US20220153802A1 - A stable parenteral dosage form of cetrorelix acetate - Google Patents
A stable parenteral dosage form of cetrorelix acetate Download PDFInfo
- Publication number
- US20220153802A1 US20220153802A1 US17/593,512 US202017593512A US2022153802A1 US 20220153802 A1 US20220153802 A1 US 20220153802A1 US 202017593512 A US202017593512 A US 202017593512A US 2022153802 A1 US2022153802 A1 US 2022153802A1
- Authority
- US
- United States
- Prior art keywords
- dosage form
- cetrorelix
- parenteral dosage
- aqueous solution
- stable
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 108700008462 cetrorelix Proteins 0.000 title claims abstract description 150
- KFEFLCOCAHJBEA-ANRVCLKPSA-N cetrorelix acetate Chemical compound CC(O)=O.C([C@@H](C(=O)N[C@H](CCCNC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 KFEFLCOCAHJBEA-ANRVCLKPSA-N 0.000 title claims abstract description 150
- 239000006201 parenteral dosage form Substances 0.000 title claims abstract description 66
- 229960001865 cetrorelix acetate Drugs 0.000 title claims abstract description 64
- 239000007864 aqueous solution Substances 0.000 claims abstract description 92
- 239000007924 injection Substances 0.000 claims abstract description 30
- 238000002347 injection Methods 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 25
- 102000009151 Luteinizing Hormone Human genes 0.000 claims abstract description 7
- 108010073521 Luteinizing Hormone Proteins 0.000 claims abstract description 7
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 7
- 229940040129 luteinizing hormone Drugs 0.000 claims abstract description 7
- 230000002611 ovarian Effects 0.000 claims abstract description 7
- 230000002028 premature Effects 0.000 claims abstract description 7
- 230000000638 stimulation Effects 0.000 claims abstract description 7
- 239000012535 impurity Substances 0.000 claims description 104
- 229960003230 cetrorelix Drugs 0.000 claims description 84
- 239000000243 solution Substances 0.000 claims description 50
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- 239000003085 diluting agent Substances 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- 238000002360 preparation method Methods 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 13
- 229940090047 auto-injector Drugs 0.000 claims description 12
- 239000002357 osmotic agent Substances 0.000 claims description 12
- 230000004044 response Effects 0.000 claims description 11
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 10
- 230000014759 maintenance of location Effects 0.000 claims description 9
- 150000007524 organic acids Chemical class 0.000 claims description 9
- 239000000902 placebo Substances 0.000 claims description 8
- 229940068196 placebo Drugs 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- 239000002552 dosage form Substances 0.000 claims description 7
- 229940071643 prefilled syringe Drugs 0.000 claims description 7
- 239000012086 standard solution Substances 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000011550 stock solution Substances 0.000 claims description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 5
- 235000019253 formic acid Nutrition 0.000 claims description 5
- 238000007920 subcutaneous administration Methods 0.000 claims description 4
- 238000007918 intramuscular administration Methods 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 239000000872 buffer Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 238000003860 storage Methods 0.000 description 37
- 230000002776 aggregation Effects 0.000 description 17
- 239000011521 glass Substances 0.000 description 17
- 239000008215 water for injection Substances 0.000 description 15
- 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 14
- MGRLKUUPMWECHK-UVOPDSLESA-N [H]N(C(=O)C1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](CC(=O)[C@@H](CCCNC(N)=O)NC(=O)[C@@H](CC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)[C@@H](Cc1ccc(Cl)cc1)NC(=O)[C@@H](Cc1ccc2ccccc2c1)N([H])C(C)=O)Cc1cccnc1)Cc1ccc(O)cc1)CC(C)C)[C@H](C)C(C)=O Chemical compound [H]N(C(=O)C1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](CC(=O)[C@@H](CCCNC(N)=O)NC(=O)[C@@H](CC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)[C@@H](Cc1ccc(Cl)cc1)NC(=O)[C@@H](Cc1ccc2ccccc2c1)N([H])C(C)=O)Cc1cccnc1)Cc1ccc(O)cc1)CC(C)C)[C@H](C)C(C)=O MGRLKUUPMWECHK-UVOPDSLESA-N 0.000 description 14
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 14
- 238000004220 aggregation Methods 0.000 description 13
- 150000001875 compounds Chemical class 0.000 description 11
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 10
- 108090000765 processed proteins & peptides Proteins 0.000 description 10
- 235000002639 sodium chloride Nutrition 0.000 description 10
- 229920001971 elastomer Polymers 0.000 description 9
- 239000005060 rubber Substances 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- 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 8
- 229930195725 Mannitol Natural products 0.000 description 8
- 238000003556 assay Methods 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 8
- 239000000594 mannitol Substances 0.000 description 8
- 235000010355 mannitol Nutrition 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 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 7
- 239000000174 gluconic acid Substances 0.000 description 7
- 235000012208 gluconic acid Nutrition 0.000 description 7
- 239000004310 lactic acid Substances 0.000 description 7
- 235000014655 lactic acid Nutrition 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- 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 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 230000015556 catabolic process Effects 0.000 description 6
- 238000006731 degradation reaction Methods 0.000 description 6
- 239000004033 plastic Substances 0.000 description 5
- 229920003023 plastic Polymers 0.000 description 5
- 102000004196 processed proteins & peptides Human genes 0.000 description 5
- 238000000527 sonication Methods 0.000 description 5
- 229910001220 stainless steel Inorganic materials 0.000 description 5
- 239000010935 stainless steel Substances 0.000 description 5
- 244000043261 Hevea brasiliensis Species 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 238000005054 agglomeration Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000011049 filling Methods 0.000 description 4
- -1 for example Polymers 0.000 description 4
- 229920003052 natural elastomer Polymers 0.000 description 4
- 229920001194 natural rubber Polymers 0.000 description 4
- 238000012430 stability testing Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000003002 pH adjusting agent Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000009517 secondary packaging Methods 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 229920005557 bromobutyl Polymers 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 229940112106 cetrotide Drugs 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000008139 complexing agent Substances 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 239000007857 degradation product Substances 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000002474 gonadorelin antagonist Substances 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 229920000098 polyolefin Polymers 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 238000004007 reversed phase HPLC Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- QGQXAMBOYWULFX-LZWSPWQCSA-N 2-morpholin-4-ylethyl (e)-6-(4,6-dihydroxy-7-methyl-3-oxo-1h-2-benzofuran-5-yl)-4-methylhex-4-enoate Chemical compound OC=1C=2C(=O)OCC=2C(C)=C(O)C=1C\C=C(/C)CCC(=O)OCCN1CCOCC1 QGQXAMBOYWULFX-LZWSPWQCSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 125000001433 C-terminal amino-acid group Chemical group 0.000 description 1
- 229920000089 Cyclic olefin copolymer Polymers 0.000 description 1
- 229920000858 Cyclodextrin Polymers 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
- 102000012673 Follicle Stimulating Hormone Human genes 0.000 description 1
- 108010079345 Follicle Stimulating Hormone Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- NMJREATYWWNIKX-UHFFFAOYSA-N GnRH Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CC(C)C)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 NMJREATYWWNIKX-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical group NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 1
- 229940123973 Oxygen scavenger Drugs 0.000 description 1
- 239000004695 Polyether sulfone Substances 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- MGRLKUUPMWECHK-LRUCHESVSA-N [H]N(C(=O)C1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](CC(=O)[C@@H](CCCNC(N)=O)NC(=O)[C@@H](CC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)C(Cc1ccc(Cl)cc1)NC(=O)[C@@H](Cc1ccc2ccccc2c1)N([H])C(C)=O)Cc1cccnc1)Cc1ccc(O)cc1)CC(C)C)[C@H](C)C(C)=O Chemical compound [H]N(C(=O)C1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](CC(=O)[C@@H](CCCNC(N)=O)NC(=O)[C@@H](CC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)C(Cc1ccc(Cl)cc1)NC(=O)[C@@H](Cc1ccc2ccccc2c1)N([H])C(C)=O)Cc1cccnc1)Cc1ccc(O)cc1)CC(C)C)[C@H](C)C(C)=O MGRLKUUPMWECHK-LRUCHESVSA-N 0.000 description 1
- AMXAOBKXTOIARQ-GPKLNVDASA-N [H]N(C(=O)C1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](CC(=O)[C@@H](CCCNC(N)=O)NC(=O)[C@@H](CC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)[C@@H](Cc1ccc(Cl)cc1)NC(=O)[C@@H](Cc1ccc2ccccc2c1)N([H])C(C)=O)Cc1cccnc1)Cc1ccc(O)cc1)CC(C)C)[C@H](C)C(=O)O Chemical compound [H]N(C(=O)C1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](CC(=O)[C@@H](CCCNC(N)=O)NC(=O)[C@@H](CC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)[C@@H](Cc1ccc(Cl)cc1)NC(=O)[C@@H](Cc1ccc2ccccc2c1)N([H])C(C)=O)Cc1cccnc1)Cc1ccc(O)cc1)CC(C)C)[C@H](C)C(=O)O AMXAOBKXTOIARQ-GPKLNVDASA-N 0.000 description 1
- LMWLZWDTISZWRK-GPKLNVDASA-N [H]N(C(=O)C1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](CC(=O)[C@@H](CCCNC(N)=O)NC(=O)[C@@H](CC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)[C@@H](Cc1ccc(Cl)cc1)NC(=O)[C@@H](Cc1ccc2ccccc2c1)N([H])C(C)=O)Cc1cccnc1)Cc1ccc(O)cc1)CC(C)C)[C@H](C)C(N)=O Chemical compound [H]N(C(=O)C1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](CC(=O)[C@@H](CCCNC(N)=O)NC(=O)[C@@H](CC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)[C@@H](Cc1ccc(Cl)cc1)NC(=O)[C@@H](Cc1ccc2ccccc2c1)N([H])C(C)=O)Cc1cccnc1)Cc1ccc(O)cc1)CC(C)C)[C@H](C)C(N)=O LMWLZWDTISZWRK-GPKLNVDASA-N 0.000 description 1
- FISOXWHYKSJRLO-NXKSJULHSA-N [H]N(C(=O)C1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](CC(=O)[C@@H](CCCNC(N)=O)NC(=O)[C@@H](CC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)[C@@H](Cc1ccc(Cl)cc1)NC(=O)[C@H](N)Cc1ccc2ccccc2c1)Cc1cccnc1)Cc1ccc(O)cc1)CC(C)C)[C@H](C)C(C)=O Chemical compound [H]N(C(=O)C1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](CC(=O)[C@@H](CCCNC(N)=O)NC(=O)[C@@H](CC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)[C@@H](Cc1ccc(Cl)cc1)NC(=O)[C@H](N)Cc1ccc2ccccc2c1)Cc1cccnc1)Cc1ccc(O)cc1)CC(C)C)[C@H](C)C(C)=O FISOXWHYKSJRLO-NXKSJULHSA-N 0.000 description 1
- HHWCBQQBQSQESY-MWVCTTIVSA-N [H]N(C(C)=O)[C@H](Cc1ccc2ccccc2c1)C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)C[C@H](Cc1cccnc1)C(=O)N[C@@H](CO)C(=O)C[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](CCCNC(N)=O)C(=O)C[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCCC1C(C)=O Chemical compound [H]N(C(C)=O)[C@H](Cc1ccc2ccccc2c1)C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)C[C@H](Cc1cccnc1)C(=O)N[C@@H](CO)C(=O)C[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](CCCNC(N)=O)C(=O)C[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCCC1C(C)=O HHWCBQQBQSQESY-MWVCTTIVSA-N 0.000 description 1
- OXEMZNYFUMFKFA-CBBLTUMVSA-N [H]N(C(C)=O)[C@H](Cc1ccc2ccccc2c1)C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)C[C@H](Cc1cccnc1)C(=O)N[C@@H](CO)C(=O)C[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](CCCNC(N)=O)C(=O)C[C@@H](CC(C)C)C(C)=O Chemical compound [H]N(C(C)=O)[C@H](Cc1ccc2ccccc2c1)C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)C[C@H](Cc1cccnc1)C(=O)N[C@@H](CO)C(=O)C[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](CCCNC(N)=O)C(=O)C[C@@H](CC(C)C)C(C)=O OXEMZNYFUMFKFA-CBBLTUMVSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 238000002144 chemical decomposition reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229920005556 chlorobutyl Polymers 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000013536 elastomeric material Substances 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 229940028334 follicle stimulating hormone Drugs 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 229940121381 gonadotrophin releasing hormone (gnrh) antagonists Drugs 0.000 description 1
- 229920001903 high density polyethylene Polymers 0.000 description 1
- 239000004700 high-density polyethylene Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 229920001684 low density polyethylene Polymers 0.000 description 1
- 239000004702 low-density polyethylene Substances 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000001817 pituitary effect Effects 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 229920006393 polyether sulfone Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HRQDCDQDOPSGBR-UHFFFAOYSA-M sodium;octane-1-sulfonate Chemical compound [Na+].CCCCCCCCS([O-])(=O)=O HRQDCDQDOPSGBR-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 229920003048 styrene butadiene rubber Polymers 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
-
- 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
- A61K38/00—Medicinal preparations containing peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
- A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
-
- 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
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- 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
- A61K9/0029—Parenteral nutrition; Parenteral nutrition compositions as drug carriers
-
- 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
- A61K9/08—Solutions
-
- 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
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/59—Follicle-stimulating hormone [FSH]; Chorionic gonadotropins, e.g.hCG [human chorionic gonadotropin]; Luteinising hormone [LH]; Thyroid-stimulating hormone [TSH]
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/16—Injection
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N2030/022—Column chromatography characterised by the kind of separation mechanism
- G01N2030/027—Liquid chromatography
Definitions
- the present invention relates to a stable parenteral dosage form with a ready-to-inject, sterile, stable, aqueous solution of cetrorelix acetate.
- the invention also relates to an injection device prefilled with the ready-to-inject, sterile, stable, aqueous solution of cetrorelix acetate.
- the present invention relates to a method of inhibiting premature luteinizing hormone surges in women undergoing controlled ovarian stimulation comprising a stable parenteral dosage form with a ready-to-inject, sterile, stable, aqueous solution of cetrorelix acetate.
- Cetrorelix is gonadotropin releasing hormone antagonist (GnRH antagonist) acetyl-D-3-(2′-naphtyl)-alanine-D-4-chlorophenylalanine-D-3-(3′-pyridyl)-alanine-L-serine-L-tyrosine-D-citruline-L-leucine-L-arginine-L-proline-D-alanine-amide (C 70 H 92 ClN 17 O 14 ) having the below formula. It is a decapeptide with a terminal acid amide group. It acts by blocking the action of GnRH upon the pituitary, thus rapidly suppressing the production and action of leutinizing hormone and follicle stimulating hormone.
- GnRH antagonist gonadotropin releasing hormone antagonist
- Aqueous solutions of peptides are required for parenteral administration.
- aqueous solutions of peptides such as cetrorelix are susceptible to chemical degradation. They are also prone to aggregation whereby the turbidity or cloudiness of the solution increases on storage.
- the first product on the market was Cetrotide®. It is available as a lyophilized powder in glass vials containing 0.25 mg or 3 mg of cetrorelix. A prefilled glass syringe having 1 ml or 3 ml of sterile water for injection is provided separately and the solution is prepared only prior to injection. Therefore, the first product solved the problem of degradation in aqueous solution simply by avoiding preparing a dosage form containing an aqueous solution that needed to be stored over time. Instead the water was removed and a lyophilizate was prepared to avoid instability problems.
- U.S. Pat. No. 7,718,599 discloses that aqueous solutions of cetrorelix were prone to aggregation. Under a polarized light microscope, liquid crystalline structures were observed. To cetrorelix acetate solutions (2.5 mg/ml), gluconic acid was added, whereby at concentrations of gluconic acid less than 0.07%, resulting in a pH of 3.7, aggregation was seen within 2 days. Similar failure was reported when the pH was more than 3.7. When the concentration of gluconic acid was increased to 0.71%, resulting in a pH of 3.1, the aggregation was seen in 12 days indicating that higher concentrations of gluconic acid and thus lower pH led to improvement.
- U.S. Pat. No. 7,214,662 discloses aqueous solutions of peptides including cetrorelix acetate and suggested solutions to the problem of aggregation. It taught that carboxylic acids and especially hydroxycarboxylic acids, preferably gluconic acid, in combination with a surfactant reduces aggregation. The use of carboxylic acid according to U.S. Pat. No. 7,214,662 resulted in a low pH such as pH 2.5 to 3.
- the object of the present invention is to provide a parenteral dosage form comprising a ready-to-inject sterile stable aqueous solution of cetrorelix acetate.
- Another object of the invention is to provide an injection device pre-filled with the sterile stable aqueous solution of cetrorelix acetate.
- ready-to-inject refers to a ready-to-inject, sterile, stable, aqueous solution of cetrorelix acetate which is suitable for direct subcutaneous or intramuscular administration, i.e., it is ready-to-inject and there is no requirement of reconstitution or dilution before injection.
- the sterile stable aqueous solution of cetrorelix acetate dispensed in an injection device be ready-to-inject, not only be physically stable in terms of control on aggregation or turbidity development but also be chemically stable such that impurities remain low while the parenteral dosage form is stored on the shelf and until it is injected into the patient subcutaneously or intra-muscularly.
- Impurity A represented by the compound of Formula I given below:
- the present invention found that not only could the stable aqueous solution of cetrorelix acetate be prepared at a pH 3 to 5 without agglomeration problems but also the level of Impurity A and total impurities were well controlled and remain at low concentrations upon storage of the parenteral dosage form at 25° C./60% RH for at least 1 month, at least 2 months, at least 3 months, or at least 6 months.
- the parenteral dosage form could also be stored at 2 to 8° C. with good stability for at least 24 months.
- the present invention provides a parenteral dosage form comprising a stable aqueous solution comprising:
- the parenteral dosage form comprises impurity of Formula I in an amount less than 4% w/v of cetrorelix base. More preferably, the parenteral dosage form comprises impurity of Formula I in an amount less than 3% w/v of cetrorelix base. More preferably, the parenteral dosage form comprises impurity of Formula I in an amount less than 2% w/v of cetrorelix base. More preferably, the parenteral dosage form comprises impurity of Formula I in an amount less than 1% w/v of cetrorelix base.
- the parenteral dosage form further comprises an osmotic agent and water for injection.
- the present invention provides a parenteral dosage form comprising a stable aqueous solution comprising:
- the present invention provides a parenteral dosage form comprising a stable, aqueous solution comprising:
- the present invention provides a parenteral dosage form comprising a ready-to-inject, sterile, stable, aqueous solution comprising:
- the invention provides a parenteral dosage form comprising a ready-to-inject sterile, stable, aqueous solution consisting of:
- the parenteral dosage form comprising the ready-to-inject sterile, stable aqueous solution of cetrorelix according to the present invention remains physically and chemically stable when stored at 2 to 8° C. for at least 1 month, at least 3 months, at least 6 months, at least 12 months, at least 18 months, or at least 24 months; or at room temperature (25° C./60% RH) for at least 1 month, at least 3 months, or at least 6 months.
- Preferred embodiments of the stable parenteral dosage form can be labelled with a shelf life at 2 to 8° C. of at least 24 months or of 24 months. More preferred embodiments of the parenteral dosage form can be labelled with a shelf life of at least 6 months or of 6 months at room temperature (25° C./60% RH) storage condition.
- the concentration of decapeptides of formula I remains in the range of 0.001% to 1.0%, preferably 0.05 to 0.5% by weight of cetrorelix base, single maximum unknown impurity remains less than 0.5% by weight of cetrorelix base and total impurity remains not more than 3.5% by weight of cetrorelix base upon storage at 2 to 8° C. for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 12 months, at least 18 months or at least 24 months and/or at room temperature (25° C./60% RH) for at least 1 month, at least 2 months, at least 3 months, or at least 6 months.
- the parenteral dosage form comprising the ready-to-inject sterile aqueous solution of cetrorelix according to the present invention is physically stable with no aggregation, gel formation or precipitation of the aqueous solution during the shelf-life.
- the aggregation or gel formation can be determined by measuring the cloudiness or turbidity of the solution. It is measured in FTU unit (Formazin Turbidity Unit) or NTU unit (Nephelometric Turbidity Unit).
- the test is performed according to the protocol described in European Pharmacopoeia 9.0.
- the solution is said to be free of any aggregation or gel formation if the cloudiness/turbidity value is less than or equal to 8 FTU/NTU.
- the higher the FTU/NTU values the higher the cloudiness or turbidity in the solution and vice-versa.
- the NTU values of the ready-to-inject, parenteral dosage form according to the present invention remains less than 2 NTU, preferably less than 1 NTU, more preferably less than 0.5 NTU, initially and upon long term storage of the dosage form at 2 to 8° C.
- the parenteral dosage form comprising the ready-to-inject, sterile, stable, aqueous solution of cetrorelix according to the present invention contains cetrorelix acetate at a concentration ranging from 0.26 mg/ml to 0.28 mg/ml, which amount is equivalent to 0.25 mg/ml of cetrorelix base.
- cetrorelix acetate is present in the ready-to-inject sterile, stable aqueous solution at a concentration equivalent to 0.25 mg/ml of cetrorelix base.
- the pH of the ready-to-inject sterile, stable aqueous solution according to the present invention may be for example, 3, 3.05, 3.10, 3.15, 3.20, 3.25, 3.30, 3.35, 3.40, 3.45, 3.5, 3.55, 3.60, 3.65, 3.70, 3.75, 3.80, 3.85, 3.90, 3.95, 4.00, 4.05, 4.10, 4.15, 4.20, 4.25, 4.30, 4.35, 4.40, 4.45, 4.50, 4.55, 4.60, 4.65, 4.70, 4.75, 4.80, 4.85, 4.90, 4.95, 5.00, 5.05, 5.10, 5.15, 5.20, 5.25, 5.30, 5.35, 5.40, 5.45, 5.50, 5.55 and 6 or intermediate ranges thereof.
- the organic acid may be selected from any parenterally acceptable organic acid soluble in water but is preferably acetic acid, more preferably lactic acid.
- lactic acid may be used in the ready-to-inject sterile aqueous solution according to the present invention at a concentration ranging from about 0.013 mg/ml to 0.53 mg/ml, preferably in amount ranging from about 0.033 mg/ml to about 0.53 mg/ml; and intermediate ranges thereof.
- the ready-to-inject sterile, stable aqueous solution of cetrorelix comprise cetrorelix (base) and organic acid in a weight ratio ranging from 5 0.47:1 to 19.23:1, preferably in a weight ratio ranging from about 0.47:1 to 7.57:1, more preferably in a weight ratio ranging from about 1.56:1 to 7.57:1 and intermediate ranges thereof.
- the parenteral dosage form comprising the ready-to-inject sterile, stable aqueous solution of cetrorelix according to the present invention comprises an osmotic agent or tonicity adjusting agent, in amounts suitable to adjust the osmolality of the solution in the range of about 250-375 mOsm/kg, preferably 270-330 mOsm/kg.
- the osmotic agent that may be used in the aqueous solution according to present invention is selected from, but not limited to, mannitol, glycerol, sorbitol, sodium chloride, potassium chloride, dextrose, sucrose, and the like and mixtures thereof.
- the osmotic agent is mannitol and it may be used in the aqueous solution in an amount ranging from about 40.0 mg/ml to 60.0 mg/ml, preferably in an amount ranging from about 50.0 mg/ml to 58.0 mg/ml. In one preferred embodiment, the osmotic agent is mannitol and it is used in the ready-to-inject sterile aqueous solution in an amount of about 55.0 mg/ml.
- the ready-to-inject, sterile, aqueous solution of the parenteral dosage form of the present invention does not contain lactic acid in the form of its derivatives, polymer or copolymers such as polylactic acid or polylactic-co-glycolic acid.
- lactic acid is used as a sole pH adjusting agent.
- the ready-to-inject sterile, aqueous solution is free of any surfactant, such as tween 80, polysorbates, poloxamers, spans and the like.
- the ready-to-inject sterile, aqueous solution of the parenteral dosage form avoids use of surfactants, complexing agents, preservative or anti-oxidants for solubilization or stabilization.
- the solution is free of complexing agents like cyclodextrins, free of co-solvents such as alcohols or glycols and is also free of preservatives and antioxidants.
- the present invention provides the sterile, aqueous solution of cetrorelix acetate as above which remains stable for at least 1 month, preferably for at least 3 months and more preferably for at least 6 months at 25° C. temperature and 60% relative humidity.
- the present invention provides the sterile, aqueous solution of cetrorelix acetate as above which remains stable for at least 1 month, preferably for at least 3 months, more preferably for at least 6 months, even more preferably for at least 12 months or 18 months, and most preferably for at least 24 months at 2-8° C.
- the stable parenteral dosage form comprising the ready-to-inject, sterile, stable aqueous solution of cetrorelix according to the present invention is suitable for administration by subcutaneous route or intra-muscular route.
- the ready-to-inject, sterile, stable aqueous solution is suitable for direct subcutaneous administration, i.e., it is ready-to-inject or ready-to-self-administer and there is no requirement of reconstitution or dilution before use.
- the ready-to-inject, sterile, stable aqueous solution according to the present invention does not involve lyophilization.
- the stable parenteral dosage form of the present invention is suitable for self-administration and enables the patient to self-administer a small volume of the aqueous solution subcutaneously.
- the volume of the ready-to-inject sterile, aqueous solution of cetrorelix filled in the reservoir of the injection device ranges from about 0.5 ml to 10.0 ml, preferably 1.0 ml to 2.0 ml, more preferably 1.0 ml.
- the ready-to-inject, sterile, stable, aqueous solution of cetrorelix is filled in the reservoir of the injection device in volume of 1.0 ml.
- the parenteral dosage form according to the present invention is suitable for administering a single dose of cetrorelix acetate.
- the parenteral dosage form comprises a fill volume of about 1.0 ml of aqueous solution of cetrorelix acetate suitable for self-administration as a single dose.
- the parenteral dosage form may comprise aqueous solution of cetrorelix at a fill volume of about 10.0 ml, suitable for multiple dose administration.
- the injection device according to the stable, parenteral, dosage form of the present invention may be selected from, but not limited to, prefilled syringes, autoinjectors and the like.
- the injection device is a prefilled syringe.
- the injection device is an autoinjector such as a pen auto-injector.
- the injection device is a prefilled syringe.
- the prefilled syringe comprises the following components: a reservoir such as, for example, a barrel or a cartridge, which stores the aqueous solution; a stalked needle attached at one end of the reservoir; a needle shield or tip cap that covers the needle and seals the needle tip opening, optionally, a rigid shield covering the needle shield or tip cap; a plunger stopper at other end of the reservoir that stoppers and seals the aqueous solution filled in the reservoir; a plunger rod that fits into the plunger stopper and is used to push the plunger stopper along with the solution towards the needle end while administering the drug.
- the injection device is an autoinjector.
- the auto-injector can have varied designs.
- the autoinjector comprises the following components: a central assembly or body portion that is suitable to hold a pre-filled syringe, the syringe comprising a reservoir such as a barrel or a cartridge which stores the aqueous solution, the reservoir having a stalked needle at one end and a plunger stopper at other end.
- the central body portion may have a clear inspection window through which the solution in the reservoir is visible.
- the autoinjector further comprises a front assembly having a cap portion that holds a needle shield or tip cap, and it is attachable to the central assembly covering the stalked needle and sealing the needle tip opening.
- the autoinjector further comprises a rear assembly which comprises a plastic rod with a spring assembly and an activation button.
- a rear assembly which comprises a plastic rod with a spring assembly and an activation button.
- the reservoir may be a barrel or a cartridge, such as, for example, a barrel of a pre-filled syringe or a cartridge of an auto-injector. It may be made up of a material selected from glass, plastic or a polymeric material. In some preferred embodiments, the reservoir is made up of glass, such as USP Type I siliconized glass or non-pyogenic glass material. In other embodiments, the reservoir is made up of a non-glass plastic or polymeric material selected from cycloolefin polymer, cycloolefin copolymer, polyolefins, styrene-polyolefin based polymers and block co-polymers, polycarbonates and the like. In one preferred embodiment, the reservoir is a non-pyogenic glass barrel of a pre-filled syringe or non-pyogenic glass cartridge of an auto-injector.
- the reservoir may have a stacked needle at one end.
- the reservoir is needleless and has a luer tipped lock at one end with provision for attaching a needle at the leur tip before use.
- the stalked needle may be made up of stainless steel.
- the needle tip is shielded or covered with a needle shield or tip cap.
- the reservoir containing the sterile aqueous solution of drug is further sealed with a stopper such as a plunger stopper at the other end.
- the plunger stopper, the needle shield/tip cap or the cap of leur lock is made up of a non-glass component.
- the non-glass component may be a rubber or elastomeric material such as for example, bromobutyl rubber, chlorobutyl rubber, USP type II rubber, natural rubber made up of poly-cis-1,4-isoprene, styrene butadiene rubber and the like. Other suitable materials include high density polyethylene or low density polyethylene or other plastic materials.
- the plunger stopper is made up of bromobutyl rubber and the needle shield or tip cap is made up of natural rubber.
- the needle shield may further be covered on an outer side by a rigid shield made up of polypropylene. It protects the needle shield from damage and enhances removal of needle shield before injection.
- the injection device assembly may have a plunger rod that attaches to the plunger stopper and is used to push the plunger stopper along with the solution towards the needle end while administering the drug.
- the ready-to-inject, sterile, stable aqueous solution of cetrorelix is filled in the reservoir of the injection device and stoppered in such a manner that there is substantially no headspace air left inside the reservoir.
- the aqueous solution in the reservoir always remains in contact with the plunger stopper made up of elastomeric or rubber material during storage.
- the plunger stopper made up of elastomeric or rubber material during storage.
- the aqueous solution remains in contact with the needle and the needle shield or tip cap during storage.
- the injection device may optionally be packaged or enclosed in a secondary packaging.
- the secondary packaging may be a blister pack or an aluminum pouch and/or an opaque carton.
- a suitable oxygen scavenger may optionally be placed inside the secondary packaging.
- the stability testing of the parenteral dosage form is done by storing the dosage form at 2-8° C. and at room temperature (25° C./60% relative humidity). During stability testing, the ready-to-inject sterile solution of cetrorelix remains in contact with the plunger stopper and needle shield made up of elastomeric rubber material as well as with the stacked needle made up of stainless steel.
- the parenteral dosage form comprising the ready-to-inject sterile aqueous solution of cetrorelix according to the present invention remains physically and chemically stable for a period of 1 year, preferably 2 years when stored at 2-8° C. and at least for 6 months at room temperature (25° C., 60% relative humidity).
- the concentration of Impurity A remains less than 1.0% by weight of cetrorelix base upon storage of the filled injection device at room temperature (25° C./60% relative humidity) for at least 6 months and at 2-8° C. for at least 24 months.
- the present invention relates to a method of inhibiting premature luteinizing hormone surges in women undergoing controlled ovarian stimulation comprising:
- a parenteral dosage form comprising: a ready-to-inject sterile, stable aqueous solution comprising:
- the stable aqueous solution comprises impurity of Formula I in an amount less than 4% w/v of cetrorelix base. More preferably, the stable aqueous solution comprises impurity of Formula I in an amount less than 3% w/v of cetrorelix base. More preferably, the stable aqueous solution comprises impurity of Formula I in an amount less than 2% w/v of cetrorelix base. More preferably, the stable aqueous solution comprises impurity of Formula I in an amount less than 1% w/v of cetrorelix base.
- the stable aqueous solution further comprises an osmotic agent and water for injection.
- the present invention relates to a method of inhibiting premature luteinizing hormone surges in women undergoing controlled ovarian stimulation comprising:
- a parenteral dosage form comprising: a ready-to-inject sterile, stable aqueous solution comprising:
- the present invention relates to a method of inhibiting premature luteinizing hormone surges in women undergoing controlled ovarian stimulation comprising: a parenteral dosage form comprising: a ready-to-inject sterile, stable aqueous solution comprising:
- the present invention relates to a method of inhibiting premature luteinizing hormone surges in women undergoing controlled ovarian stimulation comprising: a parenteral dosage form comprising: a ready-to-inject, sterile, stable aqueous solution comprising:
- this disclosure provides a decapeptide of formula I
- Impurity A This compound is termed “Impurity A” herein, as it is an impurity of a cetrorelix solution.
- composition comprising a decapeptide of formula I:
- the disclosure provides a process to identify the decapeptide of Formula I by HPLC analysis, the process comprising:
- This disclosure also provides a decapeptide of Formula I, identified by HPLC analysis, the process comprising:
- peptide related substances of cetrorelix were prepared by the known technique of solid phase peptide synthesis.
- the synthesis involved coupling of one amino acid at a time sequentially starting from c-terminal amino acid on a resin.
- the synthesis of the peptide chain was carried out using the Fluorenylmethyloxycarboyl (Fmoc)/tButyl (Fmoc/tBu) with N,N′-diisopropyl carbodiimide (DIPC) as the coupling reagent.
- DIPC N,N′-diisopropyl carbodiimide
- the peptide formed on resin was finally cleaved using trifluoroacetic acid to obtain related substances which were further purified by reverse phase high performance liquid chromatography (RP-HPLC) on a C18 Silica column using a gradient of acetonitrile/water containing 0.1% trifluoroacetic acid.
- the purified peptide related substances were lyophilized to obtain pure solid form.
- the structure of these related substances were characterized by Proton NMR, Carbon NMR, Mass spectroscopy and elemental analysis and they were referred to as Impurity A, B, D and F.
- Example 1B The details of the HPLC method is provided in Example 1B below:
- Cetrorelix and the identified impurities namely, Impurity A, Impurity B, Impurity D and Impurity F from the aqueous solution samples were separated on a reverse phase (C-18) column using gradient technique (Column: X-Select CHS C18, (150 ⁇ 4.6) mm, 2.5p. (by Waters, Ireland, Part No: 186006729), detected and quantified by Ultraviolet spectroscopy at 225 nm wavelength.
- the mobile phase was run at a flow rate of 0.7 ml/min and 1.0 ml/min. The run time of the chromatogram was 150 minutes.
- Mobile Phase A A mixture of buffer solution as below, with acetonitrile and tetrahydrofuran in the ratio of (700:280:20), degassed by sonication.
- Mobile Phase B A mixture of buffer solution as below, with acetonitrile and tetrahydrofuran in the ratio of (500:480:20), degassed by sonication.
- Buffer 2.5 g of Ammonium dihydrogen orthophsphate and 0.75 g of 1-Octane sulphonic acid sodium salt in 1000 ml water with pH adjusted to 8.0 ⁇ 0.05 using triethylamine.
- Diluent A mixture of water, acetonitrile and formic acid in the ratio of (700:300:1).
- Impurity A 3.125 mg each of Impurity A; Impurity B, Impurity D and Impurity F were taken in a 50 ml volumetric flask and dissolved in about 5 ml of diluent by sonication, followed by making up the volume using the diluent.
- the standard solution of cetrorelix acetate was prepared by weighing and transferring 20 mg of cetrorelix acetate working standard into 250 ml volumetric flask and dissolving it in about 50 ml of diluent by sonication and making up the volume with the diluent. Two ml of this solution was transferred into 250 ml volumetric flask and volume made up to the mark using the diluent with mixing.
- the aqueous solution of cetrorelix acetate from about 10 pre-filled syringes of the sample to be tested was mixed in a container.
- the solution comprises cetrorelix acetate, an organic acid, an osmotic agent and water for injection.
- Accurately about 5.0 ml of this solution was transferred in 10 ml volumetric flask and about 3 ml of the diluent was added and the solution was sonicated for 5 minutes with intermediate shaking. Volume made up using the diluent with mixing.
- the placebo was prepared by transferring accurately about 5.0 ml of placebo solution in 10 ml volumetric flask, adding about 3 ml diluent and sonicating for 5 minutes with intermediate shaking. Volume made up using the diluent with mixing 50 microlitres injections in duplicate of diluent as blank were injected into the chromatographic system. Subsequently, the system suitability solution was injected and the chromatogram was recorded. The resolution between Impurity D and Impurity F is not less than 2.0. Following this, six replicates of standard solution were injected. Subsequently, the sample and placebo preparation were injected into the chromatographic system.
- the percentage of Impurities A, B, D, F and unknown impurity was calculated excluding peaks from diluent and placebo. The sum of all known and unknown impurities provided % total impurities.
- the % of identified impurities (A, B, D, F) was calculated by following formula:
- Water for injection was taken at temperature between 2° C. to 8° C. in a vessel. Mannitol was added and dissolved gradually in water for injection with stirring, until a clear solution was obtained. To this cetrorelix acetate was added and dissolved gradually with stirring. The pH of the solution was checked and was adjusted to the pH as mentioned in Table 3 for each example of the invention and comparative examples, using specified amount (volume) of 0.1% w/v lactic acid solution. The volume was made up with water for injection. The solutions were stirred for 10-15 minutes. The solutions of the Examples were filtered aseptically through a bed of 0.2 micron membrane filter.
- the solution was aseptically filled in the reservoir of injection device, i.e., in the barrel of 1 ml glass syringe with a fill volume of 1.1 ml.
- the stacked needle in the barrel was stoppered by elastomeric needle shield, covered by a rigid cap before filling.
- the glass syringe (barrel) was stoppered with plunger stopper by vacuum stoppering in such a manner that there was substantially no headspace air left inside the syringe.
- the aqueous solution remains in contact with the plunger stopper made up of rubber, stacked needle made up of stainless steel and needle shield made up of natural rubber upon storage.
- the ready-to-inject, aqueous solution of working examples 1 to 9 and comparative examples 10 to 14 were subjected to chemical analysis at different stages. Initially, the % assay of cetrorelix in the solution before and after filtration was analyzed by the HPLC method described above. The change in the chemical assay % before and after filtration was determined.
- the solutions of the examples contained in the glass syringes were then subjected to storage stability testing.
- the % assay, the level of degradation products like the compounds of formula I, II, III and IV and the level of unknown and total impurities in the filtered solution filled in injection device of the parenteral dosage form at initial time point and upon storage at different time points at room temperature (25° C./60% relative humidity) and at 2 to 8° C. were determined using the high performance liquid chromatographic method described above.
- the parenteral dosage form of the present invention is chemically stable over a long period of time. It was found that the solutions did not exhibit any problems of agglomeration or increase in viscosity when prepared and when filled into the injection device and stored. The data also demonstrated that there was no absorption or adsorption of cetrorelix onto or into the components of the device, for instance, the rubber stopper which was in contact with the solution during the period of storage.
- the parenteral dosage form comprising the ready-to-inject aqueous solution of cetrorelix acetate of the present invention remains stable at room temperature for a prolonged period of time whereby there occurs substantially no degradation or increase in level of Impurity A, other impurities or total impurities upon storage and the solution have an extrapolated shelf life of more than 24 months.
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)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Organic Chemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Dermatology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biochemistry (AREA)
- Nutrition Science (AREA)
- Genetics & Genomics (AREA)
- Zoology (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Toxicology (AREA)
- Gynecology & Obstetrics (AREA)
- Pathology (AREA)
- Analytical Chemistry (AREA)
- General Physics & Mathematics (AREA)
- Physics & Mathematics (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Peptides Or Proteins (AREA)
Abstract
The present invention relates to a stable parenteral dosage form with a ready-to-inject sterile stable aqueous solution of cetrorelix acetate. The invention also relates to an injection device prefilled with the ready-to-inject sterile stable aqueous solution of cetrorelix acetate. The present invention relates a method of inhibiting premature luteinizing hormone surges in women undergoing controlled ovarian stimulation comprising a stable parenteral dosage form with a ready-to-inject sterile stable aqueous solution of cetrorelix acetate.
Description
- The present invention relates to a stable parenteral dosage form with a ready-to-inject, sterile, stable, aqueous solution of cetrorelix acetate. The invention also relates to an injection device prefilled with the ready-to-inject, sterile, stable, aqueous solution of cetrorelix acetate. The present invention relates to a method of inhibiting premature luteinizing hormone surges in women undergoing controlled ovarian stimulation comprising a stable parenteral dosage form with a ready-to-inject, sterile, stable, aqueous solution of cetrorelix acetate.
- Cetrorelix is gonadotropin releasing hormone antagonist (GnRH antagonist) acetyl-D-3-(2′-naphtyl)-alanine-D-4-chlorophenylalanine-D-3-(3′-pyridyl)-alanine-L-serine-L-tyrosine-D-citruline-L-leucine-L-arginine-L-proline-D-alanine-amide (C70H92ClN17O14) having the below formula. It is a decapeptide with a terminal acid amide group. It acts by blocking the action of GnRH upon the pituitary, thus rapidly suppressing the production and action of leutinizing hormone and follicle stimulating hormone.
- Aqueous solutions of peptides are required for parenteral administration. However, aqueous solutions of peptides such as cetrorelix are susceptible to chemical degradation. They are also prone to aggregation whereby the turbidity or cloudiness of the solution increases on storage.
- The first product on the market was Cetrotide®. It is available as a lyophilized powder in glass vials containing 0.25 mg or 3 mg of cetrorelix. A prefilled glass syringe having 1 ml or 3 ml of sterile water for injection is provided separately and the solution is prepared only prior to injection. Therefore, the first product solved the problem of degradation in aqueous solution simply by avoiding preparing a dosage form containing an aqueous solution that needed to be stored over time. Instead the water was removed and a lyophilizate was prepared to avoid instability problems. However, this solution to the problem has clear disadvantages—(1) expensive and time consuming process; (2) product is not ready-to-inject and requires reconstitution before administration; and (3) reconstituted solution is stable only for a short period of time. Cetrotide® thus did not fulfil a need for a ready-to-inject aqueous solution.
- U.S. Pat. No. 7,718,599 discloses that aqueous solutions of cetrorelix were prone to aggregation. Under a polarized light microscope, liquid crystalline structures were observed. To cetrorelix acetate solutions (2.5 mg/ml), gluconic acid was added, whereby at concentrations of gluconic acid less than 0.07%, resulting in a pH of 3.7, aggregation was seen within 2 days. Similar failure was reported when the pH was more than 3.7. When the concentration of gluconic acid was increased to 0.71%, resulting in a pH of 3.1, the aggregation was seen in 12 days indicating that higher concentrations of gluconic acid and thus lower pH led to improvement. The disadvantage of the method is that the degree of resolution of the problem of aggregation is dependent on the gluconic acid concentration and with more gluconic acid the pH decreases. However, U.S. Pat. No. 7,718,599 did not report the effect of pH on the chemical stability of cetrorelix. Moreover, there were no formulations where aggregation was not seen during long term storage stability studies. US 2013/0303464 discloses a ready-to-use aqueous preparation of cetrorelix comprising cetrorelix acetate, glacial acetic acid, a tonicity adjusting agent and water for injection. A suitable pH was illustrated by working examples where the pH was about 3. The preferred pH according to the invention was pH 2.8 to 3.5.
- U.S. Pat. No. 7,214,662 discloses aqueous solutions of peptides including cetrorelix acetate and suggested solutions to the problem of aggregation. It taught that carboxylic acids and especially hydroxycarboxylic acids, preferably gluconic acid, in combination with a surfactant reduces aggregation. The use of carboxylic acid according to U.S. Pat. No. 7,214,662 resulted in a low pH such as pH 2.5 to 3.
- The object of the present invention is to provide a parenteral dosage form comprising a ready-to-inject sterile stable aqueous solution of cetrorelix acetate. Another object of the invention is to provide an injection device pre-filled with the sterile stable aqueous solution of cetrorelix acetate. The term “ready-to-inject” as used herein refers to a ready-to-inject, sterile, stable, aqueous solution of cetrorelix acetate which is suitable for direct subcutaneous or intramuscular administration, i.e., it is ready-to-inject and there is no requirement of reconstitution or dilution before injection. More particularly, it is another objective that the sterile stable aqueous solution of cetrorelix acetate dispensed in an injection device be ready-to-inject, not only be physically stable in terms of control on aggregation or turbidity development but also be chemically stable such that impurities remain low while the parenteral dosage form is stored on the shelf and until it is injected into the patient subcutaneously or intra-muscularly.
- Degradation of peptides can lead to generation of other peptides and/or peptide derivatives which may themselves have pharmacological activity. Therefore the objective more particularly was to develop an appropriate method to separate individual impurities and quantify them. The objective was to limit the concentration of such impurities. The inventors discovered a High Performance Liquid Chromatographic (“HPLC”) method which gave separate peaks for several impurities which were here before not reported in the prior art. Whereas the prior art advocated low pH values to decrease the tendency for agglomeration, the inventors found with the use of their HPLC method that in the parenteral dosage form of the present invention, a pH of 3 to 5 was optimal for chemical stability in terms of increases in level of impurities over a period of time and also the aqueous solution of cetrorelix acetate could be prepared at this higher pH without agglomeration problems.
- A novel impurity discovered by the inventors was Impurity A represented by the compound of Formula I given below:
- Impurity B is characterized to have a structure represented by the compound of Formula II given below:
- Impurity D is characterized to have a structure represented by the compound of Formula III given below:
- Impurity F is characterized to have a structure represented by the compound of Formula IV given below:
- The prior art considered low pH of 3.0 to be the optimum pH for stability; however, the present invention found that at pH values of 2.5 to 3.0 advocated by the prior art, the level of Impurity A increases significantly upon storage of the solution at 25° C./60% relative humidity.
- None of the prior art identified the compounds of formula I, II, III and IV, i.e. Impurities A, B, D and F respectively.
- The present invention found that not only could the stable aqueous solution of cetrorelix acetate be prepared at a pH 3 to 5 without agglomeration problems but also the level of Impurity A and total impurities were well controlled and remain at low concentrations upon storage of the parenteral dosage form at 25° C./60% RH for at least 1 month, at least 2 months, at least 3 months, or at least 6 months. The parenteral dosage form could also be stored at 2 to 8° C. with good stability for at least 24 months.
- In one aspect, the present invention provides a parenteral dosage form comprising a stable aqueous solution comprising:
-
- (i) cetrorelix or a pharmaceutically acceptable salt thereof; and
- (ii) an impurity of Formula I in an amount less than 5% w/v of cetrorelix base,
- Preferably, the parenteral dosage form comprises impurity of Formula I in an amount less than 4% w/v of cetrorelix base. More preferably, the parenteral dosage form comprises impurity of Formula I in an amount less than 3% w/v of cetrorelix base. More preferably, the parenteral dosage form comprises impurity of Formula I in an amount less than 2% w/v of cetrorelix base. More preferably, the parenteral dosage form comprises impurity of Formula I in an amount less than 1% w/v of cetrorelix base.
- The parenteral dosage form further comprises an osmotic agent and water for injection.
- In a preferable aspect, the present invention provides a parenteral dosage form comprising a stable aqueous solution comprising:
-
- (i) cetrorelix or a pharmaceutically acceptable salt thereof; and
- (ii) an impurity of Formula I in an amount less than 1% w/v of cetrorelix base,
- In another aspect, the present invention provides a parenteral dosage form comprising a stable, aqueous solution comprising:
-
- (i) cetrorelix or a pharmaceutically acceptable salt thereof; and
- (ii) an impurity of Formula I in an amount less than 1% w/v of cetrorelix base,
- In another aspect, the present invention provides a parenteral dosage form comprising a ready-to-inject, sterile, stable, aqueous solution comprising:
-
- (i) cetrorelix or a pharmaceutically acceptable salt thereof,
- (ii) an organic acid to adjust the pH in the range of 3 to 5,
- (iii) Impurity A, a decapeptide of formula I, in an amount less than 1% w/v of cetrorelix base
-
- (iv) an osmotic agent; and
- (v) water for injection.
- In one embodiment, the invention provides a parenteral dosage form comprising a ready-to-inject sterile, stable, aqueous solution consisting of:
-
- (i) cetrorelix or a pharmaceutically acceptable salt thereof,
- (ii) an organic acid to adjust the pH in the range of 3 to 5,
- (iii) Impurity A, a decapeptide of formula I, in an amount less than 1% w/v of cetrorelix base
-
- (iv) an osmotic agent, and
- (v) water for injection.
- The parenteral dosage form comprising the ready-to-inject sterile, stable aqueous solution of cetrorelix according to the present invention remains physically and chemically stable when stored at 2 to 8° C. for at least 1 month, at least 3 months, at least 6 months, at least 12 months, at least 18 months, or at least 24 months; or at room temperature (25° C./60% RH) for at least 1 month, at least 3 months, or at least 6 months.
- Preferred embodiments of the stable parenteral dosage form can be labelled with a shelf life at 2 to 8° C. of at least 24 months or of 24 months. More preferred embodiments of the parenteral dosage form can be labelled with a shelf life of at least 6 months or of 6 months at room temperature (25° C./60% RH) storage condition.
- The concentration of decapeptides of formula I (Impurity A) remains in the range of 0.001% to 1.0%, preferably 0.05 to 0.5% by weight of cetrorelix base, single maximum unknown impurity remains less than 0.5% by weight of cetrorelix base and total impurity remains not more than 3.5% by weight of cetrorelix base upon storage at 2 to 8° C. for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 12 months, at least 18 months or at least 24 months and/or at room temperature (25° C./60% RH) for at least 1 month, at least 2 months, at least 3 months, or at least 6 months.
- The parenteral dosage form comprising the ready-to-inject sterile aqueous solution of cetrorelix according to the present invention is physically stable with no aggregation, gel formation or precipitation of the aqueous solution during the shelf-life. The aggregation or gel formation can be determined by measuring the cloudiness or turbidity of the solution. It is measured in FTU unit (Formazin Turbidity Unit) or NTU unit (Nephelometric Turbidity Unit).
- The test is performed according to the protocol described in European Pharmacopoeia 9.0. The solution is said to be free of any aggregation or gel formation if the cloudiness/turbidity value is less than or equal to 8 FTU/NTU. The higher the FTU/NTU values the higher the cloudiness or turbidity in the solution and vice-versa. The NTU values of the ready-to-inject, parenteral dosage form according to the present invention remains less than 2 NTU, preferably less than 1 NTU, more preferably less than 0.5 NTU, initially and upon long term storage of the dosage form at 2 to 8° C. for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 12 months, at least 18 months or at least 24 months and/or at room temperature (25° C./60% RH) for at least 6 months. Thus, there occurs no aggregation, gel formation or precipitation of the aqueous solution during the shelf-life. Also, there occurs no substantial increase in viscosity of the solution upon storage.
- The parenteral dosage form comprising the ready-to-inject, sterile, stable, aqueous solution of cetrorelix according to the present invention contains cetrorelix acetate at a concentration ranging from 0.26 mg/ml to 0.28 mg/ml, which amount is equivalent to 0.25 mg/ml of cetrorelix base. Preferably, cetrorelix acetate is present in the ready-to-inject sterile, stable aqueous solution at a concentration equivalent to 0.25 mg/ml of cetrorelix base.
- In one embodiment, the parenteral dosage form comprising the ready-to-inject sterile, stable aqueous solution of cetrorelix according to the present invention comprises a pH adjusting agent at a concentration sufficient to adjust the pH in the range of 3 to 6.
- In a preferred embodiment, the parenteral dosage form comprising the ready-to-inject, sterile, stable aqueous solution of cetrorelix according to the present invention comprises an organic acid as a pH adjusting agent at a concentration sufficient to adjust the pH in the range of 3 to 5, more preferably in the range of 4 to 4.5. The pH of the ready-to-inject sterile, stable aqueous solution according to the present invention may be for example, 3, 3.05, 3.10, 3.15, 3.20, 3.25, 3.30, 3.35, 3.40, 3.45, 3.5, 3.55, 3.60, 3.65, 3.70, 3.75, 3.80, 3.85, 3.90, 3.95, 4.00, 4.05, 4.10, 4.15, 4.20, 4.25, 4.30, 4.35, 4.40, 4.45, 4.50, 4.55, 4.60, 4.65, 4.70, 4.75, 4.80, 4.85, 4.90, 4.95, 5.00, 5.05, 5.10, 5.15, 5.20, 5.25, 5.30, 5.35, 5.40, 5.45, 5.50, 5.55 and 6 or intermediate ranges thereof.
- The organic acid may be selected from any parenterally acceptable organic acid soluble in water but is preferably acetic acid, more preferably lactic acid. For example, lactic acid may be used in the ready-to-inject sterile aqueous solution according to the present invention at a concentration ranging from about 0.013 mg/ml to 0.53 mg/ml, preferably in amount ranging from about 0.033 mg/ml to about 0.53 mg/ml; and intermediate ranges thereof.
- Preferably, according to the present invention, the ready-to-inject sterile, stable aqueous solution of cetrorelix comprise cetrorelix (base) and organic acid in a weight ratio ranging from 5 0.47:1 to 19.23:1, preferably in a weight ratio ranging from about 0.47:1 to 7.57:1, more preferably in a weight ratio ranging from about 1.56:1 to 7.57:1 and intermediate ranges thereof.
- The parenteral dosage form comprising the ready-to-inject sterile, stable aqueous solution of cetrorelix according to the present invention comprises an osmotic agent or tonicity adjusting agent, in amounts suitable to adjust the osmolality of the solution in the range of about 250-375 mOsm/kg, preferably 270-330 mOsm/kg. The osmotic agent that may be used in the aqueous solution according to present invention is selected from, but not limited to, mannitol, glycerol, sorbitol, sodium chloride, potassium chloride, dextrose, sucrose, and the like and mixtures thereof.
- According to one preferred embodiment, the osmotic agent is mannitol and it may be used in the aqueous solution in an amount ranging from about 40.0 mg/ml to 60.0 mg/ml, preferably in an amount ranging from about 50.0 mg/ml to 58.0 mg/ml. In one preferred embodiment, the osmotic agent is mannitol and it is used in the ready-to-inject sterile aqueous solution in an amount of about 55.0 mg/ml.
- The ready-to-inject, sterile, aqueous solution of the parenteral dosage form of the present invention does not contain lactic acid in the form of its derivatives, polymer or copolymers such as polylactic acid or polylactic-co-glycolic acid. Preferably, lactic acid is used as a sole pH adjusting agent. In preferred embodiments, the ready-to-inject sterile, aqueous solution is free of any surfactant, such as tween 80, polysorbates, poloxamers, spans and the like. The ready-to-inject sterile, aqueous solution of the parenteral dosage form avoids use of surfactants, complexing agents, preservative or anti-oxidants for solubilization or stabilization. In certain embodiments, the solution is free of complexing agents like cyclodextrins, free of co-solvents such as alcohols or glycols and is also free of preservatives and antioxidants.
- In another aspect, the present invention provides the sterile, aqueous solution of cetrorelix acetate as above which remains stable for at least 1 month, preferably for at least 3 months and more preferably for at least 6 months at 25° C. temperature and 60% relative humidity.
- In yet another aspect, the present invention provides the sterile, aqueous solution of cetrorelix acetate as above which remains stable for at least 1 month, preferably for at least 3 months, more preferably for at least 6 months, even more preferably for at least 12 months or 18 months, and most preferably for at least 24 months at 2-8° C.
- The stable parenteral dosage form comprising the ready-to-inject, sterile, stable aqueous solution of cetrorelix according to the present invention is suitable for administration by subcutaneous route or intra-muscular route. The ready-to-inject, sterile, stable aqueous solution is suitable for direct subcutaneous administration, i.e., it is ready-to-inject or ready-to-self-administer and there is no requirement of reconstitution or dilution before use. The ready-to-inject, sterile, stable aqueous solution according to the present invention does not involve lyophilization.
- The stable parenteral dosage form of the present invention is suitable for self-administration and enables the patient to self-administer a small volume of the aqueous solution subcutaneously. The volume of the ready-to-inject sterile, aqueous solution of cetrorelix filled in the reservoir of the injection device ranges from about 0.5 ml to 10.0 ml, preferably 1.0 ml to 2.0 ml, more preferably 1.0 ml. According to one of the preferred embodiments, the ready-to-inject, sterile, stable, aqueous solution of cetrorelix is filled in the reservoir of the injection device in volume of 1.0 ml. Preferably the parenteral dosage form according to the present invention is suitable for administering a single dose of cetrorelix acetate. In one embodiment, the parenteral dosage form comprises a fill volume of about 1.0 ml of aqueous solution of cetrorelix acetate suitable for self-administration as a single dose. In some embodiment, the parenteral dosage form may comprise aqueous solution of cetrorelix at a fill volume of about 10.0 ml, suitable for multiple dose administration.
- The injection device according to the stable, parenteral, dosage form of the present invention may be selected from, but not limited to, prefilled syringes, autoinjectors and the like. In one preferred embodiment, the injection device is a prefilled syringe. In another preferred embodiment, the injection device is an autoinjector such as a pen auto-injector. These pre-filled syringes or auto-injectors are suitable for self-administration or auto-injection of the drug solution by the patients in need thereof, thus providing a user friendly approach.
- In one preferred embodiment, the injection device is a prefilled syringe. The prefilled syringe comprises the following components: a reservoir such as, for example, a barrel or a cartridge, which stores the aqueous solution; a stalked needle attached at one end of the reservoir; a needle shield or tip cap that covers the needle and seals the needle tip opening, optionally, a rigid shield covering the needle shield or tip cap; a plunger stopper at other end of the reservoir that stoppers and seals the aqueous solution filled in the reservoir; a plunger rod that fits into the plunger stopper and is used to push the plunger stopper along with the solution towards the needle end while administering the drug.
- In another preferred embodiment, the injection device is an autoinjector. The auto-injector can have varied designs. In one preferred design, the autoinjector comprises the following components: a central assembly or body portion that is suitable to hold a pre-filled syringe, the syringe comprising a reservoir such as a barrel or a cartridge which stores the aqueous solution, the reservoir having a stalked needle at one end and a plunger stopper at other end. The central body portion may have a clear inspection window through which the solution in the reservoir is visible. The autoinjector further comprises a front assembly having a cap portion that holds a needle shield or tip cap, and it is attachable to the central assembly covering the stalked needle and sealing the needle tip opening. The autoinjector further comprises a rear assembly which comprises a plastic rod with a spring assembly and an activation button. During self-administration of the aqueous solution, first, the cap along with needle shield is removed from the body portion exposing the needle and subsequently after placing the body portion of the autoinjector at the site of administration the activation button is pressed, which pushes the plastic rod with spring assembly towards the plunger stopper which leads to delivery of the aqueous solution through the needle to the patient.
- The reservoir may be a barrel or a cartridge, such as, for example, a barrel of a pre-filled syringe or a cartridge of an auto-injector. It may be made up of a material selected from glass, plastic or a polymeric material. In some preferred embodiments, the reservoir is made up of glass, such as USP Type I siliconized glass or non-pyogenic glass material. In other embodiments, the reservoir is made up of a non-glass plastic or polymeric material selected from cycloolefin polymer, cycloolefin copolymer, polyolefins, styrene-polyolefin based polymers and block co-polymers, polycarbonates and the like. In one preferred embodiment, the reservoir is a non-pyogenic glass barrel of a pre-filled syringe or non-pyogenic glass cartridge of an auto-injector.
- In one or more embodiments, the reservoir may have a stacked needle at one end. In some other embodiments, the reservoir is needleless and has a luer tipped lock at one end with provision for attaching a needle at the leur tip before use. The stalked needle may be made up of stainless steel. The needle tip is shielded or covered with a needle shield or tip cap. The reservoir containing the sterile aqueous solution of drug is further sealed with a stopper such as a plunger stopper at the other end. These stoppers, needle shields or tip caps provide a physical and sterility barrier against exterior environment.
- Preferably, the plunger stopper, the needle shield/tip cap or the cap of leur lock is made up of a non-glass component. The non-glass component may be a rubber or elastomeric material such as for example, bromobutyl rubber, chlorobutyl rubber, USP type II rubber, natural rubber made up of poly-cis-1,4-isoprene, styrene butadiene rubber and the like. Other suitable materials include high density polyethylene or low density polyethylene or other plastic materials. In preferred embodiments, the plunger stopper is made up of bromobutyl rubber and the needle shield or tip cap is made up of natural rubber. The needle shield may further be covered on an outer side by a rigid shield made up of polypropylene. It protects the needle shield from damage and enhances removal of needle shield before injection. The injection device assembly may have a plunger rod that attaches to the plunger stopper and is used to push the plunger stopper along with the solution towards the needle end while administering the drug.
- Preferably, the ready-to-inject, sterile, stable aqueous solution of cetrorelix is filled in the reservoir of the injection device and stoppered in such a manner that there is substantially no headspace air left inside the reservoir. The aqueous solution in the reservoir always remains in contact with the plunger stopper made up of elastomeric or rubber material during storage. In the case of prefilled syringes having a stalked needle made up of stainless steel, the needle being covered by a needle shield or tip cap, the aqueous solution remains in contact with the needle and the needle shield or tip cap during storage.
- The injection device may optionally be packaged or enclosed in a secondary packaging. The secondary packaging may be a blister pack or an aluminum pouch and/or an opaque carton. A suitable oxygen scavenger may optionally be placed inside the secondary packaging.
- The stability testing of the parenteral dosage form is done by storing the dosage form at 2-8° C. and at room temperature (25° C./60% relative humidity). During stability testing, the ready-to-inject sterile solution of cetrorelix remains in contact with the plunger stopper and needle shield made up of elastomeric rubber material as well as with the stacked needle made up of stainless steel. In preferred embodiments, the parenteral dosage form comprising the ready-to-inject sterile aqueous solution of cetrorelix according to the present invention remains physically and chemically stable for a period of 1 year, preferably 2 years when stored at 2-8° C. and at least for 6 months at room temperature (25° C., 60% relative humidity). The concentration of Impurity A remains less than 1.0% by weight of cetrorelix base upon storage of the filled injection device at room temperature (25° C./60% relative humidity) for at least 6 months and at 2-8° C. for at least 24 months. The extrapolated shelf life of the aqueous solution of cetrorelix determined by Minitab computation for Impurity A considering levels of not more than 1%, is found to be 122 months.
- In one aspect, the present invention relates to a method of inhibiting premature luteinizing hormone surges in women undergoing controlled ovarian stimulation comprising:
- a parenteral dosage form comprising: a ready-to-inject sterile, stable aqueous solution comprising:
-
- (i) cetrorelix or a pharmaceutically acceptable salt thereof; and
- (ii) an impurity of Formula I in an amount less than 5% w/v of cetrorelix base,
- Preferably, the stable aqueous solution comprises impurity of Formula I in an amount less than 4% w/v of cetrorelix base. More preferably, the stable aqueous solution comprises impurity of Formula I in an amount less than 3% w/v of cetrorelix base. More preferably, the stable aqueous solution comprises impurity of Formula I in an amount less than 2% w/v of cetrorelix base. More preferably, the stable aqueous solution comprises impurity of Formula I in an amount less than 1% w/v of cetrorelix base.
- The stable aqueous solution further comprises an osmotic agent and water for injection.
- In one aspect, the present invention relates to a method of inhibiting premature luteinizing hormone surges in women undergoing controlled ovarian stimulation comprising:
- a parenteral dosage form comprising: a ready-to-inject sterile, stable aqueous solution comprising:
-
- (i) cetrorelix or a pharmaceutically acceptable salt thereof,
- (ii) Impurity A, a decapeptide of formula I in an amount less than 1% w/v of cetrorelix base,
- In one aspect, the present invention relates to a method of inhibiting premature luteinizing hormone surges in women undergoing controlled ovarian stimulation comprising: a parenteral dosage form comprising: a ready-to-inject sterile, stable aqueous solution comprising:
-
- (i) cetrorelix or a pharmaceutically acceptable salt thereof,
- (ii) Impurity A, a decapeptide of formula I, in an amount less than 1% w/v of cetrorelix base,
- In one preferable aspect, the present invention relates to a method of inhibiting premature luteinizing hormone surges in women undergoing controlled ovarian stimulation comprising: a parenteral dosage form comprising: a ready-to-inject, sterile, stable aqueous solution comprising:
-
- (i) cetrorelix or a pharmaceutically acceptable salt thereof,
- (ii) an organic acid to adjust the pH in the range of 3 to 5,
- (iii) Impurity A, a decapeptide of formula I, in an amount less than 1% w/v of cetrorelix base,
-
- (iv) an osmotic agent, and
- (v) water for injection.
- In another aspect, this disclosure provides a decapeptide of formula I
- This compound is termed “Impurity A” herein, as it is an impurity of a cetrorelix solution.
- This disclosure also provides a composition comprising a decapeptide of formula I:
- In another aspect, the disclosure provides a process to identify the decapeptide of Formula I by HPLC analysis, the process comprising:
-
- a) injecting a diluent comprising water, acetonitrile and formic acid into the chromatographic system,
- b) injecting a system suitability solution comprising cetrorelix acetate, diluent and impurity stock solution and recording the chromatogram,
- c) injecting a standard solution comprising cetrorelix acetate and diluent into the chromatographic system,
- d) injecting a sample comprising aqueous solution of cetrorelix acetate and placebo preparation into the chromatographic system, and
- e) determining the relative retention time and relative response factor of impurities and cetrorelix acetate with respect to cetrorelix acetate.
- This disclosure also provides a decapeptide of Formula I, identified by HPLC analysis, the process comprising:
-
- 1. injecting a diluent comprising water, acetonitrile and formic acid into the chromatographic system,
- 2. injecting a system suitability solution comprising cetrorelix acetate, diluent and impurity stock solution and recording the chromatogram,
- 3. injecting a standard solution comprising cetrorelix acetate and diluent into the chromatographic system,
- 4. injecting a sample comprising aqueous solution of cetrorelix acetate and placebo preparation into the chromatographic system, and
- 5. determining the relative retention time and relative response factor of impurities and cetrorelix acetate with respect to cetrorelix acetate,
- Hereinafter, the invention will be more specifically described by way of Examples. The examples are not intended to limit the scope of the invention and are merely used as illustrations.
- In order to investigate the degradation of cetrorelix, peptide related substances of cetrorelix were prepared by the known technique of solid phase peptide synthesis. The synthesis involved coupling of one amino acid at a time sequentially starting from c-terminal amino acid on a resin. The synthesis of the peptide chain was carried out using the Fluorenylmethyloxycarboyl (Fmoc)/tButyl (Fmoc/tBu) with N,N′-diisopropyl carbodiimide (DIPC) as the coupling reagent. The Fmoc groups were removed via treatment with 20% piperidine in dimethylformamide. The peptide formed on resin was finally cleaved using trifluoroacetic acid to obtain related substances which were further purified by reverse phase high performance liquid chromatography (RP-HPLC) on a C18 Silica column using a gradient of acetonitrile/water containing 0.1% trifluoroacetic acid. The purified peptide related substances were lyophilized to obtain pure solid form. The structure of these related substances were characterized by Proton NMR, Carbon NMR, Mass spectroscopy and elemental analysis and they were referred to as Impurity A, B, D and F.
- Impurity-A: Ac-2-D-Nal-4-Cl-D-Phe-3-D-Pal-Ser-Tyr-D-Cit-Leu-Arg-Pro-D-Ala-OH (detailed structure depicted as the Compound of Formula I),
- Impurity-B: 2-D-Nal-4-Cl-D-Phe-3-D-Pal-Ser-Tyr-D-Cit-leu-Arg-Pro-D-Ala-NH2 (detailed structure depicted as the Compound of Formula II),
- Impurity-D: Ac-2-D-Nal-4-Cl-D-Phe-3-D-Pal-Ser-Tyr-D-Cit-Leu-OH (detailed structure depicted as the Compound of Formula III), and
- Impurity-F: Ac-2-D-Nal-4-Cl-D-Phe-3-D-Pal-Ser-Tyr-D-Cit-Leu-Arg-Pro-OH (detailed structure depicted as the Compound of Formula IV).
- The degradation peaks separated on the HPLC column, were identified to be these compounds based on their relative retention time. The details of the HPLC method is provided in Example 1B below:
- Cetrorelix and the identified impurities namely, Impurity A, Impurity B, Impurity D and Impurity F from the aqueous solution samples were separated on a reverse phase (C-18) column using gradient technique (Column: X-Select CHS C18, (150×4.6) mm, 2.5p. (by Waters, Ireland, Part No: 186006729), detected and quantified by Ultraviolet spectroscopy at 225 nm wavelength. The mobile phase was run at a flow rate of 0.7 ml/min and 1.0 ml/min. The run time of the chromatogram was 150 minutes.
- Mobile Phase A: A mixture of buffer solution as below, with acetonitrile and tetrahydrofuran in the ratio of (700:280:20), degassed by sonication.
Mobile Phase B: A mixture of buffer solution as below, with acetonitrile and tetrahydrofuran in the ratio of (500:480:20), degassed by sonication.
Buffer: 2.5 g of Ammonium dihydrogen orthophsphate and 0.75 g of 1-Octane sulphonic acid sodium salt in 1000 ml water with pH adjusted to 8.0±0.05 using triethylamine.
Diluent: A mixture of water, acetonitrile and formic acid in the ratio of (700:300:1). -
TABLE 1 Details of gradient elution Time Flow Mobile Phase A Mobile Phase B (minutes) Rate (% v/v) (% v/v) 0 0.7 100 0 65 0.7 100 0 75 0.7 0 100 76 1.0 0 100 135 1.0 0 100 136 0.7 100 0 150 0.7 100 0 - 3.125 mg each of Impurity A; Impurity B, Impurity D and Impurity F were taken in a 50 ml volumetric flask and dissolved in about 5 ml of diluent by sonication, followed by making up the volume using the diluent.
- This was prepared by weighing and transferring about 12.5 mg of cetrorelix acetate working standard in 100 ml volumetric flask and dissolving it in about 50 ml of diluent by sonication, followed by addition of about 2 ml of impurity stock solution and making up the volume using the diluent.
- The standard solution of cetrorelix acetate was prepared by weighing and transferring 20 mg of cetrorelix acetate working standard into 250 ml volumetric flask and dissolving it in about 50 ml of diluent by sonication and making up the volume with the diluent. Two ml of this solution was transferred into 250 ml volumetric flask and volume made up to the mark using the diluent with mixing.
- The aqueous solution of cetrorelix acetate from about 10 pre-filled syringes of the sample to be tested (prepared according to example as described above) was mixed in a container. The solution comprises cetrorelix acetate, an organic acid, an osmotic agent and water for injection. Accurately about 5.0 ml of this solution was transferred in 10 ml volumetric flask and about 3 ml of the diluent was added and the solution was sonicated for 5 minutes with intermediate shaking. Volume made up using the diluent with mixing.
- The placebo was prepared by transferring accurately about 5.0 ml of placebo solution in 10 ml volumetric flask, adding about 3 ml diluent and sonicating for 5 minutes with intermediate shaking. Volume made up using the diluent with mixing 50 microlitres injections in duplicate of diluent as blank were injected into the chromatographic system. Subsequently, the system suitability solution was injected and the chromatogram was recorded. The resolution between Impurity D and Impurity F is not less than 2.0. Following this, six replicates of standard solution were injected. Subsequently, the sample and placebo preparation were injected into the chromatographic system.
- The relative retention time and relative response factor of cetrorelix acetate and Impurities A, B, D and F with respect to cetrorelix acetate are presented in Table 2.
-
TABLE 2 Name of Retention Time Relative retention compound (minute) time Cetrorelix 42.3 1.00 Impurity A 23.5 0.55 Impurity B 56.8 1.34 Impurity D 16.9 0.39 Impurity F 20.3 0.48 - The percentage of Impurities A, B, D, F and unknown impurity was calculated excluding peaks from diluent and placebo. The sum of all known and unknown impurities provided % total impurities.
- The % of identified impurities (A, B, D, F) was calculated by following formula:
-
-
-
- A1=Peak response of each known impurity in the chromatogram of test preparation AS=Average peak response of cetrorelix in the chromatogram of standard preparation WS=Weight of cetrorelix acetate working standard in mg
- V=Volume of sample taken in ml
- P=% potency of cetrorelix working standard (on as is basis) LC=Label claim of cetrorelix in mg per ml (0.25 mg/ml) RRF=Relative response factor of each Impurity
- The % of Unknown impurity was calculated by following formula
-
-
-
- A1=Peak response of each unknown impurity in the chromatogram of test preparation AS=Average peak response of cetrorelix in the chromatogram of Standard preparation WS=Weight of cetrorelix acetate working standard in mg
- V=Volume of sample taken in ml
- P=% potency of cetrorelix working standard (on as is basis) LC=Label claim of cetrorelix in mg per ml (0.25 mg/ml)
- The total impurities (%)=Sum of % known impurities and % unknown impurities.
-
TABLE 3 Composition Example Examples of the invention Comparative examples Numbers 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Ingredients Quantity (mg/ml) Cetrorelix 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 acetate expressed as cetrorelix base Mannitol 54.8 54.8 54.8 54.8 54.8 54.8 54.8 54.8 54.8 54.8 54.8 54.8 54.8 54.8 Lactic acid q.s to adjust pH pH 3 3.1 3.2 3.3 3.4 3.5 4 4.5 5 2.5 2.6 2.7 2.8 2.9 Water for q.s to 1 ml Injection - Water for injection was taken at temperature between 2° C. to 8° C. in a vessel. Mannitol was added and dissolved gradually in water for injection with stirring, until a clear solution was obtained. To this cetrorelix acetate was added and dissolved gradually with stirring. The pH of the solution was checked and was adjusted to the pH as mentioned in Table 3 for each example of the invention and comparative examples, using specified amount (volume) of 0.1% w/v lactic acid solution. The volume was made up with water for injection. The solutions were stirred for 10-15 minutes. The solutions of the Examples were filtered aseptically through a bed of 0.2 micron membrane filter. The solution was aseptically filled in the reservoir of injection device, i.e., in the barrel of 1 ml glass syringe with a fill volume of 1.1 ml. The stacked needle in the barrel was stoppered by elastomeric needle shield, covered by a rigid cap before filling. After filling, the glass syringe (barrel) was stoppered with plunger stopper by vacuum stoppering in such a manner that there was substantially no headspace air left inside the syringe. The aqueous solution remains in contact with the plunger stopper made up of rubber, stacked needle made up of stainless steel and needle shield made up of natural rubber upon storage.
- The ready-to-inject, aqueous solution of working examples 1 to 9 and comparative examples 10 to 14 were subjected to chemical analysis at different stages. Initially, the % assay of cetrorelix in the solution before and after filtration was analyzed by the HPLC method described above. The change in the chemical assay % before and after filtration was determined.
- The solutions of the examples contained in the glass syringes were then subjected to storage stability testing. The % assay, the level of degradation products like the compounds of formula I, II, III and IV and the level of unknown and total impurities in the filtered solution filled in injection device of the parenteral dosage form at initial time point and upon storage at different time points at room temperature (25° C./60% relative humidity) and at 2 to 8° C. were determined using the high performance liquid chromatographic method described above.
- It was found that after 6 months of storage at room temperature the level of Impurities A, B, single maximum unknown impurity and the total impurities remained unchanged or the change was small. Based on this data it is expected that the parenteral dosage form of the present invention is chemically stable over a long period of time. It was found that the solutions did not exhibit any problems of agglomeration or increase in viscosity when prepared and when filled into the injection device and stored. The data also demonstrated that there was no absorption or adsorption of cetrorelix onto or into the components of the device, for instance, the rubber stopper which was in contact with the solution during the period of storage.
- The stability results for the stable parenteral dosage form at 25° C./60% RH and 2-8° C. according to the present invention are provided in Table 4 and Table 5 below:
-
TABLE 4 Observation at different time points upon storage at (25° C./60% RH) Impurity Impurity Single maximum unknown Total A (%) B (%) impurity (%) impurity (%) Time points (months) pH 0 1 3 6 0 1 3 6 0 1 3 6 0 1 3 6 3 BQL 0.20 0.54 1.0 0.055 ND ND BQL 0.113 0.123 0.112 0.431 0.363 0.398 0.748 1.829 3.5 BQL 0.07 0.23 0.40 0.068 ND BQL BQL 0.105 0.148 0.189 0.392 0.335 0.292 0.623 1.059 4 BQL BQL 0.09 0.15 0.039 ND ND ND 0.095 0.162 0.196 0.388 0.308 0.302 0.496 0.792 4.5 ND BQL BQL 0.04 0.058 ND ND ND BQL 0.159 0.204 0.331 0.308 0.237 0.331 0.563 5 BQL BQL — — ND BQL — — 0.119 0.125 0.205 0.208 — — ND: Not Detected; RH—Relative Humidity; BQL: Below Quantifiable limit -
TABLE 5 Observation at different time points upon storage at (2-8° C.) Impurity Impurity A (%) B (%) Time points (months) pH 0 1 3 6 12 18 24 0 1 3 6 12 18 24 3 BQL 0.05 0.08 0.18 0.363 0.49 0.545 0.055 ND ND ND BQL BQL BQL 3.5 BQL BQL BQL 0.06 0.144 0.171 0.238 0.068 BQL ND ND BQL BQL BQL 4 BQL BQL BQL 0.03 0.055 0.068 0.078 0.039 ND ND ND ND ND BQL 4.5 ND BQL ND BQL BQL BQL BQL 0.058 ND ND ND ND BQL ND Observation at different time points upon storage at (2-8° C.) Single maximum unknown impurity (%) Total impurity (%) Time points (months) pH 0 1 3 6 12 18 24 0 1 3 6 12 18 24 3 0.113 0.079 0.08 0.146 0.109 0.138 0.15 0.363 0.206 0.161 0.333 0.551 0.628 0.695 3.5 0.105 0.087 0.069 0.135 0.108 0.139 0.149 0.335 0.087 0.069 0.197 0.337 0.31 0.387 4 0.095 0.16 0.144 0.138 0.105 0.186 0.15 0.308 0.23 0.144 0.174 0.242 0.398 0.228 4.5 BQL 0.142 0.136 0.136 0.107 0.134 0.15 0.308 0.213 0.136 0.136 0.193 0.202 0.15 ND: Not Detected; RH—Relative Humidity; BQL: Below Quantifiable limit -
TABLE 6 Assay of Cetrorelix acetate eq. to Cetrorelix (%) Storage conditions Un- 2-8° C. 25° C./60% RH pH filtered Initial 1M 2M 3M 6M 12M 18M 24M 1M 2M 3M 6M 2.5 104.05 103.97 103.03 105.51 105.04 104.54 103.7 — — 102.76 102.9 102.9 99.97 3 103.56 101.11 101.8 104.9 105.42 104 103.5 104.93 104.77 102.09 104.71 105.08 102.36 3.5 103.86 102.51 101.82 104.88 102.88 104.2 103.1 104.13 104.16 103.65 103.62 102.23 103.68 4 103.76 102.96 104 104.17 104.75 104.84 103.3 104.48 103.61 102.58 103.28 103.72 103.39 4.5 102.52 99.56 103.43 103.97 103.57 103.59 102.6 103.97 103.86 101.66 103.62 102.79 102.77 5 99.48 — — — — — 99.02 — — — - The stability results for additional intermediate pH ranges were studied at different time points upon storage at 25° C./60% RH and 2-8° C. are given in Table 7 below:
-
TABLE 7 Observation at different time points upon storage Impurity A (%) Time 0M 1M 3M 6M 12M points pH I II III I II III I II III I II III I II III At 3.1 0.04 NA NA 0.28 0.27 0.27 0.53 0.54 0.53 0.62 0.63 0.62 — — — (25° C. 3.2 BQL NA NA 0.29 0.29 0.30 0.57 0.57 0.57 0.64 0.63 0.64 — — — 60% 3.3 BQL NA NA 0.17 0.18 0.17 0.37 0.37 0.37 0.42 0.42 0.42 — — — RH) 3.4 BQL NA NA 0.2 0.2 0.20 0.34 0.34 0.34 0.39 0.39 0.39 — — — At 3.1 0.04 NA NA 0.14 0.15 0.14 0.25 0.24 0.24 0.17 0.17 0.18 0.24 0.25 0.24 2-8° C. 3.2 BQL NA NA 0.14 0.15 0.15 0.26 0.27 0.26 0.17 0.17 0.18 0.29 0.29 0.29 3.3 BQL NA NA 0.1 0.09 0.10 0.17 0.18 0.18 0.11 0.11 0.11 0.18 0.18 0.18 3.4 BQL NA NA 0.09 0.10 0.09 — — — — — — — — — Observation at different time points upon storage Single maximum unknown impurity (%) Time points (months) Time 0M 1M 3M 6M 12M points pH I II III I II III I II III I II III I II III At 3.1 0.13 NA NA 0.15 0.124 0.143 0.223 0.211 0.224 0.192 0.153 0.178 — — — (25° C. 3.2 0.129 NA NA 0.136 0.141 0.138 0.214 0.21 0.208 0.18 0.173 0.171 — — — 60% 3.3 0.137 NA NA 0.139 0.153 0.137 0.214 0.213 0.211 0.175 0.184 0.175 — — — RH) 3.4 0.131 NA NA 0.165 0.15 0.12 0.21 0.204 0.203 0.166 0.174 0.167 — — — At 3.1 0.13 NA NA 0.128 0.115 0.123 0.115 0.143 0.129 0.129 0.127 0.134 0.116 0.119 0.121 2-8° C. 3.2 0.129 NA NA 0.134 0.127 0.127 0.131 0.139 0.126 0.135 0.129 0.134 0.119 0.119 0.123 3.3 0.137 NA NA 0.123 0.126 0.12 0.126 0.12 0.123 0.118 0.129 0.129 0.138 0.135 0.13 3.4 0.131 NA NA 0.123 0.128 0.124 — — — — — — — — — Observation at different time points upon storage Impurity B (%) Time 0M 1M 3M 6M 12M points pH I II III I II III I II III I II III I II III At 3.1 ND NA NA ND ND — BQL BQL BQL BQL BQL BQL — — — (25° C. 3.2 ND NA NA BQL BQL BQL BQL BQL BQL BQL BQL BQL — — — 60% 3.3 ND NA NA ND ND ND BQL BQL BQL BQL BQL BQL — — — RH) 3.4 ND NA NA ND ND ND BQL BQL BQL BQL BQL BQL — — — At 3.1 ND NA NA ND ND ND BQL BQL BQL BQL BQL BQL — — — 2-8° C. 3.2 ND NA NA ND ND ND BQL BQL BQL BQL BQL BQL BQL BQL BQL 3.3 ND NA NA ND ND ND BQL BQL BQL BQL BQL BQL ND ND ND 3.4 ND NA NA ND ND ND BQL BQL BQL BQL BQL BQL ND ND ND Observation at different time points upon storage Total impurity (%) Time points (months) Time 0M 1M 3M 6M 12M points pH I II III I II III I II III I II III I II III At 3.1 0.178 NA NA 0.567 0.517 0.55 0.865 0.873 0.866 0.934 0.898 0.93 — — — (25° C. 3.2 0.129 NA NA 0.569 0.57 0.571 0.906 0.896 0.892 1.037 0.932 0.935 — — — 60% 3.3 0.228 NA NA 0.512 0.448 0.429 0.7 0.7 0.586 0.72 0.725 0.719 — — — RH) 3.4 0.201 NA NA 0.523 0.49 0.485 0.667 0.656 0.66 0.678 0.693 0.687 — — — At 3.1 0.178 NA NA 0.381 0.361 0.365 0.365 0.46 0.373 0.299 0.293 0.311 0.358 0.365 0.364 2-8° C. 3.2 0.129 NA NA 0.423 0.436 0.48 0.504 0.581 0.501 0.379 0.303 0.311 0.492 0.405 0.41 3.3 0.228 NA NA 0.315 0.4 0.386 0.419 0.415 0.415 0.294 0.236 0.238 0.321 0.319 0.312 3.4 0.201 NA NA 0.333 0.332 0.327 — — — — — — — — — -
TABLE 8 Assay of Cetrorelix acetate eq. to Cetrorelix (%) Storage conditions 2-8° C. 25° C./60% RH pH Unfiltered Initial 1M 3M 6M 12M 1M 3M 6M 3.1 99.96 98.67 99.12 99.32 98.98 98.94 98.65 97.65 97.52 3.2 100.89 100.21 99.9 100.89 99.61 101.27 100.06 100.38 98.2 3.3 99.96 99.05 98.58 100.03 99.13 100.29 98.97 99.87 98.13 3.4 100.02 98.54 99.59 — — — 99.91 99.97 99.03 -
TABLE 9 Stability data of cetrorelix acetate Injection 0.25 mg/ml, 1 ml PFS at pH 5 Each mL contains cetrorelix acetate eq. to cetrorelix 0.25 Mg, Mannitol 54.8 mg, Lactic acid q.s. to pH adjusted 5.0, Water For Injection q.s. to 1 mL Related Substances Unknown Assay of Impurities Cetrorelix Highest acetate eq. To Known Impurities Unknown Total Cetrorelix Impurity A Impurity B Impurity Impurities 95.0% to Not more Not more Not more Not more Description 105.0% of LC than 1.0% than 1.0% than 0.5% than 3.5% UNFILTER * 99.59 INITIAL * 99.67 BQL (<0.035%) ND 0.131 0.131 2-8° C. 1M * 98.13 BQL (<0.035%) ND 0.11 0.182 OTS 2M * 98.6 ND ND 0.109 0.208 3M * 99.98 ND ND 0.112 0.198 25° C./60% 1M * 98 BQL (<0.035%) ND 0.106 0.106 RH 2M * 98.24 0.074 ND 0.109 0.369 OTS 3M * 98.18 0.18 ND 0.107 0.353 ND: Not Detected; RH—Relative Humidity; BQL: Below Quantifiable limit; * Clear colorless solution filled in 1 ml PFS -
TABLE 10 Observation at different time points upon storage Impurity A (%) Time 0M 1M 3M 6M 12M points pH I II III I II III I II III I II III I II III At 2.5 0.08 — — 0.82 — — 1.97 — — 3.38 — — — — — (25° C. 2.6 0.08 0.08 0.08 1.28 1.29 1.29 2.20 2.19 2.19 — — — — — — 60% 2.7 0.58 0.59 0.58 0.99 1.00 0.98 1.65 1.65 1.64 1.85 1.84 1.86 — — — RH) 2.8 0.06 0.07 0.07 0.80 0.81 0.80 1.38 1.39 1.39 1.56 1.56 1.56 — — — 2.9 0.06 0.06 0.05 0.67 0.66 0.66 1.12 1.13 1.12 1.30 1.32 1.30 — — — At 2- 2.5 0.08 — — 0.20 — — 0.35 — — 0.63 — — 1.33 8° C. 2.6 0.08 0.08 0.08 0.72 0.73 0.72 1.12 1.13 1.15 — — — — — — 2.7 0.58 0.59 0.58 0.58 ND ND 0.90 0.91 0.91 0.60 0.6 0.59 — — — 2.8 0.06 0.07 0.07 0.48 0.49 0.48 0.74 0.77 0.74 0.46 0.45 0.46 — — — 2.9 0.06 0.06 0.05 0.42 0.42 0.41 0.63 0.63 0.61 0.39 0.39 0.40 — — — Observation at different time points upon storage Single maximum unknown impurity (%) Time points (months) Time 0M 1M 3M 6M 12M points pH I II III I II III I II III I II III I II III At 2.5 0.105 — — 0.159 — — 0.178 — — 0.417 — — — — — (25° C. 2.6 0.138 0.125 0.121 0.155 0.154 0.151 0.18 0.199 0.201 — — — — — — 60% 2.7 0.141 0.153 0.141 0.145 0.148 0.189 0.266 0.237 0.245 0.191 0.2 0.194 — — — RH) 2.8 0.14 0.133 0.145 0.173 0.129 0.133 0.25 0.218 0.247 0.21 0.166 0.165 — — — 2.9 0.142 0.131 0.14 0.137 0.132 0.139 0.23 0.222 0.223 0.19 0.159 0.167 — — — At 2- 2.5 0.105 — — 0.173 — — 0.131 — — 0.139 — — 0.11 — — 8° C. 2.6 0.138 0.125 0.121 0.107 0.122 0.114 0.14 0.14 0.142 — — — — — — 2.7 0.141 0.153 0.141 0.116 0.109 0.111 0.135 0.146 0.191 0.126 0.132 0.113 — — — 2.8 0.14 0.133 0.145 0.11 0.135 0.135 0.141 0.14 0.125 0.124 0.111 0.11 — — — 2.9 0.142 0.131 0.14 0.126 0.124 0.117 0.137 0.126 0.147 0.112 0.135 0.123 — — — Observation at different time points upon storage Impurity B (%) Time 0M 1M 3M 6M 12M points pH I II III I II III I II III I II III I II III At 2.5 0.072 — — BQL — — 0.23 — — 0.36 — — — — — (25° C. 2.6 ND — — ND ND ND 0.23 0.21 0.25 — — — — — — 60% 2.7 ND — — ND ND ND 0.21 0.18 BQL 0.182 0.22 0.19 — — — RH) 2.8 ND — — ND ND ND BQL 0.183 BQL BQL BQL BQL — — — 2.9 ND — — ND ND ND BQL BQL BQL 0.204 0.204 0.194 — — — At 2- 2.5 0.072 — — BQL — — BQL — — BQL — — BQL — — 8° C. 2.6 ND — — BQL ND ND BQL BQL BQL — — — — — — 2.7 ND — — ND ND ND BQL BQL BQL BQL BQL BQL — — — 2.8 ND — — ND ND ND BQL BQL BQL BQL BQL BQL — — — 2.9 ND — — ND ND ND BQL BQL BQL BQL BQL BQL — — — Observation at different time points upon storage Total Impurity (%) Time points (months) Time 0M 1M 3M 6M 12M points pH I II III I II III I II III I II III I II III 2.5 0.409 — — 1.067 — — 2.57 — — 4.404 — — — — — At 2.6 0.227 0.214 0.21 1.708 1.69 1.721 2.821 2.789 2.896 — — — — — — (25° C. 2.7 0.381 0.393 0.311 1.365 1.344 1.46 2.313 2.269 2.092 2.424 2.486 2.423 — — — 60% 2.8 0.277 0.209 0.299 1.214 1.162 1.149 1.767 1.909 1.831 2.032 2.011 1.914 — — — RH) 2.9 0.272 0.283 0.195 0.939 0.919 1.048 1.496 1.459 1.457 1.902 1.788 1.799 — — — 2.5 0.409 — — 0.43 — — 0.484 — — 0.842 — — 1.521 — — At 2- 2.6 0.227 0.214 0.21 0.923 1.022 0.93 1.353 1.374 1.383 — — — — — — 8° C. 2.7 0.381 0.393 0.311 0.863 0.866 0.786 1.163 1.188 1.373 0.798 0.731 0.779 — — — 2.8 0.277 0.209 0.299 0.679 0.731 0.731 1.077 1.121 0.991 0.655 0.646 0.725 — — — 2.9 0.272 0.283 0.195 0.673 0.664 0.636 0.897 0.884 0.872 0.505 0.525 0.526 — — — ND: Not Detected; RH—Relative Humidity; BQL: Below Quantifiable limit; NA: Not available -
TABLE 11 Assay of Cetrorelix acetate eq. to Cetrorelix (%) Storage conditions 2-8° C. Initial 1M 3 6M pH Unfiltered I II III I II III I II III I II III 2.6 100.05 100.25 100.04 99.63 98.65 98.32 99.27 98.27 98.22 97.45 2.7 — 100.75 100.4 100.66 98.69 99.22 98.78 98.94 98.74 99.77 99.87 97.82 99 2.8 — 100.7 100.93 100.99 99.39 98.76 99.05 98.69 99.33 98.57 99.85 100.18 99.92 2.9 — 97.55 97.6 97.68 98.64 98.62 98.47 95.37 95.42 95.55 97.75 97.8 98.52 Assay of Cetrorelix acetate eq. to Cetrorelix (%) Storage conditions 25° C./60% RH 1M 3M 6M pH Unfiltered I II III I II III I II III 2.6 100.05 97 97.76 97.21 96.58 96.25 96.63 2.7 — 98.36 98.22 98.55 97.4 98.04 97.55 96.97 97.07 97.09 2.8 — 97.64 97.62 97.65 97.74 97.65 97.94 98.12 96.51 96.04 2.9 — 96.92 96.84 96.56 95.19 94.8 94.8 94.23 94.32 95.26 - An aqueous solution of cetrorelix acetate was prepared as per the disclosure of US 2013/0303464 (Patel et al.). The composition is illustrated below in Table 12:
-
TABLE 12 Ingredients Quantity (mg/ml) Cetrorelix acetate 0.25 Mannitol 42.0 Glacial Acetic acid q.s to pH 3.0 Water for injection 1 ml - Method of Preparation: Water for injection was taken at temperature between 2° C. to 8° C. in a vessel Mannitol was added and dissolved gradually in water for injection with stirring, until a clear solution was obtained. To this cetrorelix acetate was added and dissolved gradually with stirring. Glacial acetic acid was then added and the pH of the solution was adjusted to about 3.0. The volume was made up with water for injection. The solution was stirred for 10-15 minutes and subsequently filtered aseptically through a bed of 0.2 μm membrane filter (optiscale 47 capsule, Polyethersulfone membrane filter by Millipore). The solution was aseptically filled in the reservoir of injection device, i.e. in the barrel of 1 ml glass syringe with a fill volume of 1.1 ml. The stacked needle in the barrel was stoppered by elastomeric needle shield, covered by a rigid cap before filling. After filling, the glass syringe (barrel) was stoppered with plunger stopper by vacuum stoppering in such a manner that there was substantially no headspace air left inside the syringe. The aqueous solution remains in contact with the plunger stopper made up of rubber, stacked needle made up of stainless steel and needle shield made up of natural rubber upon storage.
- The solution of this comparative example (comparative example 2) filled in glass syringe was subjected to storage stability testing. The level of Impurity A, Impurity B and total impurity in the solution were analyzed initially and upon storage at room temperature (25° C./60% relative humidity) by high performance liquid chromatographic technique. The results are provided in Table 13 below.
-
TABLE 13 Stability results of comparative example 2 Impurity A (%) Impurity B (%) Total impurity (%) (25° C./60% RH) (25° C./60% RH) (25° C./60% RH) Time Point (Months) 0 3 6 0 3 6 0 3 6 0.06 0.84 1.77 ND 0.07 0.17 0.99 1.88 2.83 ND. Not detected; RH—Relative Humidity - It was observed that the solution of cetrorelix acetate of US 2013/0303464 (comparative) showed significant increase in the level of Impurity A and total impurity upon storage at room temperature. Particularly, the level of Impurity A which is a degradation impurity increases significantly and increases to 1.77% by weight of cetrorelix in 6 months. Also the level of total impurity increases to 2.83% by weight of cetrorelix in 6 months.
- In contrast, the parenteral dosage form comprising the ready-to-inject aqueous solution of cetrorelix acetate of the present invention remains stable at room temperature for a prolonged period of time whereby there occurs substantially no degradation or increase in level of Impurity A, other impurities or total impurities upon storage and the solution have an extrapolated shelf life of more than 24 months.
Claims (22)
2. The parenteral dosage form as claimed in claim 1 , wherein the dosage form is a sterile, stable, aqueous solution.
3. The parenteral dosage form as claimed in claim 1 , wherein the dosage form is a sterile, ready-to-infuse dosage form.
4. The parenteral dosage form as claimed in claim 1 , wherein the stable, aqueous solution further comprises an organic acid to adjust the pH in the range of 3 to 5.
5. The parenteral dosage form as claimed in claim 4 , wherein the stable, aqueous solution further comprises an osmotic agent.
6. A parenteral dosage form according to claim 1 , wherein the amount of cetrorelix or a pharmaceutically acceptable salt thereof is 0.25 mg/ml.
7. A parenteral dosage form according to claim 5 , wherein the osmotic agent is present in an amount sufficient for osmolality of the solution in the range of 250 to 375 mOsm/Kg.
8. The parenteral dosage form according to claim 1 , wherein the parenteral dosage form is a ready-to-inject, sterile, stable aqueous solution present in the reservoir of an injection device.
9. The parenteral dosage form according to claim 8 , wherein the injection device is a prefilled syringe.
10. The parenteral dosage form according to claim 8 , wherein the injection device is an auto-injector.
11. The parenteral dosage form according to claim 8 , wherein the injection device is a pen auto-injector.
12. The parenteral dosage form according to claim 1 , wherein the stable, aqueous solution is stable for at least 1 month at 25° C. temperature and 60% relative humidity.
13. The parenteral dosage form according to claim 1 , wherein the stable, aqueous solution is stable for at least 3 months at 25° C. temperature and 60% relative humidity.
14. The parenteral dosage form according to claim 1 , wherein the stable, aqueous solution is stable for at least 6 months at 25° C. temperature and 60% relative humidity.
15. The parenteral dosage form according to claim 1 , wherein the parenteral dosage form is suitable for subcutaneous use.
16. The parenteral dosage form according to claim 1 , wherein the parenteral dosage form is suitable for intramuscular use.
18. A method of inhibiting premature luteinizing hormone surges in women undergoing controlled ovarian stimulation comprising:
a parenteral dosage form comprising: a ready-to-inject, sterile, stable, aqueous solution comprising:
(i) cetrorelix or a pharmaceutically acceptable salt thereof,
(ii) Impurity A, a decapeptide of formula I, in an amount less than 1% w/v of cetrorelix base,
20. The decapeptide of claim 19 , wherein the decapeptide is identified by HPLC analysis, the process comprising:
a) injecting a diluent comprising water, acetonitrile and formic acid into the chromatographic system,
b) injecting a system suitability solution comprising cetrorelix acetate, diluent and impurity stock solution and recording the chromatogram,
c) injecting a standard solution comprising cetrorelix acetate and diluent into the chromatographic system,
d) injecting a sample comprising aqueous solution of cetrorelix acetate and placebo preparation into the chromatographic system, and
e) determining the relative retention time and relative response factor of impurities and cetrorelix acetate with respect to cetrorelix acetate.
21. A process to identify the decapeptide of claim 19 by HPLC analysis, the process comprising:
a) injecting a diluent comprising water, acetonitrile and formic acid into the chromatographic system,
b) injecting a system suitability solution comprising cetrorelix acetate, diluent and impurity stock solution and recording the chromatogram,
c) injecting a standard solution comprising cetrorelix acetate and diluent into the chromatographic system,
d) injecting a sample comprising aqueous solution of cetrorelix
acetate and placebo preparation into the chromatographic system, and e) determining the relative retention time and relative response factor of impurities and cetrorelix acetate with respect to cetrorelix acetate.
22. The process of claim 21 , wherein the mobile phase A and B in the HPLC analysis comprises a buffer, acetonitrile and tetrahydrofuran, and
wherein the relative retention time and relative response factor for the decapeptide is determined to be 0.57 and 1.0, respectively.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN201921043355 | 2019-10-24 | ||
IN201921043355 | 2019-10-24 | ||
PCT/IB2020/059988 WO2021079339A1 (en) | 2019-10-24 | 2020-10-23 | A stable parenteral dosage form of cetrorelix acetate |
Publications (1)
Publication Number | Publication Date |
---|---|
US20220153802A1 true US20220153802A1 (en) | 2022-05-19 |
Family
ID=69784288
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US16/814,447 Pending US20210121517A1 (en) | 2019-10-24 | 2020-03-10 | Stable parenteral dosage form of cetrorelix acetate |
US17/593,512 Pending US20220153802A1 (en) | 2019-10-24 | 2020-10-23 | A stable parenteral dosage form of cetrorelix acetate |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US16/814,447 Pending US20210121517A1 (en) | 2019-10-24 | 2020-03-10 | Stable parenteral dosage form of cetrorelix acetate |
Country Status (28)
Country | Link |
---|---|
US (2) | US20210121517A1 (en) |
EP (2) | EP3811927B8 (en) |
JP (1) | JP2023501902A (en) |
KR (1) | KR20220114533A (en) |
CN (1) | CN114599384A (en) |
AR (1) | AR120290A1 (en) |
AU (1) | AU2020369236A1 (en) |
BR (1) | BR112022007746A2 (en) |
CA (1) | CA3155348A1 (en) |
CL (1) | CL2022001021A1 (en) |
CO (1) | CO2022006820A2 (en) |
DK (1) | DK3811927T3 (en) |
ES (1) | ES2902784T3 (en) |
HR (1) | HRP20211890T1 (en) |
HU (1) | HUE058963T2 (en) |
IL (1) | IL293908A (en) |
JO (1) | JOP20220094A1 (en) |
LT (1) | LT3811927T (en) |
MA (2) | MA55417B1 (en) |
MD (1) | MD3811927T2 (en) |
MX (1) | MX2022004859A (en) |
PL (1) | PL3811927T3 (en) |
PT (1) | PT3811927T (en) |
RS (1) | RS62754B1 (en) |
SI (1) | SI3811927T1 (en) |
TW (1) | TW202128210A (en) |
WO (1) | WO2021079339A1 (en) |
ZA (1) | ZA202204282B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20210121517A1 (en) * | 2019-10-24 | 2021-04-29 | Sun Pharmaceutical Industries Limited | Stable parenteral dosage form of cetrorelix acetate |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022269572A1 (en) | 2021-06-25 | 2022-12-29 | Extrovis Ag | Pharmaceutical compositions |
CN115541733A (en) * | 2022-07-14 | 2022-12-30 | 南京锐志生物医药有限公司 | Method for measuring protected amino acid enantiomer by reverse phase chromatography |
CN115184507B (en) * | 2022-07-27 | 2024-07-05 | 南京锐志生物医药有限公司 | Method for detecting N, N-diisopropylcarbodiimide and piperidine in polypeptide |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20130303464A1 (en) * | 2010-12-06 | 2013-11-14 | Astron Research Limited | Stable ready-to-use cetrorelix injection |
CN109467591A (en) * | 2018-12-27 | 2019-03-15 | 苏州天马医药集团天吉生物制药有限公司 | A kind of purification process of Cetrorelix |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10024451A1 (en) | 2000-05-18 | 2001-11-29 | Asta Medica Ag | Pharmaceutical dosage form for peptides, process for their preparation and use |
DE10157628A1 (en) | 2001-11-26 | 2003-06-12 | Zentaris Ag | Solution for injection of an LHRH antagonist |
US7214662B2 (en) | 2001-11-27 | 2007-05-08 | Zentaris Gmbh | Injectable solution of an LHRH antagonist |
WO2003097080A1 (en) | 2002-05-15 | 2003-11-27 | Sun Pharmaceutical Industries Limited | A stable aqueous composition of a peptide |
US20130288968A1 (en) | 2012-04-30 | 2013-10-31 | Sun Pharmaceutical Industries Ltd. | Leuprolide injection |
US20130303453A1 (en) | 2012-05-09 | 2013-11-14 | Sun Pharmaceutical Industries Ltd. | Octreotide injection |
EP2823808A1 (en) | 2013-07-09 | 2015-01-14 | Ipsen Pharma S.A.S. | Pharmaceutical composition for a sustained release of lanreotide |
US20180325993A1 (en) | 2017-05-15 | 2018-11-15 | Sun Pharmaceutical Industries Limited | Octreotide injection |
PL3811927T3 (en) * | 2019-10-24 | 2022-02-07 | Sun Pharmaceutical Industries Ltd | A stable parenteral dosage form of cetrorelix acetate |
-
2020
- 2020-03-10 PL PL20162018T patent/PL3811927T3/en unknown
- 2020-03-10 PT PT201620184T patent/PT3811927T/en unknown
- 2020-03-10 LT LTEP20162018.4T patent/LT3811927T/en unknown
- 2020-03-10 RS RS20211515A patent/RS62754B1/en unknown
- 2020-03-10 HR HRP20211890TT patent/HRP20211890T1/en unknown
- 2020-03-10 ES ES20162018T patent/ES2902784T3/en active Active
- 2020-03-10 HU HUE20162018A patent/HUE058963T2/en unknown
- 2020-03-10 DK DK20162018.4T patent/DK3811927T3/en active
- 2020-03-10 EP EP20162018.4A patent/EP3811927B8/en active Active
- 2020-03-10 MA MA55417A patent/MA55417B1/en unknown
- 2020-03-10 US US16/814,447 patent/US20210121517A1/en active Pending
- 2020-03-10 SI SI202030015T patent/SI3811927T1/en unknown
- 2020-03-10 MD MDE20220046T patent/MD3811927T2/en unknown
- 2020-10-23 MX MX2022004859A patent/MX2022004859A/en unknown
- 2020-10-23 AU AU2020369236A patent/AU2020369236A1/en active Pending
- 2020-10-23 US US17/593,512 patent/US20220153802A1/en active Pending
- 2020-10-23 CA CA3155348A patent/CA3155348A1/en active Pending
- 2020-10-23 IL IL293908A patent/IL293908A/en unknown
- 2020-10-23 AR ARP200102937A patent/AR120290A1/en unknown
- 2020-10-23 JO JOP/2022/0094A patent/JOP20220094A1/en unknown
- 2020-10-23 TW TW109136923A patent/TW202128210A/en unknown
- 2020-10-23 WO PCT/IB2020/059988 patent/WO2021079339A1/en active Application Filing
- 2020-10-23 MA MA054713A patent/MA54713A/en unknown
- 2020-10-23 JP JP2022523629A patent/JP2023501902A/en active Pending
- 2020-10-23 BR BR112022007746A patent/BR112022007746A2/en unknown
- 2020-10-23 KR KR1020227017349A patent/KR20220114533A/en unknown
- 2020-10-23 EP EP20800340.0A patent/EP3908259A1/en active Pending
- 2020-10-23 CN CN202080074551.6A patent/CN114599384A/en active Pending
-
2022
- 2022-04-14 ZA ZA2022/04282A patent/ZA202204282B/en unknown
- 2022-04-22 CL CL2022001021A patent/CL2022001021A1/en unknown
- 2022-05-24 CO CONC2022/0006820A patent/CO2022006820A2/en unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20130303464A1 (en) * | 2010-12-06 | 2013-11-14 | Astron Research Limited | Stable ready-to-use cetrorelix injection |
CN109467591A (en) * | 2018-12-27 | 2019-03-15 | 苏州天马医药集团天吉生物制药有限公司 | A kind of purification process of Cetrorelix |
Non-Patent Citations (5)
Title |
---|
Agarawal et al., Chapter 11, pp. 531-622 of Challenges in Delivery of Therapeutic Genomics and Proteomics, 2011 (Year: 2011) * |
Chemistry LibreTexts, 2015, 5 pages, provided by applicant in 3/29/22 IDS (Year: 2015) * |
Machine translation of CN109467591A (Year: 2019) * |
ONdrugDELIVERY Issue No. 101, 112 pages, 10/7/2019, downloaded from the internet 6/11/24 (Year: 2019) * |
PubChem reference for Cetrorelix, downloaded from the internet 6/10/24, 58 pages (Year: 2024) * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20210121517A1 (en) * | 2019-10-24 | 2021-04-29 | Sun Pharmaceutical Industries Limited | Stable parenteral dosage form of cetrorelix acetate |
Also Published As
Publication number | Publication date |
---|---|
LT3811927T (en) | 2022-01-10 |
EP3811927B1 (en) | 2021-11-17 |
MA54713A (en) | 2021-11-17 |
CA3155348A1 (en) | 2021-04-29 |
WO2021079339A1 (en) | 2021-04-29 |
HUE058963T2 (en) | 2022-10-28 |
PT3811927T (en) | 2021-12-14 |
PL3811927T3 (en) | 2022-02-07 |
MA55417B1 (en) | 2022-02-28 |
MD3811927T2 (en) | 2022-03-31 |
BR112022007746A2 (en) | 2022-07-05 |
JOP20220094A1 (en) | 2023-01-30 |
KR20220114533A (en) | 2022-08-17 |
MX2022004859A (en) | 2022-05-19 |
ZA202204282B (en) | 2024-01-31 |
RS62754B1 (en) | 2022-01-31 |
AR120290A1 (en) | 2022-02-09 |
MA55417A (en) | 2021-04-28 |
CO2022006820A2 (en) | 2022-06-10 |
CL2022001021A1 (en) | 2023-02-03 |
TW202128210A (en) | 2021-08-01 |
DK3811927T3 (en) | 2021-12-13 |
EP3811927B8 (en) | 2022-02-23 |
JP2023501902A (en) | 2023-01-20 |
US20210121517A1 (en) | 2021-04-29 |
AU2020369236A1 (en) | 2022-05-19 |
HRP20211890T1 (en) | 2022-03-04 |
EP3908259A1 (en) | 2021-11-17 |
ES2902784T3 (en) | 2022-03-29 |
CN114599384A (en) | 2022-06-07 |
SI3811927T1 (en) | 2022-03-31 |
EP3811927A1 (en) | 2021-04-28 |
IL293908A (en) | 2022-08-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP3811927B1 (en) | A stable parenteral dosage form of cetrorelix acetate | |
US10342850B2 (en) | Octreotide injection | |
US20060029635A1 (en) | Growth hormone formulations | |
CA2523477A1 (en) | Stabilized liquid protein formulations in pharmaceutical containers | |
EP2662073B1 (en) | Octreotide Injection | |
US20170143622A1 (en) | Stable liquid ready-to-use injectable formulation of bortezomib | |
WO2020021567A1 (en) | Injection device of fentanyl | |
JP2019203020A (en) | Formulation with reduced n-formylpiperidine content and/or less collapse or shrinkage of lyophilized cake | |
OA20747A (en) | A stable parenteral dosage form of cetrorelix acetate. | |
EP4288078A1 (en) | Oxytocin ready to infuse dosage form | |
WO2023275157A1 (en) | Aqueous, room-temperature stable rocuronium composition | |
ES2853349T3 (en) | Stable pharmaceutical formulations | |
CN102210690A (en) | Fasudil hydrochloride injection composition and preparation method thereof | |
US20210338782A1 (en) | Storage stable somatostatin-dopamine chimeric compounds and salt forms thereof | |
JP2004217645A (en) | Injectable preparation | |
RU2777554C2 (en) | Octreotide injection | |
WO2024133580A1 (en) | Medical products containing an aqueous formulation of a peptide | |
US20230381282A1 (en) | Stable liquid compositions of glucagon | |
CN118302152A (en) | Preservable formulation | |
WO2019106586A1 (en) | A stable glucagon formulation for emergency treatment of hypoglycemia | |
JPH10287569A (en) | Transfusion solution type kit injection preparation of acyclovir or its salt | |
ZA200200176B (en) | Growth hormone formulations. |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: SUN PHARMACEUTICAL INDUSTRIES LIMITED, INDIA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:JOSHI, JAYDIP;THUMMAR, RAKESH;AGRAWAL, SUDEEP;AND OTHERS;SIGNING DATES FROM 20210904 TO 20210907;REEL/FRAME:057533/0842 |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NON FINAL ACTION MAILED |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NON FINAL ACTION MAILED |