ME00499B - Injekcioni rastvor koji sadrži antagonist za lhrh - Google Patents
Injekcioni rastvor koji sadrži antagonist za lhrhInfo
- Publication number
- ME00499B ME00499B MEP-2008-800A MEP80008A ME00499B ME 00499 B ME00499 B ME 00499B ME P80008 A MEP80008 A ME P80008A ME 00499 B ME00499 B ME 00499B
- Authority
- ME
- Montenegro
- Prior art keywords
- lhrh
- acid
- aqueous
- solution
- antagonist
- Prior art date
Links
- 238000002347 injection Methods 0.000 title claims abstract description 22
- 239000007924 injection Substances 0.000 title claims abstract description 22
- 229940124041 Luteinizing hormone releasing hormone (LHRH) antagonist Drugs 0.000 title claims abstract description 21
- 239000002474 gonadorelin antagonist Substances 0.000 title claims abstract description 14
- 239000000243 solution Substances 0.000 title claims description 27
- 239000002253 acid Substances 0.000 claims abstract description 10
- 108700008462 cetrorelix Proteins 0.000 claims abstract description 10
- 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 abstract description 10
- 101000904173 Homo sapiens Progonadoliberin-1 Proteins 0.000 claims abstract description 9
- 102100024028 Progonadoliberin-1 Human genes 0.000 claims abstract description 9
- 101000996723 Sus scrofa Gonadotropin-releasing hormone receptor Proteins 0.000 claims abstract description 9
- 229960003230 cetrorelix Drugs 0.000 claims abstract description 9
- 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 claims abstract description 9
- 239000004094 surface-active agent Substances 0.000 claims abstract description 8
- 239000005557 antagonist Substances 0.000 claims abstract description 7
- 239000007864 aqueous solution Substances 0.000 claims abstract description 6
- 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
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 6
- 229920000053 polysorbate 80 Polymers 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 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
- 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 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 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 3
- 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 3
- 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 3
- 108010070670 antarelix Proteins 0.000 claims description 3
- 239000000945 filler Substances 0.000 claims description 3
- 235000012208 gluconic acid Nutrition 0.000 claims description 3
- 239000000174 gluconic acid Substances 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 229950011372 teverelix Drugs 0.000 claims description 3
- 229920000136 polysorbate Polymers 0.000 claims description 2
- 229940102223 injectable solution Drugs 0.000 claims 4
- 239000012047 saturated solution Substances 0.000 claims 2
- 230000002776 aggregation Effects 0.000 abstract description 8
- 238000004220 aggregation Methods 0.000 abstract description 8
- 108700032141 ganirelix Proteins 0.000 description 5
- 229960003794 ganirelix Drugs 0.000 description 5
- 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 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 229960002184 abarelix Drugs 0.000 description 3
- 108010023617 abarelix Proteins 0.000 description 3
- 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 description 3
- 238000009472 formulation 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
- 230000002611 ovarian Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 238000003860 storage Methods 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
- 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
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 description 1
- 108010050144 Triptorelin Pamoate Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009471 action Effects 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
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 229940112106 cetrotide Drugs 0.000 description 1
- 230000006957 competitive inhibition Effects 0.000 description 1
- 125000000422 delta-lactone group Chemical group 0.000 description 1
- 230000001419 dependent effect Effects 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
- 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
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 108010083551 iturelix Proteins 0.000 description 1
- QRYFGTULTGLGHU-NBERXCRTSA-N iturelix Chemical compound C([C@H](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](CCCCNC(=O)C=1C=NC=CC=1)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)CCCNC(=O)C1=CC=CN=C1 QRYFGTULTGLGHU-NBERXCRTSA-N 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
- 230000007774 longterm Effects 0.000 description 1
- 230000036651 mood Effects 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
- 239000003223 protective agent Substances 0.000 description 1
- 230000009467 reduction Effects 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
- 239000008215 water for injection Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—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
-
- 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
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Endocrinology (AREA)
- Organic Chemistry (AREA)
- Reproductive Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Gastroenterology & Hepatology (AREA)
- Diabetes (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Gynecology & Obstetrics (AREA)
- Pregnancy & Childbirth (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Manufacturing Of Micro-Capsules (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
Vodeni injekcioni rastvor koji sadrži antagonist za LHRH pored cetroreliksa koji predstavlja pomenuti antagonist za LHRH sadrži organsku, fiziološki srodnu kiselinu i surfaktant po slobodnom izboru kao i gradivnu komponentu. Antagonistu za LHRH značajno je poboljšana rastvorljivost i može da se priprema u većim koncentracijama i sa poboljšanom bioraspoloživošću. Značajno je smanjena sklonost ka agregaciji kod antagonista za LHRH.
Description
TEHNIČKA OBLAST:
Pronalazak se odnosi na vodene injekcione rastvore koji sadrže antagonist za LHRH i primese organskih fiziološki srodnih kiselina i /ili surfaktanata i njihovih preparata za sprečavanje agregacije antagonista za LHRH u rastvoru. Injekcioni rastvori koji su napravljeni prema pronalasku dovode do povećanja bioraspoloživosti rastvora i omogućavaju smanjivanje injekcionog volumena koji se primenjuje.
PRETHODNO STANJE TEHNIKE:
U kontrolisanoj stimulaciji jajnika praćenoj ukljanjanjem jajne ćelije i tehnikama asistirane reprodukcije , LHRH agonist (npr. triptorelina , buserelina ) i LHRH antagonist (cetroreliksa , ganireliksa ) su korišćeni u izvesnom vremenskom periodu a pri čemu je izbegnuto inicijalno povećanje endogene gonadotropinske sekrecije i odmah izazvane kompetitivne inhibicije hormona koji oslobadja gonadotropin [EP 0 788 799 A2; EP 0 299 402 BI]. LHRH antagonist ganireliks se trenutno koristi u formulaciji koja sadrži 0.25 mg ganireliksa u 0.5 ml vodenog rastvora koji sadrži manitol i primenjuje u obliku injekcija koje su odmah spremne za upotrebu ( Orgalutran® ) .LHRH antagonista cetroreliks (Cetrotide ® ) se zasada primenjuje u dva oblika : kao liofilizat koji sadrži 0.25 mg cetroreliksa u kombinaciji sa špricom koji sadrži lml vode za rekonstituisanje , i liofilizat koji sadrži 3 mg cetroreliksa u kombinaciji sa špricom koji sadrži 3 ml vode za rekonstituisanje.LHRH antagonisti se ne koriste samo za kontrolisanu stimulaciju jajnika već mogu da se koriste i za terapiju hormonski zavisnih kancera kao što je karcinom prostate. Supstance kao što je abareliks [WO 98/25642] ili cetroreliks [WO 00/47234] se takodje mogu koristiti u ovoj terapiji pri čemu su LHRH antagonisti alternative agonistima koji dominiraju u prodaji (leuprolid , goserelin ). S obzirom na relativno slabu rastvorljivost abareliksa u vodi ili fiziološkoj sredini, mora da se koristi depo formulacija da bi se postiglo dugotrajno delovanje. Postoje nagoveštaji da dugotrajno dejstvo može da prouzrokuje dobru rastvorljivost 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].
OPIS PRONALASKA
Predmet pronalaska odnosi se na pripremu injekcionog rastvora sa manjim injekcionim volumenom a istovremeno povećanom koncentracijom antagonista za LHRH što dovodi do poboljšanja njegove rastvorljivosti .U isto vreme, agregacijom antagonista za LHRH sprečava se nastanak relativno visoko koncentrovanog rastvora.
Neočekivano je pronadjeno je da organske, fiziološki srodne kiseline , naročito karboksilna kiselina pre svega hidroksikarboksilna kiselina ali i glukonska kiselina sama ili u kombinaciji sa surfaktantima kao što je , na primer Tween , poboljšavaju rastvorljivost antagonista za LHRH, mada značajno smanjuju sposobnost agregacije ovih supstanci.
Na osnovu pronalaska moguće je da se dobiju antagonisti za LHRH u relativno visokim koncentracijama u vodenom injekcionom rastvoru . LHRH antagonisti koji će biti pomenuti ovde su na primer cetroreliks , tevereliks , D-63 153 (Ac-D-Nal-pCl-D-Phe-3-D-Pal-Ser-N-Me-Tyrt-D-H-Cit-Nle -Arg-Pro-D-Ala-NH2) ganireliks , abareliks , antide , azalin B. Uočeno je da se karboksilna kiselina mora koristiti u višku , jer ekvimolame količine nisu dovoljne .Očigledno je da se ovaj efekat ne može objasniti in situ formulacijama soli sa baznim amino kiselinskim ostacima kao što su na primer arginin , piridilalanin , lizin .Takodje koncentracija surfaktanta ne sme da bude suviše visoka jer se rastvori isuviše pene i dolazi do pojave agregacije.
U isto vreme dodaci čine mogućim povećanje bi oraspoloži vosti dok očigledno usporavaju spontanu agregaciju u telu posle primene injekcije ili omogućavaju bržu absorpciju supstance sa mesta delovanja . Uočeno je da sniženje pH takvog injekcionog rastvora (na primer pH=2.5-3) nema uticaj na lokalnu toleranciju na injekciju. Povećanjem koncentracije moguće je redukovati volumen koji se primenjuje , na primer u slučaju cetroreliksa od 3ml do lml za oblik od 3 mg .Pokazano je da zahvaljujući ovim dodacima može da se postigne dobra stabilnost pri čuvanju (videti primer 1 ) . Mada čuvanje rastvora preko 6 meseci na 25°C/60% dovodi do povećanja količine nečistoća pri čemu bi zadovoljavajuća vrednost u svakom slučaju bila preko 90% (po pravilu najniža vređnost korišćenja je period specifikacije farmaceutskih proizvoda). Prilikom agregacije dolazi do neznatnog povećanja zamućenja. Vrednosti zamućenja preko 8 FTU (jedinica formazin zamućenje prema Evropskoj Farmakopeji) se savršeno tolerišu.
Zaštitna sredstva kao što je na primer fenol ili p-chloro-m-krezol ne interferiraju mogu se dodatno koristiti za zaštitu rastvora . Korišćenje uobičajenih punioca kao što su manitol, laktoza, glukoza i fruktoza je takodje moguće.
OPIS NAČINA IZVODJENJA PRONALASKA Primer 1:
500 mg cetroreliksa 2g Tween 80
2.4g delta laktona glukonske kiseline
95g manitola su izmešani sa vodom za injekcije u količini od 2 litre da bi se dobio homogeni rastvor. Rastvor se onda sterilno filtruje i izdaje u ampulama . Ampule su prvo analitički ispitane na čistoću (HPLC) , sadržaj (HPLC), pH i agregaciju (zamućenje) a zatim posle vremena čuvanja od 6 meseci na 2-8°C i 25°C /60% relativne vlažnosti.
Analitički rezultati:
Primer 2
Oko 500 mg D-63153 Oko 100 mg Tween 80 Oko 475 mg manitola i podešenim pH oko 2.5 korištenjem zasićenog vodenog rastvora delta laktona glukonske kiseline. Dobijena je zapremina od 50 ml .Smeša se meša do dobijanja čistog rastvora .
Analitički rezultati:
Zamućenje rastvora je prvo bilo 2,4 FTU. Posle 24 h 2 1 FTU je izmeren. Čistoća rastvora kao i sadržaj rastvora (HPLC) ostaju nepromenjeni.
Struktura LHRH antagonista D-63153.
Ac-D-Nal-pCl-D-Phe-3-D-Pal'Ser-N-Me-Tyr-D-H-Cit-Nle -Arg-Pro-D-Ala-NH2
Primer 3
Oko 100 mg tevereliksa Oko 100 mg Tween 80 Oko 475 mg manitola i podešenim pH oko 2.5 korištenjem zasitenog vodenog rastvora delta laktona glukonske kiseline . Dobijena je zapremina od 10 ml .Smeša se meša do dobijanja čistog rastvora
Analitički rezultati;
Zamućenje rastvora je prvo bilo 6,8 FTU. Posle 24h, 8,4 FTU je izmeren. Čistoća rastvora i sadržaj rastvora (HPLC) ostaju nepromenjeni.
Struktura tevereliks antagonista za LHRH :
Ac-D-Nal-pCl-D-Phe-3-D-Pal-Ser-Tyr-D-H-Cit-Leu-iPr-Lys-Pro-D-Ala-NH2
Claims (13)
1. Vodeni injekcioni rastvor antagonista za LHRH, naznačen time, što se organska fiziološki srodna kiselina dodaje antagonistu za LHRH.
2. Vodeni injekcioni rastvor prema patentnom zahtevu 1 , naznačen time da je dodata karboksilna kiselina.
3. Vodeni injekcioni rastvor prema patentnom zahtevu 1 i 2, naznačen time , da je dodata hidrokarboksilna kiselina.
4. Vodeni injekcioni rastvor prema patentnim zahtevima od 1 do 3, naznačen time daje dodata glukonska kiselina.
5. Vodeni injekcioni rastvor prema patentnim zahtevima od 1 do 4 , naznačen time , da je dodat surfaktant.
6. Vodeni injekcioni rastvor prema patentnim zahtevima od 1 do 5 , koji sadrži Tween kao surfaktant.
7. Vodeni injekcioni rastvor prema patentnom zahtevu 1 , koji kao antagonist za LHRH sadrži cetroreliks , tevereliks , D-63 153 (Ac-D-Nal-pCl-D-Phe-3-D-Pal-Ser-N-Me-Tyr-D-H-Cit-Nle -Arg-Pro-D-Ala-NH2) ganireliks , avareliks , antid ili azalin B.
8. Vodeni injekcioni rastvor prema patentnim zahtevima od 1 do 4 , naznačen time , što je kiselina prisutna u najmanje ekvimolarnom odnosu , a što je zasnovano na količini antagonista za LHRH.
9. Vodeni injekcioni rastvor antagonista za LHRH prema patentnim zahtevima od 1 do 8 koji sadrže: 500 mg cetroreliksa 2.4 g delta laktona glukonske kiseline 2.0g Tween 80 95.Og manitola u 21 injekcione vode .
10. Vodeni injekcioni rastvor antagonista za LHRH prema patentnim zahtevima od 1 do 8 koji sadrže: 500 mg D-63 153 100 mg Tween 80 475 mg manitola podešenim na 50 ml korišćenjem zasićenog rastvora delta laktona glukonske kiseline.
11. Vodeni rastvor antagonista za LHRH prema patentnim zahtevima od 1 do 8 koji sadrži: 100 mg tevereliksa 100 mg Tween 80 475 mg manitola podešenim na 10 ml zasićenog rastvora delta laktona glukonske kiseline.
12. Proces pripremanja vodenih injekcionih rastvora antagonista za LHRH , naznačen time, da su alternativno antagonist za LHRH , organska fiziološki srodna kiselina i surfaktant i punioc rastvoreni u injekcionoj vodi , homogenizovani i obradjeni za injekcije ili su antagonist za LHRH i surfaktant i punioc rastvoreni korišćenjem zasićenog vodenog rastvora organske fiziološki srodne kiseline , homogenizovani i obradjeni za injekcije.
13. Proces prema patentnom zahtevu 12 , naznačen time , da se koristi karboksilna kiselina naročito hidrokarboksilna kiselina a poželjno i glukonska kiselina.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10157628A DE10157628A1 (de) | 2001-11-26 | 2001-11-26 | Injektionslösung eines LHRH-Antagonisten |
| YUP-449/04A RS51408B (sr) | 2001-11-26 | 2002-11-15 | Injekcioni rastvor koji obuhvata antagonist za lhrh |
| PCT/EP2002/012798 WO2003045419A1 (de) | 2001-11-26 | 2002-11-15 | Injektionslösung eines lhrh-antagonisten |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ME00499B true ME00499B (me) | 2011-10-10 |
Family
ID=7706799
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| MEP-2008-800A ME00499B (me) | 2001-11-26 | 2002-11-15 | Injekcioni rastvor koji sadrži antagonist za lhrh |
Country Status (32)
| Country | Link |
|---|---|
| EP (1) | EP1448221B1 (me) |
| JP (1) | JP4343693B2 (me) |
| KR (1) | KR100936636B1 (me) |
| CN (1) | CN100404068C (me) |
| AR (1) | AR037424A1 (me) |
| AT (1) | ATE350050T1 (me) |
| AU (1) | AU2002365504B2 (me) |
| BR (1) | BRPI0214412B8 (me) |
| CO (1) | CO5580793A2 (me) |
| CY (1) | CY1106401T1 (me) |
| DE (2) | DE10157628A1 (me) |
| DK (1) | DK1448221T3 (me) |
| EA (1) | EA010787B1 (me) |
| ES (1) | ES2276970T3 (me) |
| GE (1) | GEP20063861B (me) |
| HR (1) | HRP20040587B1 (me) |
| HU (1) | HU230992B1 (me) |
| IL (2) | IL161894A0 (me) |
| IS (1) | IS2725B (me) |
| ME (1) | ME00499B (me) |
| MX (1) | MXPA04005018A (me) |
| NO (1) | NO333364B1 (me) |
| NZ (1) | NZ533712A (me) |
| PL (1) | PL206199B1 (me) |
| PT (1) | PT1448221E (me) |
| RS (1) | RS51408B (me) |
| RU (1) | RU2322969C2 (me) |
| SI (1) | SI1448221T1 (me) |
| TW (1) | TWI312283B (me) |
| UA (1) | UA81612C2 (me) |
| WO (1) | WO2003045419A1 (me) |
| ZA (1) | ZA200404051B (me) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7658938B2 (en) | 1999-02-22 | 2010-02-09 | Merrion Reasearch III Limited | Solid oral dosage form containing an enhancer |
| US8119159B2 (en) | 1999-02-22 | 2012-02-21 | Merrion Research Iii Limited | Solid oral dosage form containing an enhancer |
| MX2008012678A (es) | 2006-04-07 | 2008-12-17 | Merrion Res Iii Ltd | Forma de dosis oral solida que contiene un mejorador. |
| CA2723541A1 (en) | 2008-05-07 | 2009-11-12 | Merrion Research Iii Limited | Compositions of peptides and processes of preparation thereof |
| WO2011120033A1 (en) | 2010-03-26 | 2011-09-29 | Merrion Research Iii Limited | Pharmaceutical compositions of selective factor xa inhibitors for oral administration |
| CA2819234A1 (en) | 2011-01-07 | 2012-07-12 | Merrion Research Iii Limited | Pharmaceutical compositions of iron for oral administration |
| CN103690560B (zh) * | 2013-12-17 | 2016-08-17 | 辽宁海思科制药有限公司 | 一种转化糖电解质注射液药物组合物及其制备方法 |
| WO2016120378A1 (en) | 2015-01-29 | 2016-08-04 | Novo Nordisk A/S | Tablets comprising glp-1 agonist and enteric coating |
| RU2614234C2 (ru) * | 2015-03-31 | 2017-03-23 | Федеральное государственное бюджетное учреждение науки Институт общей генетики им. Н.И. Вавилова Российской академии наук (ИОГЕН РАН) | Фармацевтическая композиция на основе 3-(4-Метилимидазол-1-ил)имидазо[1,2-b][1,2,4,5]тетразина в качестве противоопухолевого средства |
| KR20190112029A (ko) * | 2017-01-30 | 2019-10-02 | 안테브 리미티드 | 적어도 하나의 gnrh 길항제를 포함하는 조성물 |
| PT3811927T (pt) | 2019-10-24 | 2021-12-14 | Sun Pharmaceutical Ind Ltd | Forma galénica parentérica estável de acetato de cetrorrelix |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4800191A (en) * | 1987-07-17 | 1989-01-24 | Schally Andrew Victor | LHRH antagonists |
| 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 |
| DE4305225A1 (de) * | 1993-02-19 | 1994-08-25 | Asta Medica Ag | Neues Herstellverfahren für Cetrorelix Lyophilisat |
| HK1049117A1 (zh) * | 1999-09-23 | 2003-05-02 | 赞塔里斯有限公司 | 用於治疗子宫内膜组织子宫外增生、慢性骨盆疼痛和输卵管梗助的方法 |
| DE10024451A1 (de) * | 2000-05-18 | 2001-11-29 | Asta Medica Ag | Pharmazeutische Darreichungsform für Peptide, Verfahren zu deren Herstellung und Verwendung |
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2001
- 2001-11-26 DE DE10157628A patent/DE10157628A1/de not_active Withdrawn
-
2002
- 2002-11-15 DK DK02790384T patent/DK1448221T3/da active
- 2002-11-15 KR KR1020047007807A patent/KR100936636B1/ko not_active Expired - Lifetime
- 2002-11-15 RU RU2004119821/15A patent/RU2322969C2/ru active
- 2002-11-15 HU HU0401986A patent/HU230992B1/hu unknown
- 2002-11-15 AU AU2002365504A patent/AU2002365504B2/en not_active Expired
- 2002-11-15 ME MEP-2008-800A patent/ME00499B/me unknown
- 2002-11-15 WO PCT/EP2002/012798 patent/WO2003045419A1/de not_active Ceased
- 2002-11-15 MX MXPA04005018A patent/MXPA04005018A/es active IP Right Grant
- 2002-11-15 UA UA20040503816A patent/UA81612C2/ru unknown
- 2002-11-15 EA EA200400742A patent/EA010787B1/ru unknown
- 2002-11-15 JP JP2003546920A patent/JP4343693B2/ja not_active Expired - Lifetime
- 2002-11-15 EP EP02790384A patent/EP1448221B1/de not_active Expired - Lifetime
- 2002-11-15 HR HR20040587A patent/HRP20040587B1/xx not_active IP Right Cessation
- 2002-11-15 BR BRPI0214412A patent/BRPI0214412B8/pt not_active IP Right Cessation
- 2002-11-15 IL IL16189402A patent/IL161894A0/xx unknown
- 2002-11-15 AT AT02790384T patent/ATE350050T1/de active
- 2002-11-15 GE GE5568A patent/GEP20063861B/en unknown
- 2002-11-15 PT PT02790384T patent/PT1448221E/pt unknown
- 2002-11-15 PL PL369548A patent/PL206199B1/pl unknown
- 2002-11-15 SI SI200230505T patent/SI1448221T1/sl unknown
- 2002-11-15 ES ES02790384T patent/ES2276970T3/es not_active Expired - Lifetime
- 2002-11-15 NZ NZ533712A patent/NZ533712A/en not_active IP Right Cessation
- 2002-11-15 CN CNB028234901A patent/CN100404068C/zh not_active Expired - Lifetime
- 2002-11-15 DE DE50209193T patent/DE50209193D1/de not_active Expired - Lifetime
- 2002-11-15 RS YUP-449/04A patent/RS51408B/sr unknown
- 2002-11-20 TW TW091133846A patent/TWI312283B/zh not_active IP Right Cessation
- 2002-11-25 AR ARP020104523A patent/AR037424A1/es not_active Application Discontinuation
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2004
- 2004-05-06 IS IS7251A patent/IS2725B/is unknown
- 2004-05-10 IL IL161894A patent/IL161894A/en active IP Right Grant
- 2004-05-14 CO CO04044748A patent/CO5580793A2/es not_active Application Discontinuation
- 2004-05-25 ZA ZA2004/04051A patent/ZA200404051B/en unknown
- 2004-06-11 NO NO20042449A patent/NO333364B1/no not_active IP Right Cessation
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2007
- 2007-03-20 CY CY20071100391T patent/CY1106401T1/el unknown
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