US20200085731A1 - Stable liquid formulations of melphalan - Google Patents
Stable liquid formulations of melphalan Download PDFInfo
- Publication number
- US20200085731A1 US20200085731A1 US16/694,331 US201916694331A US2020085731A1 US 20200085731 A1 US20200085731 A1 US 20200085731A1 US 201916694331 A US201916694331 A US 201916694331A US 2020085731 A1 US2020085731 A1 US 2020085731A1
- Authority
- US
- United States
- Prior art keywords
- melphalan
- propylene glycol
- monothioglycerol
- formulation
- ethanol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 title claims abstract description 37
- 229960001924 melphalan Drugs 0.000 title claims abstract description 31
- 239000012669 liquid formulation Substances 0.000 title description 4
- 239000000203 mixture Substances 0.000 claims abstract description 38
- 238000009472 formulation Methods 0.000 claims abstract description 30
- 239000007788 liquid Substances 0.000 claims abstract description 13
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 64
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 49
- OUUYBRCCFUEMLH-YDALLXLXSA-N [(1s)-2-[4-[bis(2-chloroethyl)amino]phenyl]-1-carboxyethyl]azanium;chloride Chemical compound Cl.OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 OUUYBRCCFUEMLH-YDALLXLXSA-N 0.000 claims description 23
- 229960002514 melphalan hydrochloride Drugs 0.000 claims description 21
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 14
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 13
- 229920001223 polyethylene glycol Polymers 0.000 claims description 13
- 239000003963 antioxidant agent Substances 0.000 claims description 10
- 235000006708 antioxidants Nutrition 0.000 claims description 10
- 239000002202 Polyethylene glycol Substances 0.000 claims description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 8
- 229940113088 dimethylacetamide Drugs 0.000 claims description 6
- 239000002738 chelating agent Substances 0.000 claims description 5
- 235000011187 glycerol Nutrition 0.000 claims description 4
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 3
- 235000013878 L-cysteine Nutrition 0.000 claims 1
- 239000004201 L-cysteine Substances 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 4
- 150000003839 salts Chemical class 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 20
- 238000004519 manufacturing process Methods 0.000 description 11
- 238000010790 dilution Methods 0.000 description 7
- 239000012895 dilution Substances 0.000 description 7
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 6
- 239000012535 impurity Substances 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- 238000007789 sealing Methods 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 239000002671 adjuvant Substances 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 229940098174 alkeran Drugs 0.000 description 3
- 230000003078 antioxidant effect Effects 0.000 description 3
- 235000010323 ascorbic acid Nutrition 0.000 description 3
- 239000011668 ascorbic acid Substances 0.000 description 3
- 229960005070 ascorbic acid Drugs 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- PWKSKIMOESPYIA-UHFFFAOYSA-N 2-acetamido-3-sulfanylpropanoic acid Chemical compound CC(=O)NC(CS)C(O)=O PWKSKIMOESPYIA-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 description 2
- MEJYDZQQVZJMPP-ULAWRXDQSA-N (3s,3ar,6r,6ar)-3,6-dimethoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan Chemical compound CO[C@H]1CO[C@@H]2[C@H](OC)CO[C@@H]21 MEJYDZQQVZJMPP-ULAWRXDQSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- ODJQKYXPKWQWNK-UHFFFAOYSA-N 3,3'-Thiobispropanoic acid Chemical compound OC(=O)CCSCCC(O)=O ODJQKYXPKWQWNK-UHFFFAOYSA-N 0.000 description 1
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical class OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 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 description 1
- 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 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- FSVCELGFZIQNCK-UHFFFAOYSA-N N,N-bis(2-hydroxyethyl)glycine Chemical compound OCCN(CCO)CC(O)=O FSVCELGFZIQNCK-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 239000003490 Thiodipropionic acid Substances 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- IGHJXZWUCHVVPL-PXYINDEMSA-N [H][C@](N)(Cc1ccc(C(CCl)NCCCl)cc1)C(=O)O Chemical compound [H][C@](N)(Cc1ccc(C(CCl)NCCCl)cc1)C(=O)O IGHJXZWUCHVVPL-PXYINDEMSA-N 0.000 description 1
- SNGFJIMUCHPIFN-UHFFFAOYSA-N acetamide;ethanol Chemical compound CCO.CC(N)=O SNGFJIMUCHPIFN-UHFFFAOYSA-N 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 238000012792 lyophilization process Methods 0.000 description 1
- 239000012931 lyophilized formulation Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 150000002993 phenylalanine derivatives Chemical class 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- -1 polyethylene Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical class 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 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 235000019303 thiodipropionic acid Nutrition 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000008215 water for injection Substances 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
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
- A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
Definitions
- Melphalan also known as L-phenylalanine mustard, L-PAM, or L-sarcolysin is a phenylalanine derivative of nitrogen mustard.
- Melphalan is a bifunctional alkylating agent that is active against selected human neoplastic diseases.
- the molecular formula is C 13 H 18 C 12 N 2 O 2 and the molecular weight is 305.20.
- the structural formula is:
- U.S. Pat. No. 4,997,651 to Stephen et al. discloses two-component pharmaceutical formulation of Melphalan comprising freeze-dried Melphalan hydrochloride and a solvent-diluent comprising a citrate, propylene glycol and ethanol.
- U.S patent application Nos. 2010/0311838, 2014/0213650 and 2014/0221488 disclose parenteral compositions comprising Melphalan and a cyclodextrin derivative.
- RU2060031 discloses parenteral lyophilized formulation comprising a Melphalan, polyvinylpyrrolidone, ascorbic acid, glutamic acid, hydrochloric acid and D-mannitol.
- injectable Alkeran® consists of two components comprising of Melphalan hydrochloride and polyvinylpyrrolidone lyophilized and a diluent comprising a mixture of sodium citrate, water for injection, propylene glycol and ethanol.
- the Alkeran® to be infused must be diluted to not more than 0.45 mg/ml in normal saline and infused over 15 minutes.
- One object of the invention provides ready to use liquid parenteral formulation of Melphalan.
- Another aspect of the present invention is to provide ready to use liquid parenteral formulation comprising Melphalan, one or more solvents, anti-oxidants and other pharmaceutically acceptable adjuvants thereof.
- Yet another aspect of the present invention provides method for preparing ready to use liquid parenteral formulation of Melphalan comprising Melphalan Hydrochloride, one or more solvents, anti-oxidants and other pharmaceutically acceptable adjuvants thereof.
- Melphalan refers to the pharmaceutically acceptable salts, solvates, hydrates and anhydrous forms thereof, preferably Melphalan Hydrochloride.
- melt-based Melphalan formulations refers to formulations that contain Melphalan in dissolved or solubilized form and are intended to be used as such or upon further dilution in intravenous diluents.
- liquid parenteral formulations of Melphalan comprise
- liquid parenteral formulations of Melphalan comprise
- composition according to the present invention is intended to be stored at a temperature of 2-8° C.
- Suitable solvents include, but are not limited to dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methylpyrrolidone, dimethylisosorbide, ethanol, propylene glycol, glycerine, polyethylene alcohol, propylene glycol esters, polyethylene glycols and the like.
- DMA dimethylacetamide
- DMSO dimethyl sulfoxide
- N-methylpyrrolidone dimethylisosorbide
- ethanol propylene glycol
- glycerine polyethylene alcohol
- propylene glycol esters polyethylene glycols and the like.
- Preferred solvents are dimethylacetamide (DMA), ethanol, polyethylene glycols (PEG), glycerine and propylene glycol.
- compositions of the present invention also contain one or more anti-oxidants selected from the group, but not limited to butylated hydroxyanisole (BHA), butylated hydroxyl toluene (BHT), citric acid, lactic acid, benzoic acid, tocopherol (Vitamin E), ethylenediaminetetraacetic acid, sodium metabisulfite, sodium bisulfite, monothioglycerol, ascorbic acid and their esters, L-cysteine, parabens, benzyl alcohol, propyl gallate, thioglycolic acid, tartaric acid, phosphoric acid, gluconic acid, thiodipropionic acid, acetonic dicarboxylic acid, amino acids such as histidine, cysteine, tryptophan, tyrosine; chelating agents and the like. Most preferred anti-oxidant is monothioglycerol.
- BHA butylated hydroxyanisole
- BHT butylated
- the formulation of the present invention may additionally contain buffers, pH adjusting agents, stabilizers such as, but not limited to citrate buffer, glutamate, dicarboxylic acid, lecithin, di(hydroxyethyl)glycine, sorbitol, bicarbonate, tartrate, benzoate, lactate, gluconate, glycine, TRIS buffer, acetate buffer, boric acid buffer, phosphate buffer, amino acids, meglumine and the like.
- buffers pH adjusting agents
- stabilizers such as, but not limited to citrate buffer, glutamate, dicarboxylic acid, lecithin, di(hydroxyethyl)glycine, sorbitol, bicarbonate, tartrate, benzoate, lactate, gluconate, glycine, TRIS buffer, acetate buffer, boric acid buffer, phosphate buffer, amino acids, meglumine and the like.
- liquid parenteral formulations of Melphalan comprise:
- the invention further relates to a process of preparing liquid formulations of Melphalan.
- the process comprises:
- liquid pharmaceutical formulation of Melphalan comprising of one or more solvents selected form DMA, Ethanol, PEG and propylene glycol in the presence of an anti-oxidant yields a stable liquid formulation of Melphalan overcoming the disadvantages associated with prior art.
- Melphalan Hydrochloride was added to the manufacturing vessel containing N, N, Dimethyl acetamide and ethanol and stirred to get a clear solution.
- Propylene glycol was added, followed by the addition of monothioglycerol and stirred to get homogenous solution.
- the obtained solution was filtered and filled in vials followed by capping and sealing.
- Melphalan Hydrochloride was added to the manufacturing vessel containing N,N,dimethyl acetamide and ethanol and stirred to get a clear solution.
- Propylene glycol was added, followed by the addition of monothioglycerol and stirred to get homogenous solution.
- the obtained solution was filtered and filled in vials followed by capping and sealing.
- Melphalan Hydrochloride was added to the manufacturing vessel containing polyethylene glycol and ethanol and stirred to get a clear solution.
- Propylene glycol was added, followed by the addition of monothioglycerol and stirred to get homogenous solution.
- the obtained solution was filtered and filled in vials followed by capping and sealing.
- Melphalan Hydrochloride was added to the manufacturing vessel containing polyethylene glycol. Propylene glycol was added, followed by the addition of monothioglycerol and stirred to get homogenous solution. The obtained solution was filtered and filled in vials followed by capping and sealing.
- Melphalan Hydrochloride was added to the manufacturing vessel containing polyethylene glycol. Propylene glycol was added, followed by the addition of monothioglycerol and stirred to get homogenous solution. The obtained solution was filtered and filled in vials followed by capping and sealing.
Abstract
The present invention relates to stable, liquid parenteral formulations of Melphalan or pharmaceutically acceptable salts thereof. Further this invention also describes process of preparing such formulations.
Description
- This application is a U.S. National Phase filing under 35 U.S.C. § 371 of International Application PCT/IB2016/053881, filed Jun. 29, 2016, and published as WO 2017/002030 A1 on Jan. 5, 2017. PCT/IB2016/053881 claims priority from Indian application number 3328/CHE/2015, filed Jun. 30, 2015. The entire contents of each of these applications are hereby incorporated herein by reference.
- Melphalan, also known as L-phenylalanine mustard, L-PAM, or L-sarcolysin is a phenylalanine derivative of nitrogen mustard. Melphalan is a bifunctional alkylating agent that is active against selected human neoplastic diseases. The molecular formula is C13H18C12N2O2 and the molecular weight is 305.20. The structural formula is:
- U.S. Pat. No. 4,997,651 to Stephen et al., discloses two-component pharmaceutical formulation of Melphalan comprising freeze-dried Melphalan hydrochloride and a solvent-diluent comprising a citrate, propylene glycol and ethanol.
- U.S patent application No. 2013/0131174 to Castillo et al., discloses a solid lyophilized composition of Melphalan hydrochloride having a pH between 4 and 6.
- U.S patent application Nos. 2010/0311838, 2014/0213650 and 2014/0221488 disclose parenteral compositions comprising Melphalan and a cyclodextrin derivative.
- RU2060031 discloses parenteral lyophilized formulation comprising a Melphalan, polyvinylpyrrolidone, ascorbic acid, glutamic acid, hydrochloric acid and D-mannitol.
- The commercial formulation of injectable Alkeran® consists of two components comprising of Melphalan hydrochloride and polyvinylpyrrolidone lyophilized and a diluent comprising a mixture of sodium citrate, water for injection, propylene glycol and ethanol.
- The Alkeran® to be infused must be diluted to not more than 0.45 mg/ml in normal saline and infused over 15 minutes.
- The reconstitution of the lyophilized product is clinically inconvenient and the lyophilization process is time consuming and often incurs significant expense. Hence, there is a strong need to develop alternate formulations of Melphalan.
- The inventors have developed ready to use liquid formulation of Melphalan which overcomes the disadvantages of the formulations reported in prior art.
- One object of the invention provides ready to use liquid parenteral formulation of Melphalan.
- Another aspect of the present invention is to provide ready to use liquid parenteral formulation comprising Melphalan, one or more solvents, anti-oxidants and other pharmaceutically acceptable adjuvants thereof.
- Yet another aspect of the present invention provides method for preparing ready to use liquid parenteral formulation of Melphalan comprising Melphalan Hydrochloride, one or more solvents, anti-oxidants and other pharmaceutically acceptable adjuvants thereof.
- In the context of this invention “Melphalan” refers to the pharmaceutically acceptable salts, solvates, hydrates and anhydrous forms thereof, preferably Melphalan Hydrochloride.
- As used herein, “ready to use” Melphalan formulations refers to formulations that contain Melphalan in dissolved or solubilized form and are intended to be used as such or upon further dilution in intravenous diluents.
- In one embodiment, ready to use liquid parenteral formulations of Melphalan comprise
- i. Melphalan,
- ii. one or more solvents,
- iii. anti-oxidants,
- optionally other pharmaceutically acceptable adjuvants thereof.
- In yet another embodiment, ready to use liquid parenteral formulations of Melphalan comprise
-
- i. Melphalan Hydrochloride,
- ii. one or more solvents selected from the group comprising of dimethylacetamide, polyethylene glycol, ethanol, propylene glycol and glycerine,
- iii. anti-oxidants selected from monothioglycerol, L-cysteine, ascorbic acid and optionally other pharmaceutically acceptable adjuvants thereof.
- The composition according to the present invention is intended to be stored at a temperature of 2-8° C.
- Suitable solvents include, but are not limited to dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methylpyrrolidone, dimethylisosorbide, ethanol, propylene glycol, glycerine, polyethylene alcohol, propylene glycol esters, polyethylene glycols and the like. Preferred solvents are dimethylacetamide (DMA), ethanol, polyethylene glycols (PEG), glycerine and propylene glycol.
- The pharmaceutical compositions of the present invention also contain one or more anti-oxidants selected from the group, but not limited to butylated hydroxyanisole (BHA), butylated hydroxyl toluene (BHT), citric acid, lactic acid, benzoic acid, tocopherol (Vitamin E), ethylenediaminetetraacetic acid, sodium metabisulfite, sodium bisulfite, monothioglycerol, ascorbic acid and their esters, L-cysteine, parabens, benzyl alcohol, propyl gallate, thioglycolic acid, tartaric acid, phosphoric acid, gluconic acid, thiodipropionic acid, acetonic dicarboxylic acid, amino acids such as histidine, cysteine, tryptophan, tyrosine; chelating agents and the like. Most preferred anti-oxidant is monothioglycerol.
- The formulation of the present invention may additionally contain buffers, pH adjusting agents, stabilizers such as, but not limited to citrate buffer, glutamate, dicarboxylic acid, lecithin, di(hydroxyethyl)glycine, sorbitol, bicarbonate, tartrate, benzoate, lactate, gluconate, glycine, TRIS buffer, acetate buffer, boric acid buffer, phosphate buffer, amino acids, meglumine and the like.
- Solubility studies were carried out with various solvents at 25° C. temperature, to check the solubility of Melphalan hydrochloride. The data is summarized in table 1:
-
TABLE 1 Solubility studies in various solvents Quantity of solvents Qty of Melphalan PEG- Propylene Hydrochloride DMA 400 Glycol Ethanol Result 100 mg 1.1 mL — — — Clear 100 mg 0.5 mL — — 0.5 mL Clear 100 mg — — 1 mL — Not Clear 100 mg — — — 1 mL Hazy solution 100 mg 0.3 mL — 0.05 mL 0.65 mL Clear 100 mg — 1.0 mL 0 mL — Clear after vigorous mixing 100 mg — 0.9 mL 0.1 mL — Clear 100 mg — 0.7 mL 0.3 mL — Clear 100 mg — 0.5 mL 0.5 mL — Clear 100 mg — 0.2 mL 0.8 mL — Clear 100 mg — 0.1 mL 0.9 mL — Clear - In one of the preferred embodiment, ready to use liquid parenteral formulations of Melphalan comprise:
-
i. Melphalan Hydrochloride 1 to 30% ii. dimethylacetamide or polyethylene glycol 20 to 95% iii. ethanol 0 to 50% iv. propylene glycol. 5 to 50% v. monothioglycerol 0.05 to 5%
by weight of the composition. - The invention further relates to a process of preparing liquid formulations of Melphalan. The process comprises:
-
- i. Addition of Melphalan to the manufacturing vessel containing solvent and stirred till a clear solution is obtained.
- ii. Addition of remaining solvents to the above solution and stirred.
- iii. Addition of anti-oxidant to the solution and stirred till a homogenous solution is obtained.
- iv. Filtering and filling the solution in to suitable containers or vials.
- Melphalan formulation prepared according to the invention was tested for stability at various stability conditions such as 2-8° C. and 25° C./60% RH for a period of 6 months. Stability data is summarized in table 2.
-
TABLE 2 Stability data for the product obtained from Example 5 Condition 2-8° C. 25° C./60% RH Time point Initial 1 M 3 M 6 M 1 M 3 M 6 M Assay By HPLC (%) 99.2 97.8 97.7 96.8 97.2 94.0 90.1 Total Impurities 0.17 0.24 0.32 0.75 0.89 2.26 4.33 (% w/w) - Surprisingly no significant increase in total impurities was observed even at 25° C./65% RH. The inventors have found that liquid pharmaceutical formulation of Melphalan comprising of one or more solvents selected form DMA, Ethanol, PEG and propylene glycol in the presence of an anti-oxidant yields a stable liquid formulation of Melphalan overcoming the disadvantages associated with prior art.
- Comparative dilution studies were performed to check the stability of the diluted formulations. Melphalan formulation prepared according to the invention was diluted with 0.9% NaCl to get concentration of 0.45 mg/mL. Alkeran® vial (Batch No: P283) was considered as reference for comparative dilution study. Stability of the diluted product was studied at 0 minutes, 30 mins and 60 min. The stability data of the invention formulation and reference product is summarized in table 3.
-
TABLE 3 Comparative dilution study of the invention formulation with reference product Dilution study with 0.9% NaCl Formulation Reference product Invention formulation after reconstitution with after dilution with diluent, followed by 0.9% NaCl dilution with 0.9% NaCl Time point Initial 30 min 60 min Initial 30 min 60 min Assay (%) 97.3 97.6 95.2 95.6 91.1 88.2 pH of Solution 3.51 3.48 3.48 5.83 6.06 6.35 Osmolality 352 348 354 1120 1119 1122 (mOsm/kg) Related Substances Impurities % (w/w) Impurity D 1.23 3.31 5.35 1.11 3.67 5.73 Impurity G 0.14 0.15 0.17 0.49 0.52 0.51 Total 1.6 3.8 5.8 1.94 5.08 7.65 Impurities - Surprisingly Melphalan formulation prepared according to the invention showed better stability profile compared to the reference product.
- The following examples further describe certain specific aspects and embodiments of the present invention and demonstrate the practice and advantages thereof.
-
-
Qty/vial Ingredients (mg) Melphalan Hydrochloride 20-200 N,N,Dimethyl acetamide 350-490 Ethanol 200-280 Propylene glycol 180-270 Monothioglycerol 3-8 - Melphalan Hydrochloride was added to the manufacturing vessel containing N, N, Dimethyl acetamide and ethanol and stirred to get a clear solution. Propylene glycol was added, followed by the addition of monothioglycerol and stirred to get homogenous solution. The obtained solution was filtered and filled in vials followed by capping and sealing.
- Melphalan formulation prepared according to the invention was tested for stability at various stability conditions such as 2-8° C. and 25° C./60% RH for a period of 6 months. Stability data is summarized in table 4.
-
TABLE 4 Stability data for the product obtained from Example 1 Condition 2-8° C. 25° C. Time point Initial 1 M 3 M 6 M 1 M 3 M 6 M Assay By 100.3 100.3 103.3 98.3 99.5 101.1 94.4 HPLC (%) Total 0.19 0.16 0.20 0.63 0.30 1.60 4.37 impurities *RRT: Relative Retention Time -
-
Qty/vial Qty/vial Qty/vial Ingredients (mg) (mg) (mg) Melphalan 20-200 20-200 20-200 Hydrochloride N, N, Dimethyl 380 380 380 acetamide Ethanol 240 320 280 Propylene glycol 310 210 260 Monothioglycerol 2.53 5.05 5.05 - Melphalan Hydrochloride was added to the manufacturing vessel containing N,N,dimethyl acetamide and ethanol and stirred to get a clear solution. Propylene glycol was added, followed by the addition of monothioglycerol and stirred to get homogenous solution. The obtained solution was filtered and filled in vials followed by capping and sealing.
-
-
Qty/vial Ingredients (mg) Melphalan Hydrochloride 20-200 Polyethylene glycol 570 Ethanol 240 Propylene glycol 210 Monothioglycerol 5.05 - Melphalan Hydrochloride was added to the manufacturing vessel containing polyethylene glycol and ethanol and stirred to get a clear solution. Propylene glycol was added, followed by the addition of monothioglycerol and stirred to get homogenous solution. The obtained solution was filtered and filled in vials followed by capping and sealing.
-
-
Quantity/vial Ingredients (mg) Melphalan Hydrochloride 20-200 Polyethylene glycol-400 490-620 Propylene glycol 320-390 Monothioglycerol 5.05 - Melphalan Hydrochloride was added to the manufacturing vessel containing polyethylene glycol. Propylene glycol was added, followed by the addition of monothioglycerol and stirred to get homogenous solution. The obtained solution was filtered and filled in vials followed by capping and sealing.
-
-
Quantity/vial Ingredients (mg) Melphalan Hydrochloride 20-200 Polyethylene glycol-400 590-950 Propylene glycol 120-420 Monothioglycerol 5-8 - Melphalan Hydrochloride was added to the manufacturing vessel containing polyethylene glycol. Propylene glycol was added, followed by the addition of monothioglycerol and stirred to get homogenous solution. The obtained solution was filtered and filled in vials followed by capping and sealing.
Claims (8)
1. (canceled)
2: The formulation of claim 3 , wherein the pH of the formulation is between 2 to 5.
3: A stable, liquid parenteral formulation consisting essentially of:
(i) Melphalan
(ii) one or more solvents and
(iii) one or more anti-oxidants.
4: A stable, liquid parenteral formulation consisting essentially of:
(i) Melphalan hydrochloride
(ii) one or more solvents selected from dimethyl acetamide, polyethylene glycol, ethanol, propylene glycol and glycerine.
(iii) anti-oxidants selected from monothioglycerol, L-cysteine and chelating agents.
5. (canceled)
6: The stable, liquid parenteral formulation of claim 4 consisting of:
7: The stable, liquid parenteral formulation of claim 4 consisting of:
8: A stable, liquid parenteral formulation of Melphalan consisting essentially of:
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IN3328/CHE/2015 | 2015-06-30 | ||
IN3328CH2015 | 2015-06-30 | ||
PCT/IB2016/053881 WO2017002030A1 (en) | 2015-06-30 | 2016-06-29 | Stable liquid formulations of melphalan |
US201715739034A | 2017-12-21 | 2017-12-21 | |
US16/694,331 US20200085731A1 (en) | 2015-06-30 | 2019-11-25 | Stable liquid formulations of melphalan |
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US15/739,034 Continuation US10537520B2 (en) | 2015-06-30 | 2016-06-29 | Stable liquid formulations of melphalan |
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WO2017002030A1 (en) * | 2015-06-30 | 2017-01-05 | Leiutis Pharmaceuticals Pvt Ltd | Stable liquid formulations of melphalan |
US20210145778A1 (en) * | 2018-01-01 | 2021-05-20 | Orbicular Pharmaceutical Technologies Pvt. Ltd. | Stable Liquid Compositions of Melphalan |
ES2928931T3 (en) | 2018-03-29 | 2022-11-23 | Project Pharmaceutics Gmbh | liquid pharmaceutical formulation |
US10682326B1 (en) | 2019-06-03 | 2020-06-16 | Shilpa Medicare Limited | Stable melphalan liquid injectable formulations |
EP4055005A4 (en) * | 2019-11-04 | 2023-11-29 | Intas Pharmaceuticals Ltd. | Liquid melphalan composition |
US11857677B2 (en) * | 2019-12-19 | 2024-01-02 | Rk Pharma Inc. | Ready to use injectable formulations of melphalan and processes for preparation thereof |
WO2024011169A1 (en) * | 2022-07-06 | 2024-01-11 | Good Health, Llc | Stable, liquid pharmaceutical compositions comprising melphalan |
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RU2060031C1 (en) | 1993-05-27 | 1996-05-20 | Онкологический научный центр | Method of sarcolysin preparing for intravenous injection |
US6805786B2 (en) * | 2002-09-24 | 2004-10-19 | Northrop Grumman Corporation | Precious alloyed metal solder plating process |
US7988992B2 (en) * | 2006-07-06 | 2011-08-02 | KOS Life Sciences Abbott Laboratories | Superporous hydrogels for heavy-duty applications |
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WO2012094020A1 (en) * | 2010-01-07 | 2012-07-12 | Innopharma, Inc. | Methods and compositions for delivery of taxanes in stable oil-in-water emulsions |
AR077384A1 (en) | 2010-07-05 | 2011-08-24 | Eriochem Sa | AN INJECTABLE PHARMACEUTICAL FORMULATION OF MELFALANO. |
UA119324C2 (en) * | 2013-04-02 | 2019-06-10 | Теміс Медікер Лімітед | Compositions of pharmaceutical actives containing diethylene glycol monoethyl ether or other alkyl derivatives |
-
2016
- 2016-06-29 WO PCT/IB2016/053881 patent/WO2017002030A1/en active Application Filing
- 2016-06-29 US US15/739,034 patent/US10537520B2/en active Active
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EP0317281A2 (en) * | 1987-11-19 | 1989-05-24 | The Wellcome Foundation Limited | Pharmaceutical formulations containing melphalan or melphalan hydrochloride, as well as melphalan and melphalan hydrochloride and processes for preparing them |
US20090098209A1 (en) * | 2007-10-15 | 2009-04-16 | University Of Kansas | Pharmaceutical compositions containing water-soluble derivatives of propofol and methods of administering same via pulmonary administration |
US20100311838A1 (en) * | 2009-05-29 | 2010-12-09 | Pipkin James D | Injectable Melphalan Compositions Comprising a Cyclodextrin Derivative and Methods of Making and Using the Same |
US20140005148A1 (en) * | 2012-06-29 | 2014-01-02 | Coldstream Laboratories Inc. | Stable liquid formulations of nitrogen mustards |
US20170020177A1 (en) * | 2013-11-29 | 2017-01-26 | Kewpie Corporation | Acidic oil-in-water type emulsified condiment |
US20180193255A1 (en) * | 2015-06-30 | 2018-07-12 | Leiutis Pharmaceuticals Pvt. Ltd. | Stable liquid formulations of melphalan |
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US20180193255A1 (en) | 2018-07-12 |
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