HRP20040587A2 - Injection solution comprising an lhrh antagonist - Google Patents
Injection solution comprising an lhrh antagonist Download PDFInfo
- Publication number
- HRP20040587A2 HRP20040587A2 HR20040587A HRP20040587A HRP20040587A2 HR P20040587 A2 HRP20040587 A2 HR P20040587A2 HR 20040587 A HR20040587 A HR 20040587A HR P20040587 A HRP20040587 A HR P20040587A HR P20040587 A2 HRP20040587 A2 HR P20040587A2
- Authority
- HR
- Croatia
- Prior art keywords
- lhrh antagonist
- aqueous injection
- injection solution
- acid
- solution
- Prior art date
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- 239000000243 solution Substances 0.000 title claims description 29
- 229940124041 Luteinizing hormone releasing hormone (LHRH) antagonist Drugs 0.000 title claims description 25
- 238000002347 injection Methods 0.000 title claims description 22
- 239000007924 injection Substances 0.000 title claims description 22
- 239000002474 gonadorelin antagonist Substances 0.000 title claims description 15
- 108700008462 cetrorelix Proteins 0.000 claims description 11
- SBNPWPIBESPSIF-MHWMIDJBSA-N cetrorelix Chemical compound 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 SBNPWPIBESPSIF-MHWMIDJBSA-N 0.000 claims description 11
- 229960003230 cetrorelix Drugs 0.000 claims description 10
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 8
- 229930195725 Mannitol Natural products 0.000 claims description 8
- 239000000594 mannitol Substances 0.000 claims description 8
- 235000010355 mannitol Nutrition 0.000 claims description 8
- 239000004094 surface-active agent Substances 0.000 claims 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 claims description 7
- RGHNJXZEOKUKBD-SQOUGZDYSA-N Gluconic acid Natural products OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 claims description 7
- 235000012208 gluconic acid Nutrition 0.000 claims description 7
- 239000000174 gluconic acid Substances 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 108700032141 ganirelix Proteins 0.000 claims description 6
- 229960003794 ganirelix Drugs 0.000 claims description 6
- GJNXBNATEDXMAK-PFLSVRRQSA-N ganirelix Chemical compound C([C@@H](C(=O)N[C@H](CCCCN=C(NCC)NCC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN=C(NCC)NCC)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 GJNXBNATEDXMAK-PFLSVRRQSA-N 0.000 claims description 6
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 6
- 229920000053 polysorbate 80 Polymers 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- NOENHWMKHNSHGX-IZOOSHNJSA-N (2s)-1-[(2s)-2-[[(2s)-2-[[(2r)-2-[[(2r)-2-[[(2s)-2-[[(2r)-2-[[(2s)-2-[[(2r)-2-acetamido-3-naphthalen-2-ylpropanoyl]amino]-3-(4-chlorophenyl)propanoyl]amino]-3-pyridin-3-ylpropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-6-(ca Chemical compound C([C@H](C(=O)N[C@H](CCCCNC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(C)C)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 NOENHWMKHNSHGX-IZOOSHNJSA-N 0.000 claims description 5
- KATZUZNTRINHDT-HALMFYTRSA-N (2s)-1-[(2s)-2-[[(2s)-2-[[(2r)-2-[[(2s)-2-[[(2s)-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-acetamido-3-naphthalen-2-ylpropanoyl]amino]-3-(4-chlorophenyl)propanoyl]amino]-3-pyridin-3-ylpropanoyl]amino]-3-hydroxypropanoyl]-methylamino]-3-(4-hydroxyphenyl)propanoyl]amino Chemical compound C([C@@H](C(=O)N[C@H](CCCCNC(N)=O)C(=O)N[C@@H](CCCC)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)N(C)C(=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 KATZUZNTRINHDT-HALMFYTRSA-N 0.000 claims description 5
- 108010070670 antarelix Proteins 0.000 claims description 5
- 229950011372 teverelix Drugs 0.000 claims description 5
- 108010023617 abarelix Proteins 0.000 claims description 4
- 229960002184 abarelix Drugs 0.000 claims description 4
- AIWRTTMUVOZGPW-HSPKUQOVSA-N abarelix Chemical compound C([C@@H](C(=O)N[C@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)N(C)C(=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 AIWRTTMUVOZGPW-HSPKUQOVSA-N 0.000 claims description 4
- 125000000422 delta-lactone group Chemical group 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 239000004067 bulking agent Substances 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 3
- 239000008215 water for injection Substances 0.000 claims description 3
- PHOQVHQSTUBQQK-SQOUGZDYSA-N D-glucono-1,5-lactone Chemical compound OC[C@H]1OC(=O)[C@H](O)[C@@H](O)[C@@H]1O PHOQVHQSTUBQQK-SQOUGZDYSA-N 0.000 claims description 2
- 229920000136 polysorbate Polymers 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 239000012047 saturated solution Substances 0.000 claims 3
- -1 but even better Chemical compound 0.000 claims 1
- 230000002776 aggregation Effects 0.000 description 6
- 238000004220 aggregation Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 230000002611 ovarian Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- CNMAQBJBWQQZFZ-LURJTMIESA-N (2s)-2-(pyridin-2-ylamino)propanoic acid Chemical compound OC(=O)[C@H](C)NC1=CC=CC=N1 CNMAQBJBWQQZFZ-LURJTMIESA-N 0.000 description 1
- CFKMVGJGLGKFKI-UHFFFAOYSA-N 4-chloro-m-cresol Chemical compound CC1=CC(O)=CC=C1Cl CFKMVGJGLGKFKI-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 108010037003 Buserelin Proteins 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 239000005715 Fructose Substances 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
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 description 1
- 102000006771 Gonadotropins Human genes 0.000 description 1
- 108010086677 Gonadotropins Proteins 0.000 description 1
- 108010069236 Goserelin Proteins 0.000 description 1
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 description 1
- 101000904173 Homo sapiens Progonadoliberin-1 Proteins 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 108010000817 Leuprolide Proteins 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102100024028 Progonadoliberin-1 Human genes 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
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- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 description 1
- 101000996723 Sus scrofa Gonadotropin-releasing hormone receptor Proteins 0.000 description 1
- 108010050144 Triptorelin Pamoate Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 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
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229960002719 buserelin Drugs 0.000 description 1
- CUWODFFVMXJOKD-UVLQAERKSA-N buserelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](COC(C)(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 CUWODFFVMXJOKD-UVLQAERKSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 229940112106 cetrotide Drugs 0.000 description 1
- 230000006957 competitive inhibition Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 description 1
- XLXSAKCOAKORKW-UHFFFAOYSA-N gonadorelin Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)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 XLXSAKCOAKORKW-UHFFFAOYSA-N 0.000 description 1
- 239000002622 gonadotropin Substances 0.000 description 1
- 229940035638 gonadotropin-releasing hormone Drugs 0.000 description 1
- 229960002913 goserelin Drugs 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 1
- 229960004338 leuprorelin Drugs 0.000 description 1
- 210000000287 oocyte Anatomy 0.000 description 1
- 229940070805 p-chloro-m-cresol Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229960004824 triptorelin Drugs 0.000 description 1
- VXKHXGOKWPXYNA-PGBVPBMZSA-N triptorelin Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 VXKHXGOKWPXYNA-PGBVPBMZSA-N 0.000 description 1
Classifications
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- 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
- 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
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/10—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH
- A61P5/12—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH for decreasing, blocking or antagonising the activity of the posterior pituitary hormones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/36—Antigestagens
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Endocrinology (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Reproductive Health (AREA)
- Diabetes (AREA)
- Biochemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Molecular Biology (AREA)
- Pregnancy & Childbirth (AREA)
- Dermatology (AREA)
- Gynecology & Obstetrics (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Manufacturing Of Micro-Capsules (AREA)
Description
Područje izuma Field of invention
Ovaj izum se odnosi na vodene injekcijske otopine LHRH antagonista, koristeći dodatke organskih, fiziološki podnošljivih kiselina i/ili površinski aktivnih tvari, i na njihovu pripremu za sprječavanje agregacije LHRH antagonista u otopini. Injekcijske otopine pripravljene prema izumu dodatno dovode do povećanja bioraspoloživosti i omogućuju smanjenje injekcijskog volumena koji treba davati. This invention relates to aqueous injectable solutions of LHRH antagonists, using additions of organic, physiologically tolerable acids and/or surfactants, and to their preparation for preventing aggregation of LHRH antagonists in solution. Injection solutions prepared according to the invention additionally lead to an increase in bioavailability and enable a reduction in the injection volume to be administered.
Stanje tehnike State of the art
U kontroliranoj stimulaciji jajnika kojoj slijedi odstranjivanje jajnih stanica i tehnike asistirane reprodukcije, pored LHRH agonista (na pr. triptorelin, buserelin), već se neko vrijeme koriste osobito LHRH antagonisti (cetroreliks, ganireliks), budući da se njima izbjegava inicijalno povećavanje sekrecije endogenog gonadotropina i odmah dovodi do kompetitivne inhibicije gonadotropin-oslobađajućeg hormona [EP 0788 799 A2; EP 0 299 402 B1]. LHRH antagonist ganireliks se sada koristi u formulaciji koja sadrži 0,25 mg ganireliksa u 0,5 ml vodene otopine koja sadrži manitol, u obliku šprice spremne za uporabu (Orgalutran[image] ). LHRH antagonist cetroreliks (Cetrotide[image] ) se sada dobavlja u dva oblika davanja: kao liofilizat koji sadrži 0,25 mg cetroreliksa kombiniranog sa špricom spremnom za upotrebu, koja sadrži 1 ml vode za rekonstituciju, i kao liofilizat koji sadrži 3 mg cetroreliksa kombiniranog sa špricom spremnom za uporabu koja sadrži 3 ml vode za rekonstituciju. LHRH antagonisti se međutim ne koriste samo za kontroliranu stimulaciju jajnika, nego se također mogu koristiti za terapiju hormonski ovisnih tipova raka, kao što je na primjer karcinom prostate. Supstance, kao na primjer abareliks [WO 98/25642] ili cetroreliks [WO 00/47234] bi se mogle koristiti za to, u tome što bi u ovoj terapiji LHRH antagonisti mogli biti alternativa za agoniste koji dominiraju na tržištu (leuprolid, goserelin). Zbog relativno slabe topivosti abareliksa u vodi ili fiziološkom mediju, mora se koristiti depo formulacija, kako bi se postiglo dugotrajno djelovanje. Ima međutim indikacija, da bi dugotrajno djelovanje moglo također biti uzrokovano dobrom topivošću LHRH antagonista [G. Jiang, J. Stakewski, R. Galyean, J. Dykert, C. Schteingart, P. Broqua, A. Aebi, M. L. Aubert, G. Semple, P. Robson, K. Akinsanya, R. Haigh, P. Riviere, J. Trojnar, J. L. Junien i J.E. Rivier, J. Med. Chem., 2001, 44, 453-467]. In controlled ovarian stimulation followed by oocyte removal and assisted reproduction techniques, in addition to LHRH agonists (e.g. triptorelin, buserelin), especially LHRH antagonists (cetrorelix, ganirelix) have been used for some time, since they avoid the initial increase in endogenous gonadotropin secretion and immediately leads to competitive inhibition of gonadotropin-releasing hormone [EP 0788 799 A2; EP 0 299 402 B1]. The LHRH antagonist ganirelix is now used in a formulation containing 0.25 mg of ganirelix in 0.5 ml of an aqueous solution containing mannitol, in the form of a ready-to-use syringe (Orgalutran[image] ). The LHRH antagonist cetrorelix (Cetrotide[image] ) is now available in two dosage forms: as a lyophilisate containing 0.25 mg of cetrorelix combined with a ready-to-use syringe containing 1 ml of water for reconstitution, and as a lyophilisate containing 3 mg of cetrorelix combined with a ready-to-use syringe containing 3 ml of water for reconstitution. However, LHRH antagonists are not only used for controlled ovarian stimulation, but can also be used to treat hormone-dependent types of cancer, such as prostate cancer. Substances such as abarelix [WO 98/25642] or cetrorelix [WO 00/47234] could be used for this, in that in this therapy LHRH antagonists could be an alternative to the agonists that dominate the market (leuprolide, goserelin) . Due to the relatively low solubility of abarelix in water or physiological medium, a depot formulation must be used in order to achieve a long-term effect. There are indications, however, that the long-term effect could also be caused by the good solubility of LHRH antagonists [G. Jiang, J. Stakewski, R. Galyean, J. Dykert, C. Schteingart, P. Broqua, A. Aebi, M. L. Aubert, G. Semple, P. Robson, K. Akinsanya, R. Haigh, P. Riviere, J Trojnar, J.L. Junien and J.E. Rivier, J. Med. Chem., 2001, 44, 453-467].
Predstavljanje izuma Presentation of the invention
Cilj je ovog izuma da se pripravi injekcijska otopina kojom se postiže mali volumen uštrcavanja zajedno s povećanom koncentracijom LHRH antagonista pomoću njegove poboljšane topivosti. Istovremeno bi se trebala spriječiti agregacija LHRH antagonista u relativno visoko koncentriranoj injekcijskoj otopini. The aim of the present invention is to prepare an injectable solution which achieves a small injection volume together with an increased concentration of the LHRH antagonist by means of its improved solubility. At the same time, aggregation of LHRH antagonists in a relatively highly concentrated injection solution should be prevented.
Iznenađujuće je pronađeno, da organske, fiziološki podnošljive kiseline, naročito karboksilne kiseline, osobito hidroksikarboksilne kiseline, ali još bolje glukonska kiselina kao ona sama ili u kombinaciji s površinski aktivnim tvarima, kao što je na primjer Tween, izrazito poboljšavaju topivost LHRH antagonista i tako izrazito smanjuju sklonost agregaciji ovih supstanci. It has surprisingly been found that organic, physiologically tolerable acids, especially carboxylic acids, especially hydroxycarboxylic acids, but even better gluconic acid as itself or in combination with surfactants, such as for example Tween, significantly improve the solubility of LHRH antagonists and thus significantly reduce the tendency of these substances to aggregate.
Ovaj izum stoga omogućuje da se pripreme LHRH antagonisti u relativno visokoj koncentraciji u vodenim otopinama za uštrcavanje. LHRH antagonisti koji se mogu spomenuti, su na primjer, cetroreliks, tevereliks, D-63 153 (Ac-D-NaI-pC1-D-Phe-3-D-PaI-Ser-N-Me-Tyr-D-H-Cit-Nle-Arg-Pro-D-Ala-NH2) ganireliks, abareliks, antid, azalin B. Vidjelo se, da se mora koristiti suvišak dotične karboksilne kiseline; ekvimolarne količine nisu dovoljne. Ovaj efekt se očito ne može objasniti samo formiranjem soli in situ s bazičnim ostacima aminokiselina koji su prisutni, kao što su na primjer arginin, piridilalanin, lizin. Isto tako, ne mora se odabrati previsoku koncentraciju površinski aktivne tvari, budući da inače otopine previše pjene, a agregacija se pak inducira površinski aktivnim tvarima. The present invention therefore enables LHRH antagonists to be prepared in relatively high concentration in aqueous injectable solutions. LHRH antagonists that may be mentioned are, for example, cetrorelix, teverelix, D-63 153 (Ac-D-NaI-pC1-D-Phe-3-D-PaI-Ser-N-Me-Tyr-D-H-Cit- Nle-Arg-Pro-D-Ala-NH2) ganirelix, abarelix, antid, azalin B. It was seen that an excess of the respective carboxylic acid must be used; equimolar amounts are not sufficient. This effect obviously cannot be explained only by the formation of salts in situ with basic amino acid residues that are present, such as for example arginine, pyridylalanine, lysine. In the same way, it is not necessary to choose too high a concentration of surfactant, since otherwise the solution foams too much, and aggregation is induced by surfactants.
Istovremeno, ovi dodaci omogućuju povećanje bioraspoloživosti, budući oni očito također usporavaju spontanu agregaciju u tijelu nakon uštrcavanja ili omogućuju bržu apsorpciju supstance s mjesta djelovanja. Primijećeno je, da niži pH takvih injekcijskih otopina (na pr. pH = 2,5-3) nema utjecaja na lokalnu podnošljivost uštrcavanja. Povećanjem koncentracije moguće je smanjiti volumen za davanje, na primjer u slučaju cetroreliksa od 3 ml na 1 ml za oblik od 3 mg. Također se pokazalo, da se pomoću ovih dodataka može postići dobra stabilnost uskladištenja (vidi Primjer 1). Premda je uskladištenje od preko 6 mjeseci pri 25oC/60% rel.vlage proizvelo povećanje na nečistoćama, vrijednost sadržaja je u svakom slučaju bila jasno iznad 90% (kao pravilo najniže vrijednosti specifikacije perioda upotrebe farmaceutskih produkata). Mutnoća, kao znak agregacije, se samo slabo povećavala. Vrijednosti mutnoće do 8 FTU (formazinska jedinica zamućenja, formazine turbidity unit) u skladu s Europskom farmakopejom) su potpuno podnošljive. At the same time, these supplements allow for an increase in bioavailability, since they apparently also slow down spontaneous aggregation in the body after injection or enable faster absorption of the substance from the site of action. It has been observed that the lower pH of such injection solutions (eg pH = 2.5-3) has no effect on the local tolerability of the injection. By increasing the concentration, it is possible to reduce the volume to be administered, for example in the case of cetrorelix from 3 ml to 1 ml for the 3 mg form. It has also been shown that good storage stability can be achieved with these additives (see Example 1). Although storage of more than 6 months at 25oC/60% RH produced an increase in impurities, the content value was clearly above 90% in each case (as a rule of thumb for the lowest specification value of the pharmaceutical product shelf life). Turbidity, as a sign of aggregation, only slightly increased. Turbidity values up to 8 FTU (formazine turbidity unit) in accordance with the European Pharmacopoeia) are completely tolerable.
Konzervansi, kao na primjer fenol ili p-kloro-m krezol, ne interferiraju i mogu se dodatno koristiti za konzerviranje otopina. Također je moguća uporaba uobičajenih agenasa za masu, kao što je manitol, laktoza, glukoza i fruktoza. Preservatives, such as phenol or p-chloro-m cresol, do not interfere and can be additionally used to preserve solutions. It is also possible to use common bulking agents such as mannitol, lactose, glucose and fructose.
Opis puta za izvođenje izuma Description of the method for carrying out the invention
Primjer 1 Example 1
500 mg cetroreliksa 500 mg cetrorelix
2 g Tween 80 2 g Tween 80
2,4 g glukonske kiseline delta-laktona 2.4 g gluconic acid delta-lactone
95 g manitola 95 g of mannitol
su se miješali s vodom za uštrcavanje do 2 litre da dadu homogenu otopinu. Otopina je zatim sterilno filtrirana i raspodijeljena u ampule. Ampule su na početku analitički ispitane na čistoću (HPLC), sadržaj (HPLC), pH i agregaciju (zamućenje) i nakon vremena uskladištenja od 6 mjeseci na 2-8oC i 25oC/60% rel. vlage. were mixed with water for injection up to 2 liters to give a homogeneous solution. The solution was then sterile filtered and dispensed into ampoules. The ampoules were initially analytically tested for purity (HPLC), content (HPLC), pH and aggregation (turbidity) and after a storage time of 6 months at 2-8oC and 25oC/60% rel. moisture.
Analitički rezultati: Analytical results:
[image] [image]
Primjer 2 Example 2
Oko 500 mg D-63153 About 500 mg of D-63153
Oko 100 mg Tween 80 About 100 mg of Tween 80
Oko 475 mg manitola About 475 mg of mannitol
je podešeno na pH od oko 2,5 koristeći zasićenu vodenu otopinu glukonske kiseline delta-laktona. Dobiven je volumen od oko 50 ml. Smjesu se miješalo, dok se nije dobilo bistru otopinu. was adjusted to a pH of about 2.5 using a saturated aqueous solution of delta-lactone gluconic acid. A volume of about 50 ml was obtained. The mixture was stirred until a clear solution was obtained.
Analitički rezultati: Analytical results:
Zamućenje otopine je na početku bilo 2,4 FTU. Nakon 24 h, izmjereno je 2,1 FTU. Profil čistoće i sadržaj otopine (HPLC) ostali su nepromijenjeni. The turbidity of the solution was initially 2.4 FTU. After 24 h, 2.1 FTU was measured. The purity profile and solution content (HPLC) remained unchanged.
Struktura LHRH antagonista D-63153: Structure of the LHRH antagonist D-63153:
Ac-D-Nal-pCl-D-Phe-3-D-Pal-Ser-N-Me-Tyr-D-H-Cit-Nle-Arg-Pro-D-Ala-NH2 Ac-D-Nal-pCl-D-Phe-3-D-Pal-Ser-N-Me-Tyr-D-H-Cit-Nle-Arg-Pro-D-Ala-NH2
Primjer 3 Example 3
Oko 100 mg tevereliksa About 100 mg of teverelix
Oko 100 mg Tween 80 About 100 mg of Tween 80
Oko 475 mg manitola About 475 mg of mannitol
je podešeno na pH od oko 2,5 koristeći zasićenu vodenu otopinu glukonske kiseline delta-laktona. Dobiven je volumen od oko 10 ml. Smjesu se miješalo dok se nije dobila bistra otopina. was adjusted to a pH of about 2.5 using a saturated aqueous solution of delta-lactone gluconic acid. A volume of about 10 ml was obtained. The mixture was stirred until a clear solution was obtained.
Analitički rezultati: Analytical results:
Zamućenje otopine je na početku bilo 6,8 FTU. Nakon 24 h, izmjereno je 8,4 FTU. Profil čistoće i sadržaj otopine (HPLC) ostali su nepromijenjeni. The turbidity of the solution was initially 6.8 FTU. After 24 h, 8.4 FTU was measured. The purity profile and solution content (HPLC) remained unchanged.
Struktura LHRH antagonista tevereliks: Structure of the LHRH antagonist teverelix:
Ac-D-Nal-pCL-D-Phe-3-D-Pal-Ser-Tyr-D-H-Cit-Leu-iPr-Lys-Pro-D-Ala-NH2 Ac-D-Nal-pCL-D-Phe-3-D-Pal-Ser-Tyr-D-H-Cit-Leu-iPr-Lys-Pro-D-Ala-NH2
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| DE10157628A DE10157628A1 (en) | 2001-11-26 | 2001-11-26 | Solution for injection of an LHRH antagonist |
| PCT/EP2002/012798 WO2003045419A1 (en) | 2001-11-26 | 2002-11-15 | Injection solution comprising an lhrh antagonist |
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| US8119159B2 (en) | 1999-02-22 | 2012-02-21 | Merrion Research Iii Limited | Solid oral dosage form containing an enhancer |
| US7658938B2 (en) | 1999-02-22 | 2010-02-09 | Merrion Reasearch III Limited | Solid oral dosage form containing an enhancer |
| EP2526950A1 (en) | 2006-04-07 | 2012-11-28 | Merrion Research III Limited | Solid oral dosage form containing an enhancer |
| KR20110007614A (en) | 2008-05-07 | 2011-01-24 | 메리온 리서치 Ⅲ 리미티드 | Compositions of gnrh related compounds and processes of preparation |
| WO2011120033A1 (en) | 2010-03-26 | 2011-09-29 | Merrion Research Iii Limited | Pharmaceutical compositions of selective factor xa inhibitors for oral administration |
| CN103476419A (en) | 2011-01-07 | 2013-12-25 | 梅里翁第三研究有限公司 | Pharmaceutical compositions of iron for oral administration |
| CN103690560B (en) * | 2013-12-17 | 2016-08-17 | 辽宁海思科制药有限公司 | A kind of Invert sugar electrolyte injection pharmaceutical composition and preparation method thereof |
| EP3250191B1 (en) | 2015-01-29 | 2024-01-17 | Novo Nordisk A/S | Tablets comprising glp-1 agonist and enteric coating |
| RU2614234C2 (en) * | 2015-03-31 | 2017-03-23 | Федеральное государственное бюджетное учреждение науки Институт общей генетики им. Н.И. Вавилова Российской академии наук (ИОГЕН РАН) | PHARMACEUTICAL COMPOSITION BASED ON 3-(4-METHYLIMIDAZOLE-1-YL)IMIDAZO[1,2-b][1,2,4,5]TETRAZINE AS ANTI-TUMOR AGENT |
| RU2019127027A (en) * | 2017-01-30 | 2021-03-01 | Энтив Лимитед | COMPOSITION CONTAINING AT LEAST ONE GnRH ANTAGONIST |
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| US5140009A (en) * | 1988-02-10 | 1992-08-18 | Tap Pharmaceuticals, Inc. | Octapeptide LHRH antagonists |
| US5300492A (en) * | 1988-02-10 | 1994-04-05 | Tap Pharmaceuticals | LHRH analogs |
| UA73956C2 (en) * | 1999-09-23 | 2005-10-17 | Zentaris Gmbh | Method for therapeutic management of extrauterine proliferation of endometrial tissue, chronic pelvic pain and fallopian tube obstruction due to extrauterine proliferation of endometrial tissue |
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