ZA200201743B - Formulations for parenteral use of estramustine phosphate with pharmacological properties. - Google Patents
Formulations for parenteral use of estramustine phosphate with pharmacological properties. Download PDFInfo
- Publication number
- ZA200201743B ZA200201743B ZA200201743A ZA200201743A ZA200201743B ZA 200201743 B ZA200201743 B ZA 200201743B ZA 200201743 A ZA200201743 A ZA 200201743A ZA 200201743 A ZA200201743 A ZA 200201743A ZA 200201743 B ZA200201743 B ZA 200201743B
- Authority
- ZA
- South Africa
- Prior art keywords
- estramustine phosphate
- cyclodextrin
- cancer
- sulfoalkyl ether
- human albumin
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims description 67
- ADFOJJHRTBFFOF-RBRWEJTLSA-N estramustine phosphate Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)OP(O)(O)=O)[C@@H]4[C@@H]3CCC2=C1 ADFOJJHRTBFFOF-RBRWEJTLSA-N 0.000 title claims description 66
- 238000009472 formulation Methods 0.000 title claims description 65
- 229960004750 estramustine phosphate Drugs 0.000 title claims description 63
- 230000000144 pharmacologic effect Effects 0.000 title description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 55
- 229920000858 Cyclodextrin Polymers 0.000 claims description 54
- 239000000243 solution Substances 0.000 claims description 47
- 102000008100 Human Serum Albumin Human genes 0.000 claims description 42
- 108091006905 Human Serum Albumin Proteins 0.000 claims description 42
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims description 31
- 125000004964 sulfoalkyl group Chemical group 0.000 claims description 25
- NZAQRZWBQUIBSF-UHFFFAOYSA-N 4-(4-sulfobutoxy)butane-1-sulfonic acid Chemical compound OS(=O)(=O)CCCCOCCCCS(O)(=O)=O NZAQRZWBQUIBSF-UHFFFAOYSA-N 0.000 claims description 20
- 238000001990 intravenous administration Methods 0.000 claims description 14
- 238000002347 injection Methods 0.000 claims description 12
- 239000007924 injection Substances 0.000 claims description 12
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical class CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 8
- 239000002246 antineoplastic agent Substances 0.000 claims description 7
- 229940127089 cytotoxic agent Drugs 0.000 claims description 7
- 239000003085 diluting agent Substances 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
- 238000001802 infusion Methods 0.000 claims description 6
- -1 sulfoalkyl ether Chemical compound 0.000 claims description 6
- 238000011282 treatment Methods 0.000 claims description 6
- 229960001842 estramustine Drugs 0.000 claims description 5
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 4
- 238000007911 parenteral administration Methods 0.000 claims description 4
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 206010033128 Ovarian cancer Diseases 0.000 claims description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 3
- 206010060862 Prostate cancer Diseases 0.000 claims description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 3
- 208000025865 Ulcer Diseases 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 3
- 201000001441 melanoma Diseases 0.000 claims description 3
- 201000002528 pancreatic cancer Diseases 0.000 claims description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- WUWDLXZGHZSWQZ-WQLSENKSSA-N semaxanib Chemical compound N1C(C)=CC(C)=C1\C=C/1C2=CC=CC=C2NC\1=O WUWDLXZGHZSWQZ-WQLSENKSSA-N 0.000 claims description 3
- 201000005060 thrombophlebitis Diseases 0.000 claims description 3
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 claims description 2
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 claims description 2
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 claims description 2
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 claims description 2
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 229940123237 Taxane Drugs 0.000 claims description 2
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 claims description 2
- 238000011319 anticancer therapy Methods 0.000 claims description 2
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 claims description 2
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims description 2
- 229940127093 camptothecin Drugs 0.000 claims description 2
- 229960004562 carboplatin Drugs 0.000 claims description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 2
- 229960004316 cisplatin Drugs 0.000 claims description 2
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 claims description 2
- 229960004679 doxorubicin Drugs 0.000 claims description 2
- 229960001904 epirubicin Drugs 0.000 claims description 2
- 229960005420 etoposide Drugs 0.000 claims description 2
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 claims description 2
- 229960000908 idarubicin Drugs 0.000 claims description 2
- 230000003902 lesion Effects 0.000 claims description 2
- 229940086322 navelbine Drugs 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 229960003048 vinblastine Drugs 0.000 claims description 2
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 claims description 2
- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 claims description 2
- 208000003174 Brain Neoplasms Diseases 0.000 claims 2
- 206010028980 Neoplasm Diseases 0.000 claims 2
- 201000011510 cancer Diseases 0.000 claims 2
- 239000002552 dosage form Substances 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- 241000700159 Rattus Species 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- VNDHXHMRJVTMTK-WZVRVNPQSA-H hexasodium 4-[[(1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,36R,37R,38R,39R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R)-36,37,38,39,40,41,42,43,44,45,46,47,48,49-tetradecahydroxy-10-(hydroxymethyl)-15,20,25,30,35-pentakis(4-sulfonatobutoxymethyl)-2,4,7,9,12,14,17,19,22,24,27,29,32,34-tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan-5-yl]methoxy]butane-1-sulfonate Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].OC[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@H](O[C@@H]3COCCCCS([O-])(=O)=O)O[C@H]3[C@H](O)[C@@H](O)[C@H](O[C@@H]3COCCCCS([O-])(=O)=O)O[C@H]3[C@H](O)[C@@H](O)[C@H](O[C@@H]3COCCCCS([O-])(=O)=O)O[C@H]3[C@H](O)[C@@H](O)[C@H](O[C@@H]3COCCCCS([O-])(=O)=O)O[C@H]3[C@H](O)[C@@H](O)[C@H](O[C@@H]3COCCCCS([O-])(=O)=O)O[C@H]3[C@H](O)[C@@H](O)[C@H](O[C@@H]3COCCCCS([O-])(=O)=O)O[C@H]1[C@H](O)[C@H]2O VNDHXHMRJVTMTK-WZVRVNPQSA-H 0.000 description 5
- 229940097362 cyclodextrins Drugs 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 230000000622 irritating effect Effects 0.000 description 4
- 238000005063 solubilization Methods 0.000 description 4
- 230000007928 solubilization Effects 0.000 description 4
- 102000009027 Albumins Human genes 0.000 description 3
- 108010088751 Albumins Proteins 0.000 description 3
- XCRFEYAXJYXVHT-HLZMRHSNSA-N CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)OP(O)(O)=O)[C@@H]4[C@@H]3CCC2=C1 Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)OP(O)(O)=O)[C@@H]4[C@@H]3CCC2=C1 XCRFEYAXJYXVHT-HLZMRHSNSA-N 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 238000010253 intravenous injection Methods 0.000 description 3
- 238000003760 magnetic stirring Methods 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- 239000008215 water for injection Substances 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 239000002254 cytotoxic agent Substances 0.000 description 2
- 231100000599 cytotoxic agent Toxicity 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000013020 final formulation Substances 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 231100000161 signs of toxicity Toxicity 0.000 description 2
- 239000008223 sterile water Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 229940123587 Cell cycle inhibitor Drugs 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 229940123780 DNA topoisomerase I inhibitor Drugs 0.000 description 1
- 229940124087 DNA topoisomerase II inhibitor Drugs 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 description 1
- 239000000317 Topoisomerase II Inhibitor Substances 0.000 description 1
- 102000004243 Tubulin Human genes 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 230000002942 anti-growth Effects 0.000 description 1
- 238000011394 anticancer treatment Methods 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000003886 aromatase inhibitor Substances 0.000 description 1
- 229940046844 aromatase inhibitors Drugs 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-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 1
- 239000011230 binding agent Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000009104 chemotherapy regimen Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000011970 concomitant therapy Methods 0.000 description 1
- 229940111134 coxibs Drugs 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940125697 hormonal agent Drugs 0.000 description 1
- 239000000677 immunologic agent Substances 0.000 description 1
- 229940124541 immunological agent Drugs 0.000 description 1
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical class C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002599 prostaglandin synthase inhibitor Substances 0.000 description 1
- 201000005825 prostate adenocarcinoma Diseases 0.000 description 1
- 239000003528 protein farnesyltransferase inhibitor Substances 0.000 description 1
- 239000003909 protein kinase inhibitor Substances 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000003277 telomerase inhibitor Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 230000003966 vascular damage Effects 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
Classifications
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/38—Albumins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Endocrinology (AREA)
- Pulmonology (AREA)
- Reproductive Health (AREA)
- Dermatology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
FORMULATIONS FOR PARENTERAL USE OF ESTRAMUSTINE PHOSPHATE
WITH IMPROVED PHARMACOLOGICAL PROPERTIES
The present invention relates to pharmaceutical formulations of estramustine phosphate for parenteral use with improved pharmacological properties and, more particularly, to formulations of estramustine phosphate for parenteral use further comprising sulfoalkyl ether cyclodextrins and human albumin.
Estramustine phosphate (The Merck Index, XII Ed., No. 3749, 1996) is an estradiol-17f-phosphate derivative widely known in the art as antitumor agent, currently used in the treatment of advanced adenocarcinoma of the prostate.
The drug is usually administered orally, preferably at a dose of 10-15 mg/kg/day. Intravenous administration, however, is also adopted in some particular cases.
For example, initial intravenous administration of estramustine phosphate, followed by oral administration, ) has been reported at dosages paralleling the oral administration for the drug, i.e. 300-600 mg daily given intravenously and usually repetitively over for several consecutive days (see, for a reference, British Journal of
Urology, 1977, 49, 73-79; J. Urol.108:303-306, 1972; Eur. .
Clin. Pharmacol. 26(1), 113-119, 1984; Eur. Urol. 1990, 17, 216-218).
Estramustine phosphate as well as other well-known cytotoxic compounds used in antitumor therapy are known to cause, or potentially cause, vascular damages at the site of injection when parenterally, in particular intravenously, administered.
As an example, studies in patients treated with estramustine phosphate administered as a slow intravenous injection or as a bolus, at 300 mg/day, revealed thrombophlebitis and local irritations at the peripheral intravenous injection sites.
These drawbacks are considered major limitations for the intravenous administration of estramustine phosphate, thus requiring, in many patients, the establishment of central line administration or, in some cases, even discontinuation of the treatment.
With the aim of minimising the unwanted effects associated with the intravenous administration of cytotoxic agents, a few means are reported in the art.
Among them is the use of cyclodextrins, for instance hydroxypropyl-cyclodextrin, in the preparation of formulations for parenteral administration of cytotoxic known to cause ulcerative lesions. See, for a reference, US patent No. 5,804,568 in the name of Supergen Inc.
Cyclodextrin derivatives such as sulfoalkyl ether cyclodextrins are known in the art as solubilizing agents for insoluble or poorly soluble drugs (see, for a reference, US 5,134,127 in the name of the University of
Kansas) .
Also known in the art are formulations for the intravenous administration of estramustine phosphate containing human albumin, reported to be characterised by fewer local side- effects upon injection of the active (see, for a reference, : H. Schutz et al.; Krankenhauspharmazie, II year, issue No. 3, 1988).
In this respect, we found formulations for parenteral use comprising estramustine phosphate together with sulfoalkyl ether cyclodextrins and human albumin which, unexpectedly, resulted to achieve optimal protection from side-effects associated with estramustine administration.
It is therefore the object of the present invention a formulation for parenteral use comprising estramustine phosphate in admixture with a sulfoalkyl ether cyclodextrin and human albumin.
Once administered intravenously to patients, the formulations object of the present invention do not provoke ulcerative damages, nor thrombophlebitis, at the site of injection.
Very interestingly, the estramustine phosphate formulations of the invention result to be endowed with unexpected pharmacological properties, expressed in terms of toxicity at the site of injection, markedly improved with respect to formulations containing, as a single protective excipient, a sulfoalkyl ether cyclodextrin or, alternatively, human albumin.
In the present invention, unless otherwise specified, with _— the term formulation comprising estramustine phosphate, as the active ingredient, we intend any formulation comprising estramustine phosphate either in the acid form or as a pharmaceutically acceptable salt for parenteral administration such as, for instance, a salt with a basic ) amino acid or with N-methyl glucamine, otherwise referred to as meglumine. ’
Preferably, estramustine phosphate is in the form of its meglumine salt.
With the term sulfoalkyl ether cyclodextrin we refer to any . cyclodextrin of the above type wherein alkyl stands for straight or branched C,-C, alkyl group such as methyl, ethyl, n.propyl, isopropyl, n.butyl, isobutyl, sec-butyl, tert-butyl, n.pentyl, n.hexyl and the like.
Preferably, the formulation of the present invention } comprises estramustine phosphate in admixture with - sulfobutyl ether R-cyclodextrin.
According to a preferred embodiment of the invention, the weight ratio between estramustine phosphate and sulfoalkyl i ether cyclodextrin is comprised from about 1:0.5 to about 1:5, respectively.
However, higher amounts of sulfoalkyl ether cyclodextrin with respect to the active are sill effective and hence comprised within the scope of the present invention.
According to another preferred embodiment of the invention, the above formulations are advantageously used for intravenous use.
As such, these formulations of the invention can be administered to patients either as a slow injection, e.g. over about 30 minutes to about 3 hours, or as a bolus injection, also referred to as IV (intravenous) push.
In another preferred embodiment of the invention either (i) the estramustine phosphate is in lyophilised form and the parenterally acceptable carrier or diluent is a i physiological solution for parenteral use containing the sulfoalkyl ether cyclodextrin and the human albumin, or (ii) the estramustine phosphate and sulfoalkyl ether cyclodextrin are in lyophilised form and the ) parenterally acceptable carrier or diluent is a physiological solution for parenteral use containing the human albumin.
The invention also provides a product which comprises estramustine phosphate in lyophilised form and a physiological solution for parenteral use containing human albumin.
The formulations of the invention also provide a very advantageous method for delivering estramustine phosphate intravenously, even when high doses of the active are needed.
It is therefore a further object of the invention a formulation for parenteral use comprising estramustine phosphate, as a single infusion dosage of the active exceeding 1300 mg, in admixture with a sulfoalkyl ether cyclodextrin and human albumin.
According to another preferred embodiment of the invention, 5 it is further provided a formulation for parenteral use comprising estramustine phosphate, as a single infusion dosage of the active exceeding 950 mg/m’, in admixture with a sulfoalkyl ether cyclodextrin and human albumin.
The formulations object of the present invention allow the administration of the active either as a single agent or, alternatively, in combination with known anticancer treatments such as radiation therapy or chemotherapy regimen in combination with cytostatic or cytotoxic agents, antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, e.g. aromatase inhibitors, — : immunological agents, interferon-type agents, cyclooxygenase inhibitors (e.g. COX-2 inhibitors), metallomatrixprotease inhibitors, telomerase inhibitors, tyrosine kinase inhibitors, anti-growth factor receptor ) agents, anti-HER agents, anti-EGFR agents, anti- angiogenesis agents, farnesyl transferase inhibitors, ras- } raf signal transduction pathway inhibitors, cell cycle inhibitors, other cdks inhibitors, tubulin binding agents, topoisomerase I inhibitors, topoisomerase II inhibitors, and the like.
As an example, the above formulations can be administered : in combination with one or more chemotherapeutic agents, optionally within liposomal formulations thereof.
Examples of chemotherapeutic agents are, for instance, taxane, taxane derivatives, CPT-11, camptothecin and derivatives thereof, anthracycline glycosides, e.g. doxorubicin, idarubicin or epirubicin, etoposide, navelbine, vinblastine, carboplatin, cisplatin and the like, optionally within liposomal formulations thereof.
In addition, the above formulations can be also administered in combination with protein kinase inhibitors such as, for instance, the indolinone derivatives disclosed by Sugen in the international patent applications WO 96/40116 and WO 99/61422, which are herewith incorporated by reference.
In this respect, the formulations object of the invention can be preferably administered in combination with 3-[4-(2- carboxyethyl-3,5-dimethylpyrrol-2-yl)methylidenyl]-2- indolinone and 3[(2,4-dimethylpyrrol-5-yl)methylidenyl]-2- indolinone, better known as Sugen SU 6668 and SU 5416, respectively.
The formulations of the invention may be administered sequentially with known anticancer agents when a combination formulation is inappropriate.
Therefore, it is a further object of the present invention a product containing a formulation for parenteral use of estramustine phosphate in admixture with a sulfoalkyl ether cyclodextrin and human albumin and one or more chemotherapeutic agents, as a combined preparation for simultaneous, separate or sequential use in anticancer therapy.
Toxicology : To study the local irritant effects of estramustine rhosphate after repeated intravenous administrations to rats, in comparison to a formulation of estramustine phosphate according to the present invention, the active was dissolved in different vehicles such as water solution for injection and water solution for injection further containing sulfobutyl ether f-cyclodextrin and human albumin. In addition, formulations of estramustine phosphate in admixture with sulfobutyl ether fR-cyclodextrin only or, alternatively, with human albumin only, were used for comparison.
In particular, the following water for injection solutions wherein either the active estramustine phosphate (therein referred to as EMP) as well as the excipients sulfobutyl ether R-cyclodextrin and human albumin (therein referred to as SBECD and HA, respectively) are expressed in terms of weight ratios, were prepared and tested: (a) negative control: water for injection; (b) positive control: EMP; (¢) comparison: EMP: SBECD=1:1; (d) comparison: EMP:HA=1:0.21; (e) tested solution: EMP: SBECD:HA=1:1:0.21;
Male Sprague-Dawley rats were used because of their acceptance as a predictor of toxic change in man. The rats were 6 weeks old at the start of the study.
Estramustine phosphate, in the form of meglumine salt, was
To administered to groups of rats as a repeated intravenous injection during 3 days. Rats were then sacrificed: a half of the rats at the fourth day and a half at the fifth day.
The dose level of estramustine phosphate, in all the : different tested solutions, was of 150 mg/kg/day.
Clinical observations were recorded daily. Thrombophlebitic - side effects resulted in a dark bluish/blackish coloration of the tail during the treatment period.
A score system based on tail coloration and its extension . was used to evaluate the different tested formulations.
The score system considered estramustine phosphate water solution (b) as the positive control (i.e. marked toxicity). Water for injection (a) was administered to the control group as negative control (i.e. no toxicity signs). 3 Histological evaluation was carried out on the tail of the rats treated with the composition of the invention.
Estramustine phosphate in a water solution (b) induced, at the used dose, local irritant effects at the injection site after the first administration and marked toxicity signs at the end of the experiment.
Likewise, toxicity signs at the injection site were also observed for the comparison (ec) and (d) EMP solutions containing SBECD or HA, as the sole excipients.
On the contrary, no toxicity was observed with the formulation of the invention containing sulfobutyl ether R- cyclodextrin and human albumin (e).
Moreover, histological evaluation of the tail of the rats treated with the formulation (e) did not reveal any damage when compared to the tails of the control group.
In addition, the synergistic protective effect exerted by combining both SBECD and HA excipients, as per the invention, can clearly be evidenced by considering the formulation of the invention (e) in comparison to the formulations (ec) and (4d) wherein each single excipient is present in the same amount with respect to the active.
It was thus concluded that estramustine phosphate in a water solution containing sulfoalkyl ether cyclodextrin and human albumin, according to the present invention, induced markedly less local irritant effects when compared with a water solution of estramustine phosphate itself.
Even more surprisingly, the formulation of the invention produced less local irritant effects also in comparison to analogous solutions of estramustine phosphate containing sulfoalkyl ether cyclodextrin only or human albumin only.
One particularly preferred schedule for administering the . formulation of estramustine phosphate according to the invention is a single infusion given once weekly to a maximal dose of 4000 mg or 3500 mg/m’.
Another preferred schedule is the administration of a single drug infusion once every two to four weeks.
One schedule may be preferred over another in consideration of schedules with other optional concomitant therapy. These schedules may repeat in serial or as repetitive fashion.
The formulations of the present invention are useful in antitumor therapy, particularly in the treatment of prostate cancer, breast cancer, melanoma, lung cancer, pancreatic cancer, colorectal cancer, ovarian cancer and cancers of the brain.
The formulations object of the present invention are prepared according to conventional techniques adopted in the preparation of pharmaceutical forms for parenteral use.
Typically, a proper amount of estramustine phosphate, either as a dry powder or into a 1lyophilised form, is dissolved in a pharmaceutically acceptable solution for parenteral use and then admixed with a proper amount of a oo sulfoalkyl ether cyclodextrin, for instance sulfobutyl ether fR-cyclodextrin.
The above solution is then admixed with a proper amount of human albumin, either as a dry powder or as a commercially ” available solution, e.g. human albumin 25%, 20% or 5%, optionally properly diluted. ;
As an example, a proper amount of estramustine phosphate in the form of a suitable salt such as, for instance, N-methyl glucamine salt, is dissolved in a suitable amount of . sterile water or aqueous dextrose solution, e.g. 5% dextrose in water for intravenous administration, and then admixed with a proper amount of powdered sulfobutyl ether fR-cyclodextrin.
The above admixture is subsequently added with a proper
B amount of human albumin, for instance as a dry powder, and subsequently stirred, sterilised and lyophilised according to conventional techniques.
From the foregoing it is clear to the man skilled in the art that each of the ingredients of the invention such as sulfoalkyl ether cyclodextrin and human albumin, each independently as a powder or into a suitable solution, can be admixed in any order to the active, already dissolved into a proper solution or in the form of a dry powder.
Likewise, the formulations of the invention can also be prepared by admixing the active with the aforementioned ingredients already properly combined as above indicated.
The final freeze-dried formulation is then prepared and stored in vials for injection; the addition of a proper amount of sterile water or a physiological solution for parenteral use enables the preparation of the final formulation to be injected.
The above method is also suitable for preparing high dosages estramustine phosphate formulations whilst maintaining the desired weight ratio between the components.
The unit strength of the formulation to be injected
Z depended on the concentration of the active in the solution itself and, of course, on the filling volume of the vials used to prepare the final formulation.
Additionally, the formulations of the present invention may ) optionally contain pharmaceutically acceptable excipients for parenteral administration such as, for instance, bulking agents, e.g. lactose or mannitol, pH buffering . agents, anti-oxidant agents, preservative agents, tonicity adjusters and the like.
The following examples are herewith intended to better illustrate the present invention without representing any limitation to it.
Example 1
Preparation of estramustine phosphate N-methyl glucamine salt in admixture with sulfobutyl ether A8-cyclodextrin (estramustine phosphate:sulfobutyl ether £-cyclodextrin=1:1 weight ratio)
300 mg of estramustine phosphate were weighed in a beaker and dispersed by means of magnetic stirring in 5 ml of water. 120.8 mg of N-methyl-glucamine were then added under stirring to the watery dispersion of the active and, after a few minutes, a clear solution was obtained. 312.5 mg of sulfobutyl ether {Z-cyclodextrin were added, maintaining the solution under stirring till the solubilization was completed.
The solution obtained was then brought to the final volume of 10 ml with water so as to reach a final concentration of 30 mg/ml of estramustine phosphate and 31.25 mg/ml of sulfobutyl ether #-cyclodextrin (1:1 weight ratio - 1:0.25 molar ratio respectively).
A solution prepared as previously described, properly sterilized by filtration, was tested for its local vein tolerability in rats.
Example 2 ) .
The formulation described in Example 1 was also prepared by solubilization of the commercially available Estracyt®’ freeze-dried formulation containing 300 mg/vial of the ) active. The reconstitution of the formulation was made using 10 ml of a 31.25 mg/ml sulfobutyl ether R- : cyclodextrin solution so as to obtain a final concentration of 30 mg/ml of estramustine phosphate and 31.25 mg/ml of cyclodextrin (1:1 weight ratio - 1:0.25 molar ratio 3 respectively).
Example 3 )
Preparation of estramustine phosphate N-methyl glucamine salt in admixture with human albumin (estramustine . phosphate:albumin=1:0.21 weight ratio) 300 mg of estramustine phosphate were weighed in a beaker and dispersed by means of magnetic stirring in 5 ml of water. 120.8 mg of N-methyl-glucamine were then added under stirring to the watery dispersion of the active and, after a few minutes, a clear solution was obtained. 0.250 ml of a commercially available solution of human albumin at 25% concentration were added whilst maintaining the solution under stirring.
The obtained solution was then brought to the final volume of 10 ml with water so as to reach a final concentration of 30 mg/ml of estramustine phosphate and 6.25 mg/ml of human albumin (1:0.21 weight ratio respectively).
A solution prepared as previously described, properly sterilized by filtration, was tested for its local vein tolerability in rats.
Example 4
The formulation described in Example 3 was also prepared by solubilization of the commercially available Estracyt® freeze-dried formulation containing 300 mg/vial of the active. The reconstitution of the formulation was made by using 10 ml of a 6.25 mg/ml human albumin solution so as to obtain a final concentration of 30 mg/ml of estramustine rhosphate and 6.25 mg/ml of human albumin (1:0.21 weight ratio respectively). ) The albumin solution could be prepared either by dissolving in water a proper amount of human albumin as a dry powder : or by properly diluting a commercially available human albumin solution.
Example 5
Preparation of estramustine phosphate N-methyl glucamine salt in admixture with sulfobutyl ether 8-cyclodextrin and human albumin (estramustine phosphate:sulfobutyl ether R- cyclodextrin:albumin=1:1:0.21 weight ratio, respectively). 300 mg of estramustine phosphate were weighed in a beaker and dispersed by means of magnetic stirring in 5 ml of water. 120.8 mg of N-methyl-glucamine were then added under stirring to the watery dispersion of the active and, after a few minutes, a clear solution was obtained. 312.5 mg of sulfobutyl ether R-cyclodextrin were added, maintaining the solution under stirring until complete dissolution.
0.250 ml of a commercially available solution of human albumin at 25% concentration were then added, maintaining the solution under stirring.
The solution was then brought to the final volume of 10 ml with water so as to reach a final concentration of 30 mg/ml of estramustine phosphate, 31.25 mg/ml of sulfobutyl ether
R-cyclodextrin and 6.25 mg/ml of human albumin. The weight ratio between the components of the solution were as follows: estramustine phosphate: sulfobutyl ether B- cyclodextrin:human albumin 1:1:0.21 respectively.
A solution prepared as previously described, properly sterilized by filtration, was tested for its local vein tolerability in rats.
Example 6
The formulation described in Example 4 was also prepared by solubilization of the commercially available Estracyt® 7 freeze-dried formulation containing 300 mg/vial of the oo active. The reconstitution of the formulation was made by using 10 ml of a solution containing 31.25 mg/ml of sulfobutyl ether R-cyclodextrin and 6.25 mg/ml of human - albumin so as to reach a final concentration of 30 mg/ml of the active. The weight ratio between the components of the : solution were as follows: estramustine phosphate:sulfobutyl ether R-cyclodextrin:human albumin 1:1:0.21 respectively.
Claims (24)
1. Aa pharmaceutical formulation which comprises a parenterally acceptable carrier or diluent, estramustine phosphate, a sulfoalkyl ether cyclodextrin and human albumin.
2. A formulation according to claim 1 wherein the weight ratio of estramustine phosphate to the sulfoalkyl ether cyclodextrin is from about 1:0.5 to about 1:5.
3. A formulation according to claim 1 or 2 which is in single infusion dosage form comprising at least 1300 mg, of the estramustine phosphate.
4. A formulation according to any one of the preceding claims which dis in single infusion dosage form comprising at least 950 mg/m’, of the estramustine phosphate. . 20
5. A formulation according to any one of the preceding . claims wherein the sulfoalkyl ether cyclodextrin is a straight or branched c,-C, sulfoalkyl ether cyclodextrin.
6. A formulation according to «claim 5 wherein the sulfoalkyl ether cyclodextrin is sulfobutyl ether R- : cyclodextrin.
7. A formulation according to any one of the preceding claims for intravenous use.
8. A formulation according to any one of the preceding claims wherein the estramustine phosphate is in the form of a pharmaceutically acceptable salt for intravenous use.
9. A formulation according to claim 8 wherein the estramustine phosphate is in the form of N-methyl glucamine salt.
10. A formulation according to any one of the preceding claims for use in the treatment of cancer.
11. A formulation as claimed in claim 10 wherein the cancer is prostate cancer, breast cancer, melanoma, lung cancer, pancreatic cancer, colorectal cancer, ovarian cancer or cancer of the brain.
12. A formulation according to claim 1 wherein the estramustine phosphate is in admixture with the sulfoalkyl ether cyclodextrin and the human albumin. i RB
13. A formulation according to claim 1 wherein oo (1) the estramustine phosphate is in lyophilised form and the parenterally acceptable carrier or diluent is a physiological solution containing the sulfoalkyl ether . cyclodextrin and the human albumin, or (ii) the estramustine phosphate and sulfoalkyl ether - cyclodextrin are in lyophilised form and the parenterally acceptable carrier or diluent is a physiological solution containing the human albumin.
14. A product which comprises (1) a pharmaceutical formulation which comprises a ’ parenterally acceptable carrier or diluent and estramustine phosphate in admixture with a sulfoalkyl ether cyclodextrin and human albumin, and B (ii) one or more chemotherapeutic agents, ) as a combined preparation for simultaneous, separate or sequential use in anticancer therapy.
15. A product according to claim 14 wherein the sulfoalkyl ether cyclodextrin is sulfobutyl ether f-cyclodextrin.
16. A product according to claim 14 or 15 wherein the chemotherapeutic agent is selected from taxane, taxane derivatives, CcCpT-11, camptothecin and derivatives thereof, doxorubicin, idarubicin, epirubicin, etoposide, navelbine, vinblastine, carboplatin, cisplatin, Sugen SU 6668 and Sugen SU 5416.
17. A product according to claim 14 for intravenous use.
18. A product according to claim 14 for use in the treatment of prostate cancer, breast cancer, melanoma, lung cancer, pancreatic cancer, colorectal cancer, ovarian cancer or cancer of the brain.
19. A formulation as defined in claim 7 for use in } suppressing or reducing the side-effects associated - with the intravenous administration of estramustine Cm phosphate and pharmaceutically acceptable salts
. 20 thereof. oo 20. A formulation according to claim 19 wherein the side effects comprise ulcerative lesions and thrombophlebitis at the site of injection.
21. A product which comprises estramustine phosphate in lyophilised form and a physiological solution for : parenteral use containing a sulfoalkyl ether cyclodextrin and human albumin.
22. A product which comprises estramustine phosphate and sulfoalkyl ether cyclodextrin in lyophilised form and a physiological solution for parenteral use containing human albumin.
23. Use, in the manufacture of a medicament for parenteral administration, of estramustine phosphate in admixture with a sulfoalkyl ether cyclodextrin and human albumin.
24. Use according to claim 23 wherein the medicament is for intravenous administration.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9921954.5A GB9921954D0 (en) | 1999-09-16 | 1999-09-16 | Formulations for parenteral use of estramustine phosphate with improved pharmacological properties |
Publications (1)
Publication Number | Publication Date |
---|---|
ZA200201743B true ZA200201743B (en) | 2003-05-28 |
Family
ID=10861066
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ZA200201743A ZA200201743B (en) | 1999-09-16 | 2002-03-01 | Formulations for parenteral use of estramustine phosphate with pharmacological properties. |
Country Status (20)
Country | Link |
---|---|
EP (1) | EP1212040A1 (en) |
JP (1) | JP2003509355A (en) |
KR (1) | KR20020059405A (en) |
CN (1) | CN1177583C (en) |
AU (1) | AU777763B2 (en) |
BR (1) | BR0014063A (en) |
CA (1) | CA2385063A1 (en) |
CZ (1) | CZ2002943A3 (en) |
EA (1) | EA005308B1 (en) |
GB (1) | GB9921954D0 (en) |
HK (1) | HK1047227A1 (en) |
HU (1) | HUP0202621A2 (en) |
IL (1) | IL148409A0 (en) |
MX (1) | MXPA02002859A (en) |
NO (1) | NO20021306L (en) |
NZ (1) | NZ517631A (en) |
PL (1) | PL353954A1 (en) |
SK (1) | SK3452002A3 (en) |
WO (1) | WO2001019338A1 (en) |
ZA (1) | ZA200201743B (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7658913B2 (en) | 2005-11-28 | 2010-02-09 | Verrow Pharmaceuticals, Inc. | Compositions useful for reducing nephrotoxicity and methods of use thereof |
WO2012037704A1 (en) | 2010-09-21 | 2012-03-29 | Telefonaktiebolaget L M Ericsson (Publ) | Air-interface timing synchronization sharing |
WO2019094819A2 (en) * | 2017-11-09 | 2019-05-16 | Abon Pharmaceuticals, Llc | Intravenous delivery systems for chemotherapy drugs |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS59108800A (en) * | 1982-12-13 | 1984-06-23 | Japan Atom Energy Res Inst | Fine particle having guided missile action and slow-releasing function of carcinostatic agent |
KR0166088B1 (en) * | 1990-01-23 | 1999-01-15 | . | Derivatives of cyclodextrins exhibiting enhanced aqueous solubility and the use thereof |
US5602112A (en) * | 1992-06-19 | 1997-02-11 | Supergen, Inc. | Pharmaceutical formulation |
GB9419153D0 (en) * | 1994-09-22 | 1994-11-09 | Erba Carlo Spa | Estramustine formulations with improved pharmaceutical properties |
US20020039594A1 (en) * | 1997-05-13 | 2002-04-04 | Evan C. Unger | Solid porous matrices and methods of making and using the same |
-
1999
- 1999-09-16 GB GBGB9921954.5A patent/GB9921954D0/en not_active Ceased
-
2000
- 2000-08-03 AU AU68363/00A patent/AU777763B2/en not_active Ceased
- 2000-08-03 CA CA002385063A patent/CA2385063A1/en not_active Abandoned
- 2000-08-03 KR KR1020027003498A patent/KR20020059405A/en not_active Application Discontinuation
- 2000-08-03 MX MXPA02002859A patent/MXPA02002859A/en unknown
- 2000-08-03 IL IL14840900A patent/IL148409A0/en unknown
- 2000-08-03 WO PCT/EP2000/007679 patent/WO2001019338A1/en not_active Application Discontinuation
- 2000-08-03 NZ NZ517631A patent/NZ517631A/en unknown
- 2000-08-03 BR BR0014063-5A patent/BR0014063A/en not_active IP Right Cessation
- 2000-08-03 CN CNB008129525A patent/CN1177583C/en not_active Expired - Fee Related
- 2000-08-03 CZ CZ2002943A patent/CZ2002943A3/en unknown
- 2000-08-03 SK SK345-2002A patent/SK3452002A3/en unknown
- 2000-08-03 EA EA200200369A patent/EA005308B1/en not_active IP Right Cessation
- 2000-08-03 EP EP00956409A patent/EP1212040A1/en not_active Withdrawn
- 2000-08-03 JP JP2001522973A patent/JP2003509355A/en not_active Withdrawn
- 2000-08-03 PL PL00353954A patent/PL353954A1/en not_active Application Discontinuation
- 2000-08-03 HU HU0202621A patent/HUP0202621A2/en unknown
-
2002
- 2002-03-01 ZA ZA200201743A patent/ZA200201743B/en unknown
- 2002-03-15 NO NO20021306A patent/NO20021306L/en not_active Application Discontinuation
- 2002-11-26 HK HK02108529.1A patent/HK1047227A1/en unknown
Also Published As
Publication number | Publication date |
---|---|
IL148409A0 (en) | 2002-09-12 |
HUP0202621A2 (en) | 2002-12-28 |
CA2385063A1 (en) | 2001-03-22 |
JP2003509355A (en) | 2003-03-11 |
NZ517631A (en) | 2004-01-30 |
KR20020059405A (en) | 2002-07-12 |
EA005308B1 (en) | 2004-12-30 |
NO20021306L (en) | 2002-04-24 |
AU6836300A (en) | 2001-04-17 |
MXPA02002859A (en) | 2003-07-21 |
GB9921954D0 (en) | 1999-11-17 |
HK1047227A1 (en) | 2003-02-14 |
BR0014063A (en) | 2004-06-29 |
AU777763B2 (en) | 2004-10-28 |
EP1212040A1 (en) | 2002-06-12 |
CN1177583C (en) | 2004-12-01 |
CZ2002943A3 (en) | 2002-08-14 |
CN1374858A (en) | 2002-10-16 |
NO20021306D0 (en) | 2002-03-15 |
SK3452002A3 (en) | 2002-08-06 |
EA200200369A1 (en) | 2002-08-29 |
PL353954A1 (en) | 2003-12-15 |
WO2001019338A1 (en) | 2001-03-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1214078B1 (en) | Formulations for parenteral use of estramustine phosphate and amino acids | |
US6730664B1 (en) | Formulations for parenteral use of estramustine phosphate and sulfoalkyl ether cyclodextrins | |
CA2380312A1 (en) | Formulations for parenteral use of estramustine phosphate and albumin | |
AU777763B2 (en) | Formulations for parenteral use of estramustine phosphate with improved pharmacological properties | |
ZA200201955B (en) | Formulations for parenteral use of estramustine phosphate and albumin. | |
US20040014729A1 (en) | Use of estramustine phosphate in the treatment of bone metastasis | |
ITMI991998A1 (en) | FORMULATIONS OF EXTRAMUSTINE PHOSPHATE AND ALBUMINE FOR PARENTERAL USE |