenic conditions.
- Formula I Eltrombopag Olamine
- EP1889838B1 is the molecule patent of eltrombopag olamine.
- Another application EP3041511A2 discloses pharmaceutical compounds of eltrombopag olamine in the form of tablets and the methods for their preparation.
- Eltrombopag olamine presents the formulator with unique concerns when attempting to formulate this compound into a suitable solid oral pharmaceutical dosage form, suitably a tablet, suitably a capsule, with a desirable pharmacokinetic profile.
- a suitable solid oral pharmaceutical dosage form suitably a tablet, suitably a capsule, with a desirable pharmacokinetic profile.
- Some of the concerns is that slow dissolution of the compound from solid dosage forms, the tendency of the compound to form insoluble metal complexes when contacted with excipients that contain a coordinating metal, and the tendency of the compound to under go a Maillard reaction when contacted with excipients that contain reducing sugars.
- a capsule composition comprising eltrombopag olamine and polyethylene glycol is used to overcome the disadvantages and side effects of the active agent meanwhile increasing the dissolution rate and stability in the desired manner.
- a further object of the present invention is to provide a solid oral form which eliminates the negative properties of the tablet form of eltrombopag olamine formulation in the prior art.
- Eltrompobag olamine in the capsule form instead of the tablet form as used in the prior art enhances the bioavailability by providing rapidly dissolving capsule walls and low flocculation during preparation.
- the use of capsules for eltrombopag olamine, a sensitive agent is also better in terms of stability than tablets.
- the pharmaceutical capsule composition comprises eltrombopag olamine and polyethylene glycol wherein the amount of eltrombopag olamine is between 23.0% and 40.0% by the weight of the total composition. According to one embodiment of the present invention, the amount of eltrombopag olamine is between 23.0% and 30.0% by the weight of the total composition.
- eltrombopag olamine is very sensitive to polyethylene glycol.
- polyethylene glycol ensures desired dissolution profile. Even with a small amount of polyethylene glycol, the desired dissolution is still achieved.
- the amount of polyethylene glycol is between 0.05% and 10.0%, 0.5% and 5.0% by the weight of the total composition.
- the composition further comprises pharmaceutical acceptable excipients which are selected from binders, diluents, disintegrants, glidants, lubricants or mixtures thereof.
- Suitable binders are selected from the group comprising polyvinylpyrrolidone (povidone), natural gums, agar, alginates, carbomers, carboxymethylcellulose sodium, cellulose acetate phthalate, copovidone, starch, starch mucilage, dextrates, ethylcellulose, glyceryl behenate, guar gum, methylcellulose, poloxamer, polycarbophil, polyethylene oxide, polymethacrylates, stearic acid, cetostearyl alcohol, polyoxyethilene-alkyl ethers, pullulan or mixtures thereof.
- polyvinylpyrrolidone povidone
- natural gums agar, alginates, carbomers, carboxymethylcellulose sodium, cellulose acetate phthalate, copovidone, starch, starch mucilage, dextrates, ethylcellulose, glyceryl behenate, guar gum, methylcellulose, poloxamer,
- the binder is polyvinylpyrrolidone.
- the amount of binder is between 0.5% and 10.0%, 0.5% and 7.0%, 0.5% and 5.0% by weight of the total composition.
- Suitable diluents are selected from the group comprising microcrystalline cellulose, mannitol, spray-dried mannitol, sucrose, sorbitol, xylitol, inositol, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, sodium carbonate, sodium bicarbonate, calcium carbonate or mixtures thereof.
- the diluent is microcrystalline cellulose or mannitol or mixtures thereof. This selection in the present invention provides surprisingly better stability since it does not create a Maillard reaction.
- the amount of diluents is between 20.0% and 85.0%, 30.0% and 75.0%, 40.0% and 60.0% by weight of the total composition.
- Suitable disintegrants are selected from the group comprising sodium starch glycolate, croscarmellose sodium, alginic acid, alginates, ion-exchange resins, sodium carboxymethyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, docusate sodium, low substituted hydroxypropyl cellulose, polyacryline potassium, poloxamer, sodium alginate, sodium glycine carbonate, sodium dodecyl sulfate or mixtures thereof.
- the disintegrant is sodium starch glycolate or croscarmellose sodium or mixtures thereof.
- the amount of disintegrants is between 5.0% and 20.0%, 8.0% and 18.0%, 10.0% and 16.0% by weight of the total composition.
- Suitable glidants are selected from the group comprising colloidal silicon dioxide, talc, aluminium silicate, colloidal silica, magnesium silicate, magnesium oxide, starch or mixtures thereof.
- the glidant is colloidal silicon dioxide.
- the amount of glidants is between 0.05% and 5.0%, 0.1% and 3.0% by weight of the total composition.
- Suitable lubricants are selected from group comprising sodium stearyl fumarate, magnesium stearate, stearic acid, calcium stearate, zinc stearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, mineral oil, sodium benzoate or mixtures thereof.
- the lubricant is sodium stearyl fumarate.
- the amount of lubricants is between 0.05% and 5.0%, 0.1% and 3.0% by weight of the total composition.
- process of preparing the composition is wet granulation, dry granulation, hot melt extrusion, direct compression, spray drying or mixtures thereof. Preferably it is wet granulation.
- the composition comprises;
- the composition comprises;
- microcrystalline cellulose 10.0% - 50.0% by weight of microcrystalline cellulose
- colloidal silicon dioxide 0.05% - 5.0% by weight
- the composition comprises;
- microcrystalline cellulose 10.0% - 50.0% by weight of microcrystalline cellulose
- colloidal silicon dioxide 0.05% - 5.0% by weight
- Example 1 A capsule composition is free of polyethylene glycol
- Example 2 A capsule composition comprising polyethylene glycol
- Example 3 A capsule composition is free of polyethylene glycol
- Example 4 A capsule composition comprising polyethylene glycol
- Example 5 A capsule composition comprising polyethylene glycol
- the comparison between the tests results of said five pharmaceutical formulations are carried out in same conditions given above.
- the dissolution data of Example 2, Example 4 and Example 5 which comprises polyethylene glycol proposes the desired dissolution profile with the highest value.
- the dissolution data of Example 1 and 3 are significantly lower than the dissolution data of the Example 2, Example 4 and Example 5.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2019/17244A TR201917244A1 (tr) | 2019-11-07 | 2019-11-07 | Eltrombopag olami̇n i̇çeren kapsül |
| PCT/TR2020/050997 WO2021091510A1 (en) | 2019-11-07 | 2020-10-27 | A capsule comprising eltrombopag olamine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP4054566A1 true EP4054566A1 (de) | 2022-09-14 |
| EP4054566A4 EP4054566A4 (de) | 2023-12-06 |
Family
ID=75848795
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP20884244.3A Pending EP4054566A4 (de) | 2019-11-07 | 2020-10-27 | Kapsel mit eltrombopag olamin |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP4054566A4 (de) |
| TR (1) | TR201917244A1 (de) |
| WO (1) | WO2021091510A1 (de) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114099435A (zh) * | 2021-12-16 | 2022-03-01 | 南京威凯尔生物医药科技有限公司 | 一种艾曲泊帕乙醇胺纳米胶束及其制备方法 |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ECSP077628A (es) | 2007-05-03 | 2008-12-30 | Smithkline Beechman Corp | Nueva composición farmacéutica |
| AU2014202367C1 (en) * | 2007-05-03 | 2024-11-21 | Novartis Ag | Novel pharmaceutical composition |
| CN107693515B (zh) * | 2016-08-08 | 2022-04-29 | 广东东阳光药业有限公司 | 含碱化剂和艾曲泊帕的药物组合物及其用途 |
| CN106361719A (zh) * | 2016-08-25 | 2017-02-01 | 浙江万晟药业有限公司 | 一种艾曲泊帕液体胶囊及其制备方法 |
| WO2018078644A1 (en) * | 2016-10-24 | 2018-05-03 | Hetero Labs Limited | Orally disintegrating tablets of eltrombopag |
| EP3409272B1 (de) * | 2018-03-07 | 2020-06-24 | Alfred E. Tiefenbacher (GmbH & Co. KG) | Pharmazeutische zusammensetzung mit eltrombopag olamin, reduzierendem zucker und polymerem bindemittel |
-
2019
- 2019-11-07 TR TR2019/17244A patent/TR201917244A1/tr unknown
-
2020
- 2020-10-27 WO PCT/TR2020/050997 patent/WO2021091510A1/en not_active Ceased
- 2020-10-27 EP EP20884244.3A patent/EP4054566A4/de active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| WO2021091510A1 (en) | 2021-05-14 |
| EP4054566A4 (de) | 2023-12-06 |
| TR201917244A1 (tr) | 2021-05-21 |
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