OA20228A - Cyclodextrin-based formulation of A BCL2 inhibitor. - Google Patents
Cyclodextrin-based formulation of A BCL2 inhibitor. Download PDFInfo
- Publication number
- OA20228A OA20228A OA1202100192 OA20228A OA 20228 A OA20228 A OA 20228A OA 1202100192 OA1202100192 OA 1202100192 OA 20228 A OA20228 A OA 20228A
- Authority
- OA
- OAPI
- Prior art keywords
- pharmaceutical composition
- composition according
- cyclodextrin
- compound
- cancer
- Prior art date
Links
- 229920000858 Cyclodextrin Polymers 0.000 title claims abstract description 146
- 239000000203 mixture Substances 0.000 title claims abstract description 66
- 102100013894 BCL2 Human genes 0.000 title claims description 5
- 108060000885 BCL2 Proteins 0.000 title claims description 5
- 238000009472 formulation Methods 0.000 title description 9
- 230000002401 inhibitory effect Effects 0.000 title description 5
- 239000003112 inhibitor Substances 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 159
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 118
- 239000007787 solid Substances 0.000 claims abstract description 42
- 201000011510 cancer Diseases 0.000 claims abstract description 30
- 239000000243 solution Substances 0.000 claims description 112
- 239000001116 FEMA 4028 Substances 0.000 claims description 73
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 46
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims description 45
- 229960004853 betadex Drugs 0.000 claims description 45
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 33
- 239000008103 glucose Substances 0.000 claims description 32
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-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 claims description 31
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 28
- 235000011149 sulphuric acid Nutrition 0.000 claims description 28
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 20
- 239000012458 free base Substances 0.000 claims description 20
- 206010000880 Acute myeloid leukaemia Diseases 0.000 claims description 17
- 239000002904 solvent Substances 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 13
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-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 12
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 claims description 12
- 201000009251 multiple myeloma Diseases 0.000 claims description 12
- 239000005720 sucrose Substances 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- 206010008958 Chronic lymphocytic leukaemia Diseases 0.000 claims description 10
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 claims description 10
- 206010020243 Hodgkin's disease Diseases 0.000 claims description 10
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 10
- HDTRYLNUVZCQOY-LIZSDCNHSA-N 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 claims description 10
- 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 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 239000000594 mannitol Substances 0.000 claims description 10
- 235000010355 mannitol Nutrition 0.000 claims description 10
- 208000003950 B-Cell Lymphoma Diseases 0.000 claims description 9
- 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 9
- 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 9
- 239000000600 sorbitol Substances 0.000 claims description 9
- 238000001802 infusion Methods 0.000 claims description 8
- 201000000050 myeloid neoplasm Diseases 0.000 claims description 8
- 206010012818 Diffuse large B-cell lymphoma Diseases 0.000 claims description 7
- 206010025323 Lymphomas Diseases 0.000 claims description 7
- 208000000587 Small Cell Lung Carcinoma Diseases 0.000 claims description 7
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 7
- 108009000491 Small cell lung cancer Proteins 0.000 claims description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 7
- 201000003793 myelodysplastic syndrome Diseases 0.000 claims description 7
- 210000004556 Brain Anatomy 0.000 claims description 6
- 210000000481 Breast Anatomy 0.000 claims description 6
- 206010024324 Leukaemias Diseases 0.000 claims description 6
- 210000004185 Liver Anatomy 0.000 claims description 6
- 206010033128 Ovarian cancer Diseases 0.000 claims description 6
- 208000008443 Pancreatic Carcinoma Diseases 0.000 claims description 6
- 206010060862 Prostate cancer Diseases 0.000 claims description 6
- ODLHGICHYURWBS-LKONHMLTSA-N Trappsol Cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims description 6
- 210000003932 Urinary Bladder Anatomy 0.000 claims description 6
- 201000011231 colorectal cancer Diseases 0.000 claims description 6
- 238000004090 dissolution Methods 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical class OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims description 6
- 230000003211 malignant Effects 0.000 claims description 6
- 201000001441 melanoma Diseases 0.000 claims description 6
- 201000002528 pancreatic cancer Diseases 0.000 claims description 6
- 229940097346 sulfobutylether-beta-cyclodextrin Drugs 0.000 claims description 6
- 208000002154 Non-Small-Cell Lung Carcinoma Diseases 0.000 claims description 5
- 108009000071 Non-small cell lung cancer Proteins 0.000 claims description 5
- 238000010790 dilution Methods 0.000 claims description 5
- 239000000546 pharmaceutic aid Substances 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- 230000000694 effects Effects 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 230000000051 modifying Effects 0.000 claims description 3
- 239000012062 aqueous buffer Substances 0.000 claims description 2
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims description 2
- 238000010253 intravenous injection Methods 0.000 claims description 2
- 102000005962 receptors Human genes 0.000 claims description 2
- 108020003175 receptors Proteins 0.000 claims description 2
- 230000003442 weekly Effects 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 abstract description 35
- 150000003839 salts Chemical class 0.000 abstract description 2
- VNNWQLOUMFCVJD-XIFFEERXSA-N Cc1c(cc(C#N)n1C)N(C(=O)c1cc(-c2cc(Cl)ccc2C(=O)N2Cc3ccccc3C[C@H]2CN2CCOCC2)n(C)c1C)c1ccc(O)cc1 Chemical compound Cc1c(cc(C#N)n1C)N(C(=O)c1cc(-c2cc(Cl)ccc2C(=O)N2Cc3ccccc3C[C@H]2CN2CCOCC2)n(C)c1C)c1ccc(O)cc1 VNNWQLOUMFCVJD-XIFFEERXSA-N 0.000 abstract 1
- 238000007911 parenteral administration Methods 0.000 abstract 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 66
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 34
- 229960001031 Glucose Drugs 0.000 description 31
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 19
- 238000003760 magnetic stirring Methods 0.000 description 18
- 239000000969 carrier Substances 0.000 description 15
- AOBORMOPSGHCAX-UHFFFAOYSA-N Tocophersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-UHFFFAOYSA-N 0.000 description 12
- 210000002381 Plasma Anatomy 0.000 description 11
- 229940097362 Cyclodextrins Drugs 0.000 description 10
- 238000001990 intravenous administration Methods 0.000 description 10
- 206010028980 Neoplasm Diseases 0.000 description 9
- WHGYBXFWUBPSRW-FOUAGVGXSA-N β-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 9
- 238000007792 addition Methods 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 7
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 7
- 229920001223 polyethylene glycol Polymers 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 239000004094 surface-active agent Substances 0.000 description 7
- 239000003814 drug Substances 0.000 description 6
- 229940079593 drugs Drugs 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- -1 hydroxyethyl Chemical group 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- 230000000275 pharmacokinetic Effects 0.000 description 5
- 206010029592 Non-Hodgkin's lymphomas Diseases 0.000 description 4
- 239000008351 acetate buffer Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 231100000371 dose-limiting toxicity Toxicity 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 230000001225 therapeutic Effects 0.000 description 4
- 230000035841 AUCt Effects 0.000 description 3
- 241000282465 Canis Species 0.000 description 3
- 210000001783 ELP Anatomy 0.000 description 3
- 230000036882 MTD Effects 0.000 description 3
- 239000002033 PVDF binder Substances 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 229960000583 Acetic Acid Drugs 0.000 description 2
- GNSKLFRGEWLPPA-UHFFFAOYSA-M Monopotassium phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 2
- 229940068968 Polysorbate 80 Drugs 0.000 description 2
- 230000002730 additional Effects 0.000 description 2
- 230000000259 anti-tumor Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000008364 bulk solution Substances 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000007979 citrate buffer Substances 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- 238000010979 pH adjustment Methods 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 238000000634 powder X-ray diffraction Methods 0.000 description 2
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 231100000730 tolerability Toxicity 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 230000000007 visual effect Effects 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- RGQYVQYXCZODQW-UHFFFAOYSA-L 182410-00-0 Chemical compound [Na+].[Na+].OC1C(O)C2OC(CO)C1OC(C(C1O)O)OC(CO)C1OC(C(O)C1O)OC(CO)C1OC(C(O)C1O)OC(CO)C1OC(C(O)C1O)OC(CO)C1OC(C(OCCCCS([O-])(=O)=O)C1O)OC(COCCCCS([O-])(=O)=O)C1OC(C(O)C1O)OC(CO)C1O2 RGQYVQYXCZODQW-UHFFFAOYSA-L 0.000 description 1
- AKWIAIDKXNKXDI-UHFFFAOYSA-N 1H-pyrrole-3-carboxamide Chemical compound NC(=O)C=1C=CNC=1 AKWIAIDKXNKXDI-UHFFFAOYSA-N 0.000 description 1
- PLHMLIDUVYHXHF-ZQSHRCRISA-N 2,6-Di-O-ethyl-β-cyclodextrin Chemical compound CCOC[C@H]([C@H]([C@@H]([C@H]1OCC)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC)[C@H]([C@@H]([C@H]3OCC)O)O[C@H]3O[C@H](COCC)[C@H]([C@@H]([C@H]3OCC)O)O[C@H]3O[C@H](COCC)[C@H]([C@@H]([C@H]3OCC)O)O[C@H]3O[C@H](COCC)[C@H]([C@@H]([C@H]3OCC)O)O3)[C@H](O)[C@H]2OCC)COCC)O[C@@H]1O[C@H]1[C@H](O)[C@@H](OCC)[C@@H]3O[C@@H]1COCC PLHMLIDUVYHXHF-ZQSHRCRISA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 1
- 230000035533 AUC Effects 0.000 description 1
- 229950008376 Alfadex Drugs 0.000 description 1
- 230000036868 Blood Concentration Effects 0.000 description 1
- 230000037242 Cmax Effects 0.000 description 1
- 229940061607 Dibasic Sodium Phosphate Drugs 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 235000014755 Eruca sativa Nutrition 0.000 description 1
- 244000024675 Eruca sativa Species 0.000 description 1
- 210000002683 Foot Anatomy 0.000 description 1
- 229940102223 Injectable Solution Drugs 0.000 description 1
- 239000007836 KH2PO4 Substances 0.000 description 1
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 1
- 229940111688 Monobasic potassium phosphate Drugs 0.000 description 1
- 102000002423 Octamer Transcription Factor-6 Human genes 0.000 description 1
- 108010068113 Octamer Transcription Factor-6 Proteins 0.000 description 1
- 206010025310 Other lymphomas Diseases 0.000 description 1
- 229920002556 Polyethylene Glycol 300 Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229940087562 Sodium Acetate Trihydrate Drugs 0.000 description 1
- AOBORMOPSGHCAX-DGHZZKTQSA-N Tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 1
- DSDAICPXUXPBCC-MWDJDSKUSA-N Trimethyl-β-cyclodextrin Chemical compound COC[C@H]([C@H]([C@@H]([C@H]1OC)OC)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COC)[C@H]([C@@H]([C@H]3OC)OC)O[C@H]3O[C@H](COC)[C@H]([C@@H]([C@H]3OC)OC)O[C@H]3O[C@H](COC)[C@H]([C@@H]([C@H]3OC)OC)O[C@H]3O[C@H](COC)[C@H]([C@@H]([C@H]3OC)OC)O3)[C@H](OC)[C@H]2OC)COC)O[C@@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@@H]3O[C@@H]1COC DSDAICPXUXPBCC-MWDJDSKUSA-N 0.000 description 1
- 210000002700 Urine Anatomy 0.000 description 1
- 229940046009 Vitamin E Drugs 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 229920004482 WACKER® Polymers 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 239000001202 beta-cyclodextrine Substances 0.000 description 1
- 230000004579 body weight change Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 235000012970 cakes Nutrition 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 210000004027 cells Anatomy 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- BRLQWZUYTZBJKN-UHFFFAOYSA-N epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atoms Chemical class [H]* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 238000009114 investigational therapy Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N 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 description 1
- 150000002605 large molecules Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000011068 load Methods 0.000 description 1
- 231100000682 maximum tolerated dose Toxicity 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Polymers 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000003204 osmotic Effects 0.000 description 1
- 230000002093 peripheral Effects 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 229920002496 poly(ether sulfone) Polymers 0.000 description 1
- 229920003208 poly(ethylene sulfide) Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 150000003385 sodium Chemical class 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- AYRVGWHSXIMRAB-UHFFFAOYSA-M sodium acetate trihydrate Chemical compound O.O.O.[Na+].CC([O-])=O AYRVGWHSXIMRAB-UHFFFAOYSA-M 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 229940081044 tocophersolan Drugs 0.000 description 1
- 231100000402 unacceptable toxicity Toxicity 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 150000003712 vitamin E derivatives Chemical class 0.000 description 1
- HFHDHCJBZVLPGP-JSPYPFAESA-N α-Dextrin Chemical compound OCC([C@H](C(C1O)O)O[C@H]2OC([C@@H](O[C@H]3OC(CO)[C@H](C(C3O)O)O[C@H]3OC(CO)[C@H](C(C3O)O)O[C@H]3OC(CO)[C@H](C(C3O)O)O3)C(O)C2O)CO)O[C@@H]1O[C@H]1C(O)C(O)[C@@H]3OC1CO HFHDHCJBZVLPGP-JSPYPFAESA-N 0.000 description 1
- HFHDHCJBZVLPGP-RWMJIURBSA-N α-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Abstract
The invention relates to a pharmaceutical composition comprising 5-(5-chloro-2-{[(3S)-3(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin2(1H)-yl]carbonyl} phenyl)-N-(5-cyano-1,2dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2dimethyl-1H-pyrrole-3-carboxamide, referred to herein as 'Compound A', or a pharmaceutically acceptable salt thereof, and a cyclodextrin. More specifically, the invention relates to a solid pharmaceutical composition comprising Compound A and a cyclodextrin, and a pharmaceutical composition for parenteral administration prepared by dissolving this solid pharmaceutical composition. Furthermore, the invention relates to the use of such compositions for the treatment of cancer.
Description
CYCLODEXTRIN-BASED FORMULATION OF A BCL-2 INHIBITOR
BACKGROUND OF THE INVENTION
The invention relates to a pharmaceutical composition comprising 5-(5-chloro-2-{[(3S)-3(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(177)-yl]carbonyl}phenyl)-V-(5-cyano5 l,2-dimethyl-l/f-pyrrol-3-yl)-A-(4-hydroxyphenyl)-l,2-dimethyl-17/-pyrrole-3carboxamide, referred to herein as ‘Compound A’, or a pharmaceutically acceptable sait thereof, and a cyclodextrin. More specifically, the invention relates to a solid pharmaceutical composition comprising Compound A and a cyclodextrin, and a pharmaceutical composition for parentéral administration prepared by dissolving this solid pharmaceutical composition. Furthermore, the invention relates to the use of such compositions for the treatment of cancer. ‘Compound A’ as used herein optionally includes the pharmaceutically acceptable salts thereof.
The structure of Compound A is:
5-(5-chloro-2-{[(35)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l/7)-yl]carbonyl} phenyl)-7V-(5-cyano-1,2-dimethy l-l/7-pyrrol-3-yl)-A-(4-hydroxyphenyl)-1,2-dimethyl-\Hpyrrole-3-carboxamide.
The préparation of Compound A, its use as a Bcl-2 inhibitor for the treatment of cancer and pharmaceutical formulations thereof, are described in WO 2015/011400, the content of which is incorporated by reference. The préparation is specifically disclosed in Example 386 of WO 2015/011400 in the form of a hydrochloride sait.
Compound A has limited aqueous solubility across ail pHs (< 0.01 mg/mL for the free base and 1.4 mg/mL for ‘Compound A, H2SO4 at pH=2.5), including physiologically relevant 5 pHs. In order to enable safe and effective administration of Compound A, and to elicit the required therapeutic effects, Compound A needs to be solubilized at higher concentration than its aqueous solubility.
There are different ways to solubilize poorly soluble compounds for parentéral administration. Typical approaches are the optimization of the pH or the use of co-solvents 10 (e.g. PEG300, PEG400, propylene glycol, or éthanol). If these approaches are, for any reason, not feasible, the use of surfactants may be considered (e.g. Tween® 80 or Kolliphor™ ELP). However, these types of surfactants are frequently associated with adverse effects and not always able to solubilize the compounds of interest at targeted concentrations. Cyclodextrins are established as safe solubilizing agents, yet with 15 limitations as they are not effective solubilizers for ail compounds.
The aim of the current invention is to provide a composition which can conveniently be used to solubilize and parenterally deliver Compound A at targeted concentrations for having clinical efficacy. In particular, there is a need to provide a pharmaceutical composition for Compound A which is safe and efficacious. Further aims are to provide a 20 composition which is stable in the relevant conditions and containers, and which enables administration of an appropriate dose of Compound A over a reasonable timescale. In a further aim, the composition should be able to be manufactured by a reliable and robust process for the préparation of parentéral dosage forms.
SUMMARY
The présent invention provides a composition comprising Compound A and a cyclodextrin, suitable for parentéral administration to patients. In particular, such administration is by intravenous injection or infusion. The invention further provides a solid cyclodextrin-based composition which can be dissolved in one or more solvents shortly before administration to the patient, in order to provide the composition suitable for parentéral administration. Preferably, the solid cyclodextrin-based composition according to the invention is placed in an aqueous solution. In the pharmaceutical composition thus prepared, Compound A is 5 solubilized by means of a cyclodextrin.
Preferably, the invention provides a composition comprising Compound A which has an optimal physical stability; for example the précipitation of components is avoided when the solid composition is placed in an aqueous solution and further diluted in a glucose solution and when the resulting pharmaceutical composition is injected in the plasma.
Preferably, the invention provides a pharmaceutical cyclodextrin-based composition comprising Compound A, which is chemically and physically stable. At high cyclodextrin concentration, it is well known that drug/cyclodextrin complexes hâve tendency to form large and visible particles (Saokham et al, Molécules 2018 23 page 1161). These solid microparticles obviously prevent a stérile fdtration operation. Interestingly, the drug/cyclodextrin solutions according to the invention remain perfectly clear and can be very easily filtrated on 0.2 qm fdter.
Preferably, the invention provides a solid pharmaceutical composition having an acceptable reconstitution time in solvents for injection (more preferably in water for injection), and thus allowing ease of use for the préparation of the pharmaceutical 20 composition that will be parenterally delivered.
Preferably, the invention provides a pharmaceutical cyclodextrin-based composition which enables a fast solubilisation and a good distribution of Compound A after intravenous administration.
Overall, the invention described herein enables effective administration of Compound A to 25 patients, despite the challenging physico-chemical characteristics of Compound A.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 shows the efficacy of Compound A in a cyclodextrin-based formulation after 15 and 40 mg/kg administrated i.v. once a week over two weeks in RS4;11 grafted female SCID mice.
Figure 2 shows the tolerability of Compound A in a cyclodextrin-based formulation after 15 and 40 mg/kg administrated i.v. once a week over two weeks in RS4;11 grafted female SCID mice. Body weight loss is measured versus time after treatment.
DETAILED DESCRIPTION OF THE INVENTION ‘Compound A’ means 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,410 dihydroisoquinolin-2(l//)-yl]carbonyl} phenyl)-A-(5-cyano-l,2-dimethyl-17/-pyrrol-3-yI)V-(4-hydroxyphenyl)-l,2-dimethyl-l H-pyrrole-3-carboxamide.
‘Compound A, H2SO4’ means that 5-(5-chloro-2-{[(35)-3-(morpholin-4-ylmethyl)-3,4dihydroisoquinolin-2(177)-yl]carbonyl} phenyl)-V-(5-cyano-l,2-dimethyl-l//-pyrrol-3-yl)jV-(4-hydroxyphenyl)-l,2-dimethyl-1 H-pyrrole-3-carboxamide is in the form of a hydrogen 15 sulfate sait.
‘Free molécule’ and ‘free base’ are used interchangeably herein and refer to Compound A when not in sait form.
The cyclodextrin described herein is a natural or derived cyclodextrin. Natural cyclodextrins comprise three well-known industrially produced (major and minor) cyclic 20 oligosaccharides. The most common natural cyclodextrins are α, β, and γ consisting of 6, 7, and 8 glucopyranose units. Derived cyclodextrins include hydroxyalkylated cyclodextrins selected from the group consisting of hydroxyethyl cyclodextrin, hydroxypropyl cyclodextrin and hydroxybutyl cyclodextrin. In a particular embodiment, the cyclodextrin is the β-cyclodextrin itself or its dérivatives. The dérivatives herein mean β-cyclodextrins 25 having various substituents, including methyl-β-cyclodextrin, ethyl-β-cyclodextrin, (220228 hydroxypropyl)-β-cyclodextrin, (3-hydroxypropyl)-β-cyclodextrin, (2-hydroxyethyl)-bcyclodextrin, carboxymethyl-β-cyclodextrin, carboxymethyl-ethyl-β-cyclodextrin, diethylβ-cyclodextrin, dimethyl-P-cyclodextrin, trimethyl-P-cyclodextrin, glucosyl-βcyclodextrin, hydroxybutenyl-β-cyclodextrin, maltosyl-β-cyclodextrin, randomly 5 methylated-β-cyclodextrin, sulfobutylether-β-cyclodextrin, 2-selenium-bridged βcyclodextrin, and 2-tellurium-bridged β-cyclodextrin. Besides β-cyclodextrin, 2hydroxypropyl-y-cyclodextrin can be used in the présent invention. Derived cyclodextrins also include polymerized cyclodextrins, which are high molecular weight compounds, either water-soluble or insoluble. The examples of polymerized cyclodextrins are soluble io anionic ^-cyclodextrin polymer, soluble y-cyclodextrin polymer, and epichlorohydrin βcyclodextrin polymer.
‘a-cyclodextrin’, ‘β-cyclodextrin’ and ‘y-cyclodextrin’ are also named ‘alfadex’, ‘betadex’, and ‘gammadex’, respectively.
ΉΡ- β-cyclodextrin’ is also named ‘hydroxypropyl- β-cyclodextrin’ or ‘2-hydroxypropyl15 β-cyclodextrin’ or ‘hydroxypropylbetadex’. In particular, the HP- β-cyclodextrin is marketed with the following product names: Cavitron™ W7HP7 (typical degree of substitution: 6.0-8.0 ; approximate molecular weight: 1520), Cavitron™ W7HP5 (typical degree of substitution: 4.1-5.1 ; approximate molecular weight: 1410), Kleptose™ HPB or Kleptose™ HP.
‘SBE- β-cyclodextrin’ is also named ‘sodium sulfobutylether- β-cyclodextrin’ or ‘betadex sulfobutyl ether sodium’. In particular, the SBE- β-cyclodextrin is marketed with the following product names: Dexsolve™ or Captisol™.
The pharmaceutical composition described herein is, in particular, a pharmaceutical cyclodextrin-based composition. A ‘pharmaceutical cyclodextrin-based composition’ 25 means a composition comprising a cyclodextrin, which is suitable for pharmaceutical administration.
‘TPGS’ means d-a-tocopheryl polyethylene glycol succinate or tocophersolan. It is a water-soluble form of vitamin E (a-tocopherol).
‘Tonicity adjusting agent’ means a pharmaceutically acceptable compound which can be added to a formulation to make it isotonie with human plasma. Tonicity adjusting agents 5 include for example dextrose, glucose, mannitol, sucrose, lactose, trehalose, glycérine and
NaCl, in particular sucrose or glycérine, more particularly sucrose. Tonicity is the ‘effective osmolality’ and is equal to the sum of the concentrations of the solutés which hâve the capacity to exert an osmotic force across the membrane. Parentéral formulations should be isotonie with blood plasma. Tonicity adjusting agents are well known to the 10 skilled person.
A ‘buffer’ is used to prevent changes in the pH of a solution, and suitable examples are well-known to the skilled formulator.
‘Container’ means an ampoule or vial with rubber stopper and cap, single or double chamber syringe, infusion bag or bottle made from polymeric materials or glass, suitable 15 for housing compositions for parentéral administration. It also includes any vessel for holding liquids.
As used herein, the term “solvent” is a solvent used for the reconstitution of a pharmaceutical composition suitable for parentéral administration, starting from a solid pharmaceutical composition. The solid pharmaceutical composition is preferably a 20 lyophilisate. In a preferred mode, the solvent is water. In the context of the invention, the water used is water for injection.
As used herein, the term ‘comprising’ means ‘including’, and is not intended to exclude the presence of any additional component, unless the context suggests otherwise, for example when the components together sum to 100 %.
As used herein, the term ‘treat’, ‘treating’ or ‘treatment’ of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment, ‘treat’, ‘treating’ or ‘treatment’ refers to alleviating or ameliorating at least one physical parameter including those which may not be discemible by the patient. In yet another embodiment, ‘treat’, ‘treating’ or ‘treatment’ refers to 5 modulating the disease or disorder, either physically, (e.g., stabilization of a discemible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
As used therein, a “therapeutically effective amount of the composition” means an effective amount of the composition according to the invention containing an effective dose of active principle to elicit a therapeutic benefit for the patient. The dose of io Compound A administered according to the invention is from 5 mg to 1000 mg (expressed as free base).
Mixing ‘shortly before administration to patient’ means up to three days before, in particular up to 24 hours before, and for example up to 6 hours before administration to the patient.
Embodiments
Described below are a number of embodiments of the invention.
El. A solid pharmaceutical composition comprising Compound A which is 5-(5chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l//)-yl]carbonyl} phenyl)-A-(5-cyano-l,2-dimethyl-l/Z-pyrrol-3-yl)-A-(4-hydroxyphenyl)-l,2-dimethyl-l H20 pyrrole-3-carboxamide, or a pharmaceutically acceptable sait thereof, and a cyclodextrin.
E2. A solid pharmaceutical composition according to El, wherein Compound A is in the form of the hydrochloride sait.
E3. A solid pharmaceutical composition according to El, wherein Compound A is in the form of a hydrogen sulfate sait.
E4. A solid pharmaceutical composition according to any of embodiments El to E3, wherein the cyclodextrin is a sodium sulfobutylether-β-cyclodextrine (SBE- βcyclodextrin) or a hydroxypropyl- β-cyclodextrin (HP- β-cyclodextrin).
E5. A solid pharmaceutical composition according to E4, wherein the sulfobutylether5 β-cyclodextrin is selected from Dexsolve™ and Captisol™.
E6. A solid pharmaceutical composition according to El to E3, wherein the cyclodextrin is a HP- β-cyclodextrin, more particularly Cavitron™ W7HP7, Cavitron™ W7HP5, Kleptose™ HPB or Kleptose™ HP.
E7. A solid pharmaceutical composition according to E6, wherein the molar ratio io between the HP- β-cyclodextrin and Compound A is at least 5 : 1. In another embodiment, the weight/weight ratio between the HP- β-cyclodextrin and Compound A is at least 10:1 for the solid pharmaceutical compositions according to the invention.
E8. A solid pharmaceutical composition according to E7, wherein the molar ratio between the HP- β-cyclodextrin and Compound A is 5 : 1. In another embodiment, the 15 weight/weight ratio between the HP- β-cyclodextrin and Compound A is 10 : 1 for the solid pharmaceutical compositions according to the invention.
E9. A solid pharmaceutical composition according to any of embodiments E6 to E8, wherein the HP- β-cyclodextrin is Cavitron™ W7HP5.
E10. A solid pharmaceutical composition according to any of embodiments E6 to E8, 20 wherein the HP- β-cyclodextrin is Kleptose™ HPB.
Eli. A solid pharmaceutical composition according to any of embodiments El to E10, further comprising one or more pharmaceutically acceptable excipients. In another embodiment, the pharmaceutically acceptable excipient is a surfactant.
E12. A solid pharmaceutical composition according to any of embodiments El to E10, comprising at least one pharmaceutically acceptable excipients selected from glucose, mannitol, sucrose, trehalose and sorbitol.
E13. A solid pharmaceutical composition according to any of embodiments El to El2, 5 which is a lyophilisate.
E14. A pharmaceutical composition comprising Compound A which is 5-(5-chloro-2{[(3>ST)-3-(morpholin-4-ylmethyl)-3,4-dihydiOisoquinolin-2(lÆ)-yl]carbonyl}phenyl)-A'-(5cyano-1,2-dimethyl- l//-pyrrol-3-yl)-A-(4-hydroxyphenyl)-1,2-dimethyl-1 W-pyrrole-3carboxamide, or a pharmaceutically acceptable sait thereof, a cyclodextrin and one or 10 more solvents. In another embodiment, the pharmaceutical composition further comprises a surfactant.
El5. The pharmaceutical composition according to E14 wherein the solvent is an aqueous buffer or water, and more particularly water.
E16. The pharmaceutical composition according to E14 or E15, wherein Compound A is 15 in the form of the hydrochloride sait.
E17. The pharmaceutical composition according to E14 or E15, wherein Compound A is in the form of a hydrogen sulfate sait.
El8. The pharmaceutical composition according to El7, having a pH value comprised between 2.8 and 3.2, more particularly the pH value is comprised between 2.9 and 3.1.
El9. The pharmaceutical composition according to El7 having a pH value comprised between 2.5 and 4.3, more particularly the pH value is comprised between 2.5 and 3.5.
E20. The pharmaceutical composition according to any of embodiments E14 to El9, wherein the cyclodextrin is a sodium sulfobutylether-β-cyclodextrin (SBE- β-cyclodextrin) or a hydroxypropyl- β-cyclodextrin (HP- β-cyclodextrin).
E21. The pharmaceutical composition according to E20, wherein the sulfobutylether-βcyclodextrin is selected from Dexsolve™ and Captisol™.
E22. The pharmaceutical composition according to any of embodiments E14 to El9, wherein the cyclodextrin is a HP- β-cyclodextrin, more particularly Cavitron™ W7HP7, 5 Cavitron™ W7HP5, Kleptose™ HPB or Kleptose™ HP.
E23. The pharmaceutical composition according to E22, wherein the molar ratio between the HP- β-cyclodextrin and Compound A is at least 5 : 1. In another embodiment, the weight/weight ratio between the HP- β-cyclodextrin and Compound A is at least 10:1 for the pharmaceutical compositions according to the invention.
ίο E24. The pharmaceutical composition according to E23, wherein the molar ratio between the HP- β-cyclodextrin and Compound A is 5 : 1. In another embodiment, the weight/weight ratio between HP- β-cyclodextrin and Compound A is 10 : 1 for the pharmaceutical compositions according to the invention.
E25. The pharmaceutical composition according to any of embodiments E22 to E24, 15 wherein the HP- β-cyclodextrin is Cavitron™ W7HP5.
E26. The pharmaceutical composition according to any of embodiments E22 to E24, wherein the HP- β-cyclodextrin is Kleptose™ HPB.
E27. The pharmaceutical composition according to any of embodiments E22 to E26 having a concentration comprised between 50 and 300 mg/mL of HP- β-cyclodextrin.
E28. The pharmaceutical composition according to E27 having a concentration of 200 mg/mL of HP- β-cyclodextrin.
E29. The pharmaceutical composition according to any of embodiments E22 to E26 having a concentration of 20 mg/mL of Compound A, free base.
E30. The pharmaceutical composition according to any of embodiments E14 to E29, further comprising a tonicity adjusting agent.
E31. The pharmaceutical composition according to E30, wherein the tonicity adjusting agent is selected from glucose, mannitol, sucrose, trehalose and sorbitol.
E32. The pharmaceutical composition according to E14 comprising ‘Compound A,
H2SO4’and Cavitron™ W7FIP5, and having a pH value comprised between 2.8 and 3.2, more particularly the pH value is comprised between 2.9 and 3.1. In another embodiment, the pharmaceutical composition further comprises water.
E33. The pharmaceutical composition according to E14 comprising ‘Compound A, io H2SO4’ and Cavitron™ W7HP5, and having a pH value comprised between 2.5 and 4.3, more particularly the pH value is comprised between 2.5 and 3.5. In another embodiment, the solvent used in the pharmaceutical composition is water.
E34. The pharmaceutical composition according to E14:
comprising ‘Compound A, H2SO4’, Cavitron™ W7HP5 and water,
- and having a pH value comprised between 2.5 and 4.3, more particularly the pH value is comprised between 2.5 and 3.5, wherein the molar ratio between Cavitron™ W7HP5 and Compound A (free base) is at least 5:1.
E35. The pharmaceutical composition according to E14:
- comprising ‘Compound A, H2SO4’, Cavitron™ W7HP5 and water, and having a pH value comprised between 2.5 and 4.3, more particularly the pH value is comprised between 2.5 and 3.5, wherein the molar ratio between Cavitron™ W7HP5 and Compound A (free base) is 5 : 1.
E36. The pharmaceutical composition according to El4:
comprising ‘Compound A, H2SO4’, Cavitron™ W7HP5 and water, and having a pH value comprised between 2.5 and 4.3, more particularly the pH value is comprised between 2.5 and 3.5, wherein the weight/weight ratio between Cavitron™ W7HP5 and Compound A (free base) is at least 10:1.
E37. The pharmaceutical composition according to E14:
comprising ‘Compound A, H2SO4’, Cavitron™ W7HP5 and water, and having a pH value comprised between 2.5 and 4.3, more particularly the pH value is comprised between 2.5 and 3.5,
- wherein the weight/weight ratio between Cavitron™ W7HP5 and Compound A (free base) is 10 : 1.
E38. The pharmaceutical composition according to E14 comprising ‘Compound A, H2SO4’, Cavitron™ W7HP5, water and glucose, and having a pH value comprised between 2.5 and 4.4, more particularly the pH value is comprised between 3.3 and 4.4.
E39. The pharmaceutical composition according to E14:
comprising ‘Compound A, H2SO4’, Cavitron™ W7HP5, water and glucose, and having a pH value comprised between 2.5 and 4.4, more particularly the pH value is comprised between 3.3 and 4.4, wherein the molar ratio between Cavitron™ W7HP5 and Compound A (free base) is at least 5:1.
E40. The pharmaceutical composition according to E14:
- comprising ‘Compound A, H2SO4’, Cavitron™ W7HP5, water and glucose, and having a pH value comprised between 2.5 and 4.4, more particularly the pH value is comprised between 3.3 and 4.4,
- wherein the molar ratio between Cavitron™ W7HP5 and Compound A (free base) is 5 : 1.
E41. The pharmaceutical composition according to E14:
comprising ‘Compound A, H2SO4’, Cavitron™ W7HP5, water and glucose, and having a pH value comprised between 2.5 and 4.4, more particularly the pH value is comprised between 3.3 and 4.4, wherein the weight/weight ratio between Cavitron™ W7HP5 and Compound A (free base) is at least 10:1.
E42. The pharmaceutical composition according to E14:
comprising ‘Compound A, H2SO4’, Cavitron™ W7HP5, water and glucose, and having a pH value comprised between 2.5 and 4.4, more particularly the pEI value is comprised between 3.3 and 4.4,
- wherein the weight/weight ratio between Cavitron™ W7E1P5 and Compound A (free base) is 10 : 1.
E43. The pharmaceutical composition according to any of embodiments E14 to E42, for parentéral administration.
E44. The pharmaceutical composition according to E43, for infusion or intravenous 15 injection.
E45. A process for preparing a pharmaceutical composition according to E14 suitable for parentéral administration comprising the dissolution of a solid pharmaceutical composition as defined in El to El3 in a solvent, more particularly in water.
E46. A process according to E45 comprising an additional step of dilution with an 20 infusion solution, more particularly with a solution of 5% Glucose.
E47. A process according to E45 or E46, wherein the dissolution takes place immédiately prior to administration to the patient.
E48. A method of modulating Bcl-2 receptor activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the 25 composition according to any of embodiments El4 to E44.
E49. A method of treating cancer, comprising administering to the subject a therapeutically effective amount of the composition according to any of embodiments E14 to E44.
E50. A method according to E49, wherein the cancer is selected from cancers of the 5 bladder, brain, breast and utérus, chronic lymphoid leukaemias, colorectal cancer, cancers of the œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemia, lymphomas, for example non-Hodgkin's B-cell lymphoma and diffuse large B-cell lymphoma, melanomas, malignant haemopathies, for example myelodysplastic syndrome, myelomas, for example multiple myeloma, ovarian cancer, non-small-cell lung cancer, 10 prostate cancer, pancreatic cancer and small-cell lung cancer.
E51. A method according to E50, wherein the cancer is selected from non-Hodgkin's Bcell lymphoma, diffuse large B-cell lymphoma, multiple myeloma, myelodysplastic syndrome, chronic lymphoid leukaemias and acute myeloid leukaemia, more particularly non-Hodgkin's B-cell lymphoma, multiple myeloma and acute myeloid leukaemia.
E52. A method according to any of embodiments E48 to E51, wherein the composition according to any of embodiments E14 to E36, is administered once weekly.
E53. The pharmaceutical composition according to any of embodiments E14 to E44 for use as a médicament.
E54. A pharmaceutical composition for use according to E53, wherein said use is in the 20 treatment of cancer, in particular wherein cancer is selected from cancers of the bladder, brain, breast and utérus, chronic lymphoid leukaemias, colorectal cancer, cancers of the œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemia, lymphomas, for example non-Hodgkin's B-cell lymphoma and diffuse large B-cell lymphoma, melanomas, malignant haemopathies, for example myelodysplastic syndrome, myelomas, 25 for example multiple myeloma, ovarian cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.
E55. A pharmaceutical composition for use according to embodiment E54, wherein said cancer is selected from non-Hodgkin's B-cell lymphoma, diffuse large B-cell lymphoma, multiple myeloma, myelodysplastic syndrome, chronic lymphoid leukaemias and acute myeloid leukaemia, more particularly non-Hodgkin's B-cell lymphoma, multiple myeloma 5 and acute myeloid leukaemia.
E56. Use of solid pharmaceutical composition according to any of El to E13, for the préparation of a médicament to treat cancer.
E57. The use according to E56, wherein the cancer is selected from cancers of the bladder, brain, breast and utérus, chronic lymphoid leukaemias, colorectal cancer, cancers io of the œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemia, lymphomas, for example non-Hodgkin's B-cell lymphoma and diffuse large B-cell lymphoma, melanomas, malignant haemopathies, for example myelodysplastic syndrome, myelomas, for example multiple myeloma, ovarian cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer, in particular non-Hodgkin's 15 B-cell lymphoma, diffuse large B-cell lymphoma, multiple myeloma, myelodysplastic syndrome, chronic lymphoid leukaemias and acute myeloid leukaemia, and more particularly non-Hodgkin's B-cell lymphoma, multiple myeloma and acute myeloid leukaemia.
E58. A combination comprising:
· a pharmaceutical composition according to any of embodiments E14 to E44, and • one or more therapeutically active agents, for simultaneous, sequential or separate use.
Advantageously, in a particular embodiment of the invention, there is provided a lyophilisate comprising Compound A and Cavitron™ W7HP5, which can be dissolved in a 25 solvent, preferably water, shortly before administration to produce a transparent composition. In another embodiment, the previous solution can be further diluted with a solution of Glucose 5%. In particular, this is achieved by transferring the pharmaceutical composition comprising Compound A and Cavitron™ W7HP5 as described herein into a 250 mL glucose bag.
The préparation of the solid pharmaceutical composition according to the invention may comprises a step of adjustment of the pH of the initial solution before drying. In particular, 5 the pH of the solution is adjusted by adding drop by drop, either a HCl solution or a NaOH solution, depending on the concentration of Compound A contained in the initial solution.
EXAMPLE 1: Solubility studies of Compound A in various carriers for the préparation of a formulation suitable for the parentéral route
The objective of these studies is to define the solubility at saturation of Compound A with io the aim of formulating an injectable solution characterised by a concentration of active ingrédient which is sufficiently high to meet the therapeutic needs of an administration in humans. In particular, it is necessary to hâve available a carrier which allows high daily administrable doses of active ingrédient to be achieved, considering the permitted daily exposures for the carrier itself. In particular, the permitted daily exposure for the ΗΡ-β15 cyclodextrin amounts to 320 mg/kg/day.
The solubility of‘Compound A, H2SO4 was studied in various media, including: citrate buffer (pH = 2; 50 mM), acetate buffer (pH = 4; 50 mM) and phosphate buffer (pH = 6-7.4; 67.7 mM);
- cyclodextrins of the type sulfobutyl ether β-cyclodextrin (SBE-β-cyclodextrin) or hydroxypropyl β-cyclodextrin (ΗΡ-β-cyclodextrin); more precisely, the SBE-βcyclodextrin tested is Dexsolve™ marketed by Cyclolab, while the ΗΡ-βcyclodextrins tested are Cavitron™ W7HP7 and Cavitron™ W7HP5 marketed by Wacker; Kleptose™ HP and Kleptose™ HPB marketed by Roquette;
- surfactants such as polysorbate 80 and Kolliphor™ ELP;
the mixture PEG400/ethanol/0.9% NaCl (40/10/50).
Preparation of the media containing the various carriers to be tested:
(i) 20% by weight cyclodextrin solution g of the cyclodextrin studied (Dexsolve™, Cavitron™ W7HP7, Cavitron™ W7HP5, Kleptose™ HP or Kleptose™ HPB) are weighed into a 20 mL graduated flask.
Approximately 15 mL of water are added and the whole obtained is subjected to magnetic stirring. The volume is then made up to 25 mL by the addition of water. The whole is placed under magnetic stirring for 10 minutes.
(ii) 2% by weight surfactant solutions g of the surfactant studied is weighed into a 50 mL graduated flask. The volume is then io made up to 50 mL by means of 0.9% NaCl solution. The whole is placed under magnetic stirring for 1 hour.
(iii) PEG/ethanol/0.9% NaCl solution (40/10/50) v/v/v mL of PEG 400, 5 mL of éthanol and 25 mL of NaCl are taken. The whole is placed in a 100 mL Erlenmeyer flask and stirred magnetically for 30 minutes.
Solubility test:
Approximately 340 mg of ‘Compound A, H2SO4’ are weighed into a 5 mL tube. 3 mL of the medium containing the carrier to be tested are then added. The whole is then placed under magnetic stirring for 2 hours or 24 hours. The suspension or solution so obtained is passed through a 0.2 pm filter (PVDF membrane - Millipore) before being analysed by 20 HPLC. In addition, the presence of dégradation products of Compound A was investigated in the samples stored for 72 hours at ambient température.
- 18Results:
| Carrier | Solubility after 2 h (mg/mL) | Solubility after 24 h (mg/mL) |
| Water | 2.87 | 1.56 |
| Absolute éthanol | 1.06 | 1.13 |
| PEG 400 | 11.67 | 11.22 |
| 2% Polysorbate 80 | 2.30 | 1.96 |
| 2% Kolliphor™ ELP | 2.08 | 1.74 |
| Cavitron™ W7HP7 | 17.87 | 21.15 |
| Cavitron™ W7HP5 | 25.20 | 30.22 |
| Kleptose™ HPB | - | 30-31 |
| Kleptose™ HP | - | 25-26 |
| Dexsolve™ | 23.45 | 23.15 |
| Citrate buffer | 0.24 | 0.25 |
| Acetate buffer | 0.20 | 0.18 |
| Phosphate buffer | 0.21 | 0.52 |
| PEG400/EtOH/0.9% NaCI | 10.33 | 10.75 |
Conclusion:
The 5 carriers permitting substantial solubilisation of Compound A are: Cavitron™ W7HP5 ~ Kleptose™ HPB > Kleptose™ HP ~ Dexsolve™ ~ Cavitron™ W7HP7 > 5 PEG400 > PEG400/EtOH/0.9% NaCl (40/10/50).
The solubilities in those media are between 10 and 30 mg/mL after 24 hours' stirring.
Cavitron™ W7HP5 and Kleptose™ HPB are the most effective carrier for solubilising Compound A and permitting the manufacture of solutions with a sufficient content of active ingrédient for the purpose of parentéral administration in humans. In particular, the 10 solutions wherein the molar ratio between the ΗΡ-β-cyclodextrin and Compound A is 5 : 1 are a compromise between drug loading and content of ΗΡ-β-cyclodextrin in accordance with the permitted daily exposure. Higher ratios are also acceptable within the limit of the permitted daily exposure.
The solubilities obtained after 2 hours' stirring were of the same order of magnitude. No 15 significant quantity (> 0.1%) of dégradation product or by-product was measured in the samples.
EXAMPLE 2: Solubility studies of Compound A in a ΗΡ-β-cyclodextrin as a function of the pH
Study 1 starting from Compound A, HCl
The solubility of Compound A, HCl was studied in the presence of a ΗΡ-β-cyclodextrin as 5 a function of the pH by means of various buffers (acetate pH = 4 and phosphate pH = 7.4).
Préparation of the media containing the various carriers to be tested:
(i) Acetate buffer pH 4
0.75 g of sodium acetate trihydrate (NaC2HaO2, 3H2O) is introduced into a 250 mL graduated flask. 3.5 mL of 2 N acetic acid solution (produced from glacial acetic acid) are 10 added. The volume is then made up to 250 mL by means of 0.9% NaCl solution, and the whole is then stirred. The pH is then adjusted to 4 by means of 1 N HCl solution.
(ii) Phosphate buffer pH 7.4
2.075 g of monobasic potassium phosphate (KH2PO4) and 0.238 g of dibasic sodium phosphate (Na2HPO4) are dissolved in 100 mL of water. The whole is stirred until 15 solubilisation is complété. The volume is then made up to 250 mL by means of 0.9% NaCl solution. The pH is adjusted to the desired value (7.4) by means of IN sodium hydroxide solution.
(iii) 20% by weight cyclodextrin solution g of the cyclodextrin studied (Cavitron™ W7HP5) are weighed into a 10 mL graduated 20 flask. The volume is then made up to 10 mL by means of a water/0.9% NaCl mixture (80/20) or an acetate or phosphate buffer solution, depending on the desired pH.
Test of maximum solubility:
Approximately 10 mg of Compound A, HCl are weighed. 1 mL of the medium containing the carrier to be tested, that is to say Cavitron™ W7HP5 without pH adjustment, 25 Cavitron™ W7HP5 adjusted to pH = 4 or Cavitron™ W7HP5 adjusted to pH = 7.4, is then added. The whole is then placed under magnetic stirring. Then, 5 mg of Compound A, HCl are added. The operation is repeated if the compound solubilises. The mixture is stirred for
-2024 hours. The suspension so obtained is passed through a 0.45 pm filter before being analysed by HPLC chromatography.
Results:
| Carrier | Solubility after 24 h (mg/mL) |
| Cavitron™ W7HP5 pH=3.8, i.e. pH not adjusted | 24.59 |
| Cavitron™ W7HP5 pH=4 | 12.99 |
| Cavitron™ W7HP5 pH=7.4 | 1.69 |
Study 2 starting from Compound A, H2SO4
The solubility of ‘Compound A, H2SO4’ was studied in the presence of a ΗΡ-βcyclodextrin as a function of the pH.
Préparation of the 20% m/v cyclodextrin solution (200 mg/mL) g of the cyclodextrin studied (Cavitron™ W7HP5) are placed in a 50 mL graduated flask. 40 mL of water are then added. The whole is placed under magnetic stirring. The 10 volume is then made up with water to 50 mL.
Solubility test:
Approximately 856.7 mg of ‘Compound A, H2SO4’ are weighed. 30 mL of the medium containing the carrier to be tested, that is to say Cavitron™ W7HP5, are then added. The whole is placed under magnetic stirring for 24 hours. The suspension so obtained is passed 15 through a 0.2 pm filter (PALL - PES membrane - diameter 25 mm) before being analysed by HPLC.
In other tests, the pH of the solution is then modified by means of 0.1 N NaOH solution until values of 4 and 8.8 are reached, before the analysis by HPLC chromatography is carried out.
-21 Results:
| Carrier | pH | Solubility after 24 h (mg/mL) |
| Cavitron™ W7HP5 | 1.86 (without adjustment) | 21.6 |
| Cavitron™ W7HP5 + 0.1N NaOH | 4.01 | 17.09 |
| Cavitron™ W7HP5 + 0.1N NaOH | 8.8 | 0.99 |
A precipitate is visually observed from pH 3.2.
Conclusion:
These results confirm that Compound A is solubilised effectively by Cavitron™ W7HP5. 5 The solubility is significantly dépendent on the pH of the solution. For ‘Compound A,
H2SO4’, précipitation is observed from pH 3.2 and becomes more marked when the pH increases. This critical pH value dépends on process parameters. Further experiments were carried out with optimized complexation and dissolution processes to define precisely the pH value for which précipitation occurs. This study is detailed in the Example 9.
EXAMPLE 3: Study of the phenomena of précipitation of Compound A formulated in various carriers when diluted in canine plasma
The objective of this study is to evaluate the possible précipitation of Compound A formulated in a ΗΡ-β-cyclodextrin (i.e. Cavitron™ W7HP5) or in a PEG400/EtOH/0.9% NaCl mixture (in the presence or absence of TPGS) in canine plasma.
The following 7 formulations were tested:
- 3 mg/mL of Compound A in a 200 mg/mL Cavitron™ W7HP5 solution in a water/0.9% NaCl mixture (70/30),
- 6 mg/mL of Compound A in a 200 mg/mL Cavitron™ W7HP5 solution in a water/0.9% NaCl mixture (70/30),
- 3 mg/mL of Compound A in a medium obtained by dilution in a glucose 5% solution for infusion (G5 solution) of a solution containing a dose of 20 mg/mL of Compound A in a 200 mg/mL Cavitron™ W7HP5 solution in a water/NaCl mixture (70/30),
- 3 mg/mL of Compound A in a PEG 400/EtOEI/0.9% NaCl mixture (40/10/50),
- 6 mg/mL of Compound A in a PEG 400/EtOH/0.9% NaCl mixture (40/10/50),
- 3 mg/mL of Compound A in a PEG 400/EtOH/0.9% NaCl/TPGS mixture (40/10/49.5/0.5),
- 6 mg/mL of Compound A in a PEG 400/EtOH/0.9% NaCl/TPGS mixture (40/10/49.5/0.5).
io Two protocols of addition of the formulations to the plasma were tested:
- 10 pL/min for 15 minutes at 37°C,
- 7.5 pL/min for 10 minutes at 37°C.
Préparation of the media containing the various carriers to be tested:
(i) 200 mg/mL cyclodextrins
Weigh 4 g of Cavitron™ W7HP5 into a 20 mL graduated flask. Add approximately 15 mL of water /0.9% NaCl mixture (70/30) v/v. The whole is placed under magnetic stirring until the components hâve dissolved completely. Make up the volume of the medium to 20 mL by adding the necessary quantity of water/0.9% NaCl and stir the whole magnetically for 10 minutes.
(ii) PEG400/EtOH/0.9% NaCl solution
Take 8 mL of PEG 400, 2 mL of éthanol and 10 mL of 0.9% NaCl. Introduce them into a 25 mL Erlenmeyer flask and place the whole under magnetic stirring for 1 hour.
(iii) PEG/EtOH/O.9% NaCl/TPGS solution
Take 8 mL of PEG 400, 2 mL of éthanol and 9.9 mL of 0.9% NaCl. Introduce them into a 25 25 mL Erlenmeyer flask and place the whole under magnetic stirring for 1 hour. Weigh
100 mg of TPGS and add it to the preceding mixture. Stir magnetically for 16 hours.
(iv) Préparation of the mixtures for the solubility test
Weigh the desired quantity of‘Compound A, H2SO4’ (X mg). Add 5 mL of the medium to be tested (Cavitron™ W7HP5, PEG/EtOH/O.9% NaCl solution, PEG/EtOH/O.9% NaCl/TPGS solution). Place the medium so obtained under magnetic stirring at ambient 5 température for 24 hours. It should be noted that, in order to préparé the 20 mg/mL solution of Compound A in cyclodextrin, it is necessary to heat the medium at 60°C for 2 hours. In the case of the solutions based on cyclodextrin, adjust the pH to 3. Pass the solutions so obtained through a 0.2 pm filter (PVDF membrane - Millipore).
| ‘Compound A, H2SO4’ (Xmg) | Theoretical concentration (mg/mL) |
| 17.04 | 3 |
| 34.09 | 6 |
| 113.6 | 20 |
For the solution prepared at 20 mg/mL, then perform dilution in G5 solution in order to obtain the final concentration of 3 mg/mL.
Dissolution in the plasma & Results
Place LO mL of plasma in a vial of suitable volume. Place the vial in an oven set at 37°C. Then:
add at 10 pL/min each solution to be tested for 15 minutes, or add at 7.5 pL/min each solution to be tested for 10 minutes.
Stir manually after adding the solution, then allow the mixture to stand.
Pass the solutions so obtained through a 0.2 pm filter (PVDF membrane - millipore).
For the 7 formulations tested, the pH measured after dilution in the plasma was between 20 7.5 and 8.
| Solutions of Compound A (concentration expressed for the free base) | Visual appearance of the medium after addition to the canine plasma | |
| 10 gL/min for 15 min | 7.5 gL/min for 10 min | |
| 3 mg/mL in 200 mg/mL Cavitron™ W7HP5 | no précipitation | no précipitation |
| 6 mg/mL in 200 mg/mL Cavitron™ W7HP5 | précipitation observed after 8 min | no précipitation |
| 3 mg/mL in 200 mg/mL Cavitron™ W7HP5 in G5 | no précipitation | no précipitation |
| 3 mg/mL in a PEG 400/EtOH/0.9% NaCl mixture | immédiate précipitation | immédiate précipitation |
| 6 mg/mL in a PEG 400/EtOH/0.9% NaCl mixture | immédiate précipitation | immédiate précipitation |
| 3 mg/mL in a PEG 400/Et01I/0.9% NaCl/TPGS mixture | précipitation | précipitation |
| 6 mg/mL in a PEG 400/EtQH/0.9% NaCl/TPGS mixture | précipitation | précipitation |
Whatever the protocol of addition applied, précipitation is observed for ail the following samples:
- PEG/EtOH/O.9% NaCl 3 and 6 mg/mL
- PEG/EtOH/O.9% NaCl/TPGS 3 and 6 mg/mL
This précipitation is immédiate in the samples without TPGS and appears slightly later for those containing TPGS.
Précipitation is observed from 8 minutes with the protocol of addition at 10 pL/min for 15 minutes with the solution of Cavitron™ W7HP5 containing a dose of 6 mg/mL of active ingrédient.
No précipitation is observed visually for the other tests in which Compound A is formulated in Cavitron™ W7HP5.
EXAMPLE 4: Study of the physical stability of lyophilisâtes made from Compound A 5 and a ΗΡ-β-cyclodextrin in the presence or absence of other excipients
Préparation of 20% cyclodextrin solutions containing a dose of 20 mg/mL of Compound A, in the absence or in the presence of glucose
In a 100 mL flask, introduce 20 g of Cavitron™ W7HP5 and 2.26 g of ‘Compound A, H2SO4’. Heat the whole at 60°C under vigorous magnetic stirring until solubilisation of the 10 components of the mixture is complété. Allow to return to ambient température, transfer to a beaker and then measure the pH. Adjust the pH to 3 with 0.5 N NaOH solution. Where applicable, add 1.2 g of anhydrous glucose.
Make up the volume with water to 100 mL. Then check the pH and the osmolality. Filter the solution obtained through a cellulose syringe filter. The solutions so obtained (with or 15 without glucose) are then lyophilised.
Préparation of 20 % cyclodextrin solutions containing a dose of 15 mg/mL of Compound A, in the absence or in the presence of different sugars including glucose, mannitok sucrose. trehalose and sorbitol
In a 100 mL flask, introduce 20 g of Cavitron™ W7HP5 and 1.70 g of ‘Compound A, 20 H2SO4’. Heat the whole at 60°C under vigorous magnetic stirring until solubilisation of the components of the mixture is complété. Allow to return to ambient température, transfer to a beaker and then measure the pH. Adjust the pH to 4.0 with 1.0 N NaOH solution. Where applicable, add 1.0 or 2.0 g of anhydrous glucose, mannitol, sucrose, trehalose or sorbitol. Make up the volume with water to 100 mL. Then check the pH and the osmolality. Filter 25 the solution obtained through a cellulose syringe filter. The solutions so obtained (with or without glucose) are then lyophilised.
Results
The osmolality of the solutions containing between 10 to 20 mg/mL of glucose, mannitol, sucrose, trehalose or sorbitol is greater than 400 mOsm/kg, while that of the solutions
-26without glucose is approximately 300 mosm/kg. The fact of omitting the glucose from the formulation reduces the osmolality significantly. However, the osmolality of the solutions without glucose is acceptable for the purpose of parentéral administration.
The lyophilisâtes obtained, with and without glucose, mannitol, sucrose, trehalose or 5 sorbitol, hâve robust physical properties, namely a good cake appearance and an acceptable reconstitution time.
Conclusions
This study shows that the presence of glucose, mannitol, sucrose, trehalose or sorbitol is not essential in the formulation of the lyophilisâtes, which allows the risks of dégradation io associated with this excipient to be overcome. Additional tests in the presence of 5% glucose or 5% mannitol in solutions containing a dose of 20 mg/mL of Compound A and 200 mg/mL of ΗΡ-β-cyclodextrin did not resuit in an improvement in the physical properties of the lyophilisâtes.
EXAMPLE 5: Préparation of lyophilisâtes of Compound A solubilised in a ΗΡ-β15 cyclodextrin in 20m L vials
The lyophilisâtes are prepared in 20 mL vials in which it will be possible to reconstitute the solution to be administered by the parentéral route. They are obtained by lyophilisation of a 20% Cavitron™ W7HP5 solution containing a dose of 20 mg/mL of Compound A (free base).
2o Procedure
In a 5 L reactor, weigh 1500 g of water. With magnetic stirring, create a vortex and then pour in 600 g of Cavitron™ W7HP5. Stir the medium at ambient température until the cyclodextrin is solubilised completely, and add 68.16 g of‘Compound A, H2SO4’ and heat the solution to not more than 60 °C. Place the suspension under magnetic stirring for 25 several hours and then allow the medium to return to a température below 30°C. Measure the pH of the solution so obtained, then adjust it to pH 3.0 with 0.5M NaOH solution poured slowly. Make up the solution to a volume of 3 L by adding water, while maintaining magnetic stirring.
Pass the solution so obtained through a 0.2 qm fdter.
-Tl Fill the 20 mL vials with the filtered solution so that each vial contain at least 150 mg of Compound A (expressed as free base) and subject the samples to a lyophilisation step.
The resulting lyophilisate is intended to be used for the préparation of a pharmaceutical composition for parentéral administration. Further experiments show that the pH of the 5 pharmaceutical compositions dosed at 20 mg/mL of Compound A after reconstitution in water starting from the above lyophilisate is mostly identical to the pH of the solution observed before the lyophilisation step, i.e. comprised between 2.9 and 3.1. Consequently the pH spécification of the drug product has been set up between 2.5 and 3.5.
EXAMPLE 6: Stability of the solutions of Compound A when diluted in 250 mL of io glucose 5% solution (G5)
The aim of this study is to détermine the pH for 7 different concentrations of Compound A solubilised in Cavitron™ W7H5 and diluted in a bag of 250 mL of glucose 5% (G5 solution), and then to check visually that there has been no précipitation at the different concentrations tested (12 mg, 25 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1 g of active 15 ingrédient in 250 mL of G5). The Compound A used is in the form of a hydrogen sulfate sait. Invisible particulate contamination of the solutions was also controlled by light obscuration technique.
Procedure
A mother solution containing a dose of 200 mg/mL of Cavitron™ W7H5 and 20 mg/mL of 20 Compound A (expressed for the free base) is prepared by dissolving a lyophilisate as described in Example 5 in the necessary amount of water. The solution so obtained is then diluted by means of glucose 5% solution (G5).
The pH of the solutions obtained is measured and the appearance of the solutions is observed. The pH is increased using NaOH 0.0 IN solution until a précipitation is 25 observed.
Results
The pH of G5 solution is between 3.02 and 4.353.
| mg of Compound A in 250 mL of G5 | pH | Appearance of the solution after 15 min | Précipitation pH (by light obscuration technique) | Précipitation pH (by visual observation) |
| 12 | 3.7-4.310 | clear | 5.4 | 8.609 |
| 25 | 3.9-4.240 | clear | 4.8 | 5.220 |
| 50 | 3.8-4.158 | clear | 4.5 | 5.143 |
| 100 | 3.8-4.033 | clear | 4.3 | 4.872 |
| 250 | 3.7 -3.809 | clear | 4.1 | 4.388 |
| 500 | 3.5-3.613 | clear | 4.0 | 4.378 |
| 1000 | 3.3-3.401 | clear | 4.0 | 4.254 |
The solutions of Compound A solubilised by means of a Cavitron™ W7H5 solution do not precipitate when diluted in G5 solution for concentrations between 12 and 1000 mg/250 mL of G5 solution. Compound A as formulated in the présent invention can therefore be reconstituted in water and diluted in a bag of 250 mL of glucose 5% over a 5 wide range of concentrations before being administered by the parentéral route.
Moreover, studies of physical stability over time (24 h, 48 h and 72 h) are carried out on the solutions obtained hereinbefore. In particular, these studies include the particle count of the tested solutions in accordance with the method described in the text of the European Pharmacopoeia 2.9.19. Tests l.B (i.e. counting of the sub-visible particles by light io obscuration).
Studies of Chemical stability over time (24 h, 48 h and 72 h) are also put in place in order to ensure the stability of the product under laboratory light (1500 lux) and various heat conditions (ambient température, 5°C). These studies include especially measurements of the amount of active ingrédient and dégradation products. Pharmaceutical compositions of 15 Compound A solubilised by means of a Cavitron™ W7H5 solution diluted in G5 solution were tested for the following concentrations: 12 mg/250 mL, 20 mg/250 mL and 1000 mg/250 mL of G5 solution. No significant Chemical dégradation product was observed in ail the conditions tested during 72 h. Furthermore, the rate of sub-visible
-29particles detected using the light obscuration method was in accordance with the requirement of the European Pharmacopoeia 2.9.19. In conclusion, the above pharmaceutical compositions are stable in the relevant conditions and containers for enabling the administration of an appropriate dose of Compound A over a reasonable 5 timescale.
EXAMPLE 7; Efficacy of Compound A formulated in a ΗΡ-β-cyclodextrin in RS4;11 xenograft model in mice using a once a week intravenous administration schedule
The in vivo therapeutic effect of Compound A formulated in a solution comprising 20 % of a ΗΡ-β-cyclodextrin w/v, was determined in the RS4;11 model after intravenous io administration.
Material and method
RS4;11 cell line, obtained from ATCC, were subcutaneously injected into female SCID mice, provided by Charles River. When tumors reached the appropriate tumor volume, mice were randomized using Easy stat software. Compound A (15 mg/kg or 40 mg/kg 15 expressed as free base) was injected i.v. once a week over two weeks.
Préparation of the solutions for injection:
In a 100 mL flask, introduce 20 g of Cavitron™ W7HP5 and add around 75 mL of a solution water/0.9% NaCl (70/30, v/v). Stir for 15 minutes at room température. Then, make up the solution to a volume of 100 mL by adding the previous solution water/0.9% 20 NaCl, while maintaining magnetic stirring. Weigh the necessary amount of ‘Compound A, H2SO4’ and dissolve it with the previous 20% w/v Cavitron™ W7H5 solution. Heat the whole at 60°C under vigorous magnetic stirring until solubilisation of the components of the mixture is complété. Measure the pH of the solution obtained. Adjust the pH to 3 by adding drop by drop, either HCl 0.1N or NaOH 0.1N, depending on the concentration of 25 Compound A. Stir the mixture at least for 1 hour. Filtrate the obtained solution with a 0.2 pm-filter.
A 20% w/v Cavitron™ W7H5 solution containing a dose of 4 mg/mL of Compound A was prepared following this procedure. A second solution containing a dose of 1.5 mg/mL of
Compound A was also prepared by diluting further the previous solution with the 20% w/v Cavitron™ W7H5 solution.
Mice were monitored for tumor development and body weight three times a week and tumor size was measured using electronic calipers. Tumor volume was estimated by 5 measuring the minimum and maximum tumor diameters using the formula: (minimum diameter)2(maximum diameter)/2. The last day with ail control animais still présent in the study, tumor growth inhibition was calculated using the formula: f Médian (DTV at Dx in treatedgroup) Ί
1--IX 1UU
Q Médian (DTV at Dx in Controlgroup)) wherein ‘DTV (Delta Tumor Volume) at Dx’ is calculated as follows: io TV at Dx - TV at Randomization ‘TV’ means ‘Tumor Volume’.
Mice were sacrificed at the first measurement for which tumor volume exceeded 2000 mm3 or animal health détérioration. Ail experiments were conducted in accordance with the French régulations in force in 2018. SCID mice were maintained according to 15 institutional guidelines.
Results
Compound A, formulated in a 20 % ΗΡ-β-cyclodextrin solution and administrated intravenously once a week for 2 weeks was shown to hâve antitumor activity at 15 mg/kg and 40 mg/kg on RS4;11 grafted female SCID mice (Figure 1). At the end of the study, at 20 day 21, tumor growth inhibitions were 57.83% at 15 mg/kg and 75.52% at 40 mg/kg, with an exposure of 20463 ng.h/ml and 46509 ng.h/ml respectively. The Cmax increased dose proportionally from 14692 ng/ml to 23290 ng/ml (Table 1).
-31 Table 1: PK parameters measured for RS4;11 grafted female SCIP mice after one i.v. treatment of‘Compound A, H2SO4’ formulated in a 20 % ΗΡ-β-cyclodextrin solution at 15 mg/kg and 40 mg/kg.
| Dose of Compound A (i.v. administration) | 15 mg/kg | 40 mg/kg |
| Co (ng/mL) | 14692 | 23290 |
| Ciast (ng/mL) | 58.4 | 457 |
| tlast (h) | 6 | 6 |
| tl/2,z (h) | 0.760 | 1.10 |
| AUCt (ng.h/mL) | 20399 | 45782 |
| AUC (ng.h/mL) | 20463 | 46509 |
| AUCt/Dose | 1360 | 1145 |
‘AUCt’ corresponds to the area under the observed blood concentration versus time curve 5 from the time of administration to the last point.
No clinically relevant body weight loss due to treatment was observed (Figure 2) over the study and mice did not hâve other clinical signs including necrosis for most ofthe mice. In conclusion, based on body weight changes both dosing regimens of the cyclodextrin-based formulation were well tolerated.
EXAMPLE 8: Clinical Trial Protocol
A phase I, open label, non-randomised, non-comparative, multi-center study, was set up to evaluate Compound A intravenously administered, in patients with Relapse or Refractory Acute Myeloid Leukaemia, Non Hodgkin Lymphoma or Multiple Myeloma. Approximately 60 patients will be enrolled in the study. This study is designed in two 15 parts: part one for dose escalation, part two for dose expansion.
-32Primary objectives:
Détermine the safety profile (including Dose Limiting Toxicity (DLT) and Maximum Tolerated Dose (MTD(s)) and tolerability of Compound A in patients with Acute Myeloid Leukaemia (AML), Non Hodgkin Lymphoma (NHL) or Multiple Myeloma (MM) and the 5 recommended phase II dose (RP2D(s)) according to safety, PK and preliminary efficacy results.
Secondary objectives:
- To détermine the pharmacokinetic (PK) profile of Compound A in plasma and in urine.
- To assess the preliminary anti-tumour activity of Compound A using the appropriate io response criteria for each evaluated population (AML, NHL, MM).
Test drug:
- Compound A will be administered via i.v. infusion via a central or peripheral venous line.
- Solution for infusion will be prepared using a 20 mL vials containing 150 mg of 15 Compound A (expressed as free base) formulated with a ΗΡ-β-cyclodextrin as described in Example 5.
- Duration of infusion, based on preliminary Safety and PK data, could be adapted.
Dose allocation methodology:
A Bayesian Hierarchical Model (BHM), combined for ail indications and guided by an 20 escalation with overdose control (EWOC) method, will be used to guide dose escalation and estimate the MTD(s) based on the occurrence of DLT during Cycle 1.
Altematively, an adaptative Bayesian Logistic Régression Model (BLRM) guided by an escalation with overdose control (EWOC) method, will be used to make dose recommendations based on the occurrence of DLT(s) during Cycle 1 and estimate the 25 MTD(s)/RP2D(s) for the Compound A administered as a single agent.
-33Treatment period:
The planned duration of treatment is until disease progression. Patients may be discontinued from treatment with the study drug earlier due to unacceptable toxicity and/or treatment is discontinued at the discrétion of the investigator or the patient.
EXAMPLE 9: Investigation of the pH of précipitation of Compound A by addition of NaOH to a ΗΡ-β-cyclodextrin solution
The objective of this study is to defrne the pH of précipitation of Compound A (hydrogen sulfate sait) from ΗΡ-β-cyclodextrin solution to better understand the risk of précipitation io and select the pH of the drug product.
Préparation of solution containing ΗΡ-β-cyclodextrin and Compound A
Weigh 10 g of Cavitron™ W7H5 in a 50 mL flask. Add 26 g of water and then solubilize the Cavitron™ W7H5 under magnetic agitation. Carefully add 1.14 g of Compound A under magnetic agitation and then add 6.5 mL of water. Solubilize Compound A using magnetic agitation at 60 °C. Once totally solubilized, cool down the solution at room température then rinse the upper edges of the flask with 0.5 mL of water. The total amount of water added is 35 mL.
PH adjustment using 0.5M NaOH solution
Slowly add 0.5M NaOH solution under continuous agitation (add 100 pL at each addition step) up to a précipitation is visually observed. The experiment was performed in duplicate. The precipitated solid is separated and dried to be analyzed by RMN, XRPD, XRF, and HPLC.
Results
Drug précipitation was observed at pH 4.27. The volume of added NaOH corresponded to 5 % of final bulk solution volume when reaching pH 3.0 and corresponded to 6 % of final bulk solution volume when reaching pH 4.27.
Based on this resuit, the pH of the pharmaceutical composition could be increased up to 4.3.
-34The NMR and XRPD results showed that Compound A precipitated as free base in amorphous form in the presence of ΗΡ-β-cyclodextrin at a molar ratio of 1 : 1.4. The HPLC resuit suggested that the precipitate was composed by 25 % w/w Compound A without the presence of additional impurities, which is in agreement with Compound 5 A:HP-P-cyclodextrin ratio found by NMR.
Claims (43)
1. A solid pharmaceutical composition comprising Compound A which is 5-(5-chloro-2{[(35)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l/7)-yl]carb°nyl} phenyl)-A-(5cyano-l,2-dimethyl-17/-pyrrol-3-yl)-A-(4-hydroxyphenyl)-l,2-dimethyl-177-pyrrole-3carboxamide, or a pharmaceutically acceptable sait thereof, and a cyclodextrin.
2. A solid pharmaceutical composition according to claim 1, wherein Compound A is in the form of the hydrochloride sait.
3. A solid pharmaceutical composition according to claim 1, wherein Compound A is in the form of a hydrogen sulfate sait.
4. A solid pharmaceutical composition according to any of claims 1 to 3, wherein the cyclodextrin is a sodium sulfobutylether-3-cyclodextrine (SBE- β-cyclodextrin) or a hydroxypropyl- β-cyclodextrin (HP- β-cyclodextrin).
5. A solid pharmaceutical composition according to claim 4, wherein the molar ratio between the HP- β-cyclodextrin and Compound A is at least 5:1.
6. A solid pharmaceutical composition according to claim 5, wherein the molar ratio between the HP- β-cyclodextrin and Compound A is 5 : 1.
7. A solid pharmaceutical composition according to any of claims 4 to 6, wherein the ΗΡ- β-cyclodextrin is Cavitron™ W7HP5.
8. A solid pharmaceutical composition according to any of claims 4 to 6, wherein the ΗΡβ-cyclodextrin is Kleptose™ HPB.
9. A solid pharmaceutical composition according to any of claims 1 to 8, further comprising one or more pharmaceutically acceptable excipients.
10. A solid pharmaceutical composition according to any of claims 1 to 8, comprising at least one pharmaceutically acceptable excipients selected from glucose, mannitol, sucrose, trehalose and sorbitol.
11. A solid pharmaceutical composition according to any of claims 1 to 10, which is a lyophilisate.
12. A pharmaceutical composition comprising Compound A which is 5-(5-chloro-2-{[(35')3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(lH)-yl]carbonyl}phenyl)-A-(5-cyanol,2-dimethyl-lH-pyrrol-3-yl)-?Z-(4-hydroxyphenyl)-l,2-dimethyl-l//-pyrrole-3carboxamide, or a pharmaceutically acceptable sait thereof, a cyclodextrin and one or more solvents.
13. The pharmaceutical composition according to claim 12 wherein the solvent is an aqueous buffer or water, and more particularly water.
14. The pharmaceutical composition according to claim 12 or 13, wherein Compound A is in the form of the hydrochloride sait.
15. The pharmaceutical composition according to claim 12 or 13, wherein Compound A is in the form of a hydrogen sulfate sait.
16. The pharmaceutical composition according to claim 15, having a pH value comprised between 2.5 and 4.3, more particularly the pH value is comprised between 2.5 and 3.5.
17. The pharmaceutical composition according to any of claims 12 to 16, wherein the cyclodextrin is a sodium sulfobutylether-β-cyclodextrin (SBE- β-cyclodextrin) or a hydroxypropyl- β-cyclodextrin (HP- β-cyclodextrin).
18. The pharmaceutical composition according to claim 17, wherein the HP- β-cyclodextrin is Cavitron™ W7HP5 or Kleptose™ HPB.
19. The pharmaceutical composition according to claim 18, wherein the molar ratio between the HP- β-cyclodextrin and Compound A is at least 5:1.
20. The pharmaceutical composition according to claim 19, wherein the molar ratio between the HP- β-cyclodextrin and Compound A is 5 : 1.
21. The pharmaceutical composition according to any of claims 17 to 19, wherein the ΗΡβ-cyclodextrin is Cavitron™ W7HP5.
5
22. The pharmaceutical composition according to any of claims 17 to 19, wherein the ΗΡ- β-cyclodextrin is Kleptose™ HPB.
23. The pharmaceutical composition according to any of claims 17 to 22 having a concentration of 200 mg/mL of HP- β-cyclodextrin.
24. The pharmaceutical composition according to any of claims 17 to 22 having a 10 concentration of 20 mg/mL of Compound A, free base.
25. The pharmaceutical composition according to any of claims 12 to 24, further comprising a tonicity adjusting agent.
26. The pharmaceutical composition according to claim 25, wherein the tonicity adjusting agent is selected from glucose, mannitol, sucrose, trehalose and sorbitol.
15
27. The pharmaceutical composition according to claim 12 comprising ‘Compound A,
H2SO4’, Cavitron™ W7HP5, and having a pH value comprised between 2.5 and 4.3, more particularly the pH value is comprised between 2.5 and 3.5.
28. The pharmaceutical composition according to claim 12 comprising ‘Compound A, H2SO4’, Cavitron™ W7HP5, water and glucose, and having a pH value comprised between 20 2.5 and 4.4, more particularly the pH value is comprised between 3.3 and 4.4.
29. The pharmaceutical composition according to any of claims 12 to 28, for parentéral administration.
30. The pharmaceutical composition according to claim 29, for infusion or intravenous injection.
31. A process for preparing a pharmaceutical composition according to claim 12 suitable for parentéral administration comprising the dissolution of a solid pharmaceutical composition 5 as defined in claims 1 to 11 in water.
32. A process according to claim 31 comprising an additional step of dilution with a solution of 5% Glucose.
33. A process according to claim 31 or 32, wherein the dissolution takes place immediately prior to administration to the patient.
10
34. The composition according to any of claims 12 to 30 for use in a method of modulating
Bcl-2 receptor activity in a subject.
35. The composition according to any of claims 12 to 30 for use in a method of treating cancer.
36. The composition for use according to claim 35, wherein the cancer is selected from 15 cancers of the bladder, brain, breast and utérus, chronic lymphoid leukaemias, colorectal cancer, cancers of the œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemia, lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, nonsmall-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.
37. The composition for use according to claim 36, wherein the cancer is selected from 20 non-Hodgkin's B-cell lymphoma, diffuse large B-cell lymphoma, multiple myeloma, myelodysplastic syndrome, chronic lymphoid leukaemias and acute myeloid leukaemia.
38. The composition for use according to any of claims 34 to 37, which is for administration once weekly.
39. The pharmaceutical composition according to any of claims 12 to 30 for use as a 25 médicament for treating cancer.
40. The pharmaceutical composition according to claim 39wherein the cancer is selected from cancers of the bladder, brain, breast and utérus, chronic lymphoid leukaemias, colorectal cancer, cancers of the œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemia, lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non5 small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.
41. Use of a solid pharmaceutical composition according to any of claims 1 to 11, for the préparation of a médicament to treat cancer.
42. The use according to claim 41, wherein the cancer is selected from cancers of the bladder, brain, breast and utérus, chronic lymphoid leukaemias, colorectal cancer, cancers of 10 the œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemia, lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.
43. A combination comprising:
• a pharmaceutical composition according to any of claims 12 to 30, and
15 · one or more therapeutically active agents, for simultaneous, sequential or separate use.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US62/753,164 | 2018-10-31 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| OA20228A true OA20228A (en) | 2022-03-18 |
Family
ID=
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2019373373B2 (en) | Cyclodextrin-based formulation of a Bcl-2 inhibitor | |
| US20170224662A1 (en) | Aqueous Formulations and Methods of Preparation and Use Thereof | |
| TW200829571A (en) | Liquid preparation comprising pimobendan | |
| BR112012033077B1 (en) | pharmaceutical composition for intravenous administration, use of a pharmaceutical composition, and, kit | |
| JP6246715B2 (en) | Pharmaceutical formulation comprising brexpiprazole and substituted β-cyclodextrin | |
| US20190365720A1 (en) | Novel formulations of amidine substituted beta-lactam compounds on the basis of modified cyclodextrins and acidifying agents, their preparation and use as antimicrobial pharmaceutical compositions | |
| AU2003276689B2 (en) | Liquid stable composition of oxazaphosphorine with mesna | |
| US12097197B2 (en) | Stable liquid compositions of netupitant and palonosetron | |
| JP3597239B2 (en) | Stable eye drops | |
| OA20228A (en) | Cyclodextrin-based formulation of A BCL2 inhibitor. | |
| RU2804366C2 (en) | Composition of bcl-2 inhibitor based on cyclodextrin | |
| WO2019097413A1 (en) | Stable non-aqueous pharmaceutical compositions | |
| US20220008337A1 (en) | Pharmaceutical liquid compositions of meloxicam | |
| US20020068720A1 (en) | Solution composition of an oxazolidinone antibiotic drug having enhanced drug loading | |
| WO2005102312A1 (en) | Concentrated oxaliplatin solutions | |
| AU2001285087A1 (en) | Solution of an oxazolidinone antibiotic drug | |
| EA044714B1 (en) | COMPOSITION OF BCL-2 INHIBITOR BASED ON CYCLODEXTRIN | |
| US20040202687A1 (en) | Ciprofloxacin formulations and methods of making and using the same | |
| JP2019504042A (en) | Oral preparation and production method thereof | |
| WO2021090183A1 (en) | Liquid melphalan composition | |
| Erdoğar et al. | Cyclodextrins in drug delivery | |
| JP2005520856A (en) | Eplerenone formulation stable during storage | |
| WO2018109731A1 (en) | Pharmaceutical compositions of taxane and its derivatives | |
| IL168849A (en) | Aqueous ifosfamide compositions for parenteral administration and a process for their preparation |