TW570811B - Stabilized teriparatide solutions - Google Patents
Stabilized teriparatide solutions Download PDFInfo
- Publication number
- TW570811B TW570811B TW087120429A TW87120429A TW570811B TW 570811 B TW570811 B TW 570811B TW 087120429 A TW087120429 A TW 087120429A TW 87120429 A TW87120429 A TW 87120429A TW 570811 B TW570811 B TW 570811B
- Authority
- TW
- Taiwan
- Prior art keywords
- pth
- solution
- mannitol
- quot
- human
- Prior art date
Links
- OGBMKVWORPGQRR-UMXFMPSGSA-N teriparatide Chemical compound C([C@H](NC(=O)[C@H](CCSC)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)C(C)C)[C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)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)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CNC=N1 OGBMKVWORPGQRR-UMXFMPSGSA-N 0.000 title abstract description 8
- 108010049264 Teriparatide Proteins 0.000 title description 3
- 229960005460 teriparatide Drugs 0.000 title description 3
- 108090000445 Parathyroid hormone Proteins 0.000 claims abstract description 34
- 239000000199 parathyroid hormone Substances 0.000 claims abstract description 33
- 102000003982 Parathyroid hormone Human genes 0.000 claims abstract description 31
- 239000000243 solution Substances 0.000 claims abstract description 25
- 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 abstract description 21
- 229930195725 Mannitol Natural products 0.000 claims abstract description 21
- 239000000594 mannitol Substances 0.000 claims abstract description 21
- 235000010355 mannitol Nutrition 0.000 claims abstract description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims abstract description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- 238000007911 parenteral administration Methods 0.000 claims abstract description 3
- 239000000203 mixture Substances 0.000 claims description 19
- 239000003381 stabilizer Substances 0.000 claims description 9
- 238000004108 freeze drying Methods 0.000 claims description 4
- 101001135770 Homo sapiens Parathyroid hormone Proteins 0.000 claims description 3
- 101001135995 Homo sapiens Probable peptidyl-tRNA hydrolase Proteins 0.000 claims description 3
- 102000058004 human PTH Human genes 0.000 claims description 3
- 239000007853 buffer solution Substances 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 2
- 102100036893 Parathyroid hormone Human genes 0.000 claims 3
- 150000005846 sugar alcohols Polymers 0.000 claims 2
- 239000000463 material Substances 0.000 claims 1
- 235000012054 meals Nutrition 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 229960001319 parathyroid hormone Drugs 0.000 abstract description 27
- 238000002360 preparation method Methods 0.000 abstract description 15
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 abstract description 14
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 abstract description 11
- 229940095064 tartrate Drugs 0.000 abstract description 11
- 239000000872 buffer Substances 0.000 abstract description 9
- 239000004480 active ingredient Substances 0.000 abstract description 4
- 239000006172 buffering agent Substances 0.000 abstract description 4
- 239000003755 preservative agent Substances 0.000 abstract description 4
- 239000007864 aqueous solution Substances 0.000 abstract description 2
- 230000002335 preservative effect Effects 0.000 abstract description 2
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 abstract 3
- 235000019445 benzyl alcohol Nutrition 0.000 abstract 1
- 229920005862 polyol Polymers 0.000 abstract 1
- 150000003077 polyols Chemical class 0.000 abstract 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 229940088597 hormone Drugs 0.000 description 10
- 239000005556 hormone Substances 0.000 description 10
- 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 9
- 229930006000 Sucrose Natural products 0.000 description 9
- 239000005720 sucrose Substances 0.000 description 9
- 238000011049 filling Methods 0.000 description 7
- 208000001132 Osteoporosis Diseases 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 210000000988 bone and bone Anatomy 0.000 description 4
- 238000003745 diagnosis Methods 0.000 description 4
- 239000012634 fragment Substances 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 108010062796 arginyllysine Proteins 0.000 description 3
- 239000011975 tartaric acid Substances 0.000 description 3
- 235000002906 tartaric acid Nutrition 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 102000009027 Albumins Human genes 0.000 description 2
- 108010088751 Albumins Proteins 0.000 description 2
- ULBHWNVWSCJLCO-NHCYSSNCSA-N Arg-Val-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCN=C(N)N ULBHWNVWSCJLCO-NHCYSSNCSA-N 0.000 description 2
- WIDVAWAQBRAKTI-YUMQZZPRSA-N Asn-Leu-Gly Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O WIDVAWAQBRAKTI-YUMQZZPRSA-N 0.000 description 2
- XQFLFQWOBXPMHW-NHCYSSNCSA-N Asp-Val-His Chemical compound N[C@@H](CC(=O)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)O XQFLFQWOBXPMHW-NHCYSSNCSA-N 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 102000008100 Human Serum Albumin Human genes 0.000 description 2
- 108091006905 Human Serum Albumin Proteins 0.000 description 2
- 208000000038 Hypoparathyroidism Diseases 0.000 description 2
- POMXSEDNUXYPGK-IHRRRGAJSA-N Leu-Met-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N POMXSEDNUXYPGK-IHRRRGAJSA-N 0.000 description 2
- OWRUUFUVXFREBD-KKUMJFAQSA-N Lys-His-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(C)C)C(O)=O OWRUUFUVXFREBD-KKUMJFAQSA-N 0.000 description 2
- HVAUKHLDSDDROB-KKUMJFAQSA-N Lys-Lys-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O HVAUKHLDSDDROB-KKUMJFAQSA-N 0.000 description 2
- MUPFEKGTMRGPLJ-RMMQSMQOSA-N Raffinose Natural products O(C[C@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O[C@@]2(CO)[C@H](O)[C@@H](O)[C@@H](CO)O2)O1)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 MUPFEKGTMRGPLJ-RMMQSMQOSA-N 0.000 description 2
- NIOYDASGXWLHEZ-CIUDSAMLSA-N Ser-Met-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(O)=O NIOYDASGXWLHEZ-CIUDSAMLSA-N 0.000 description 2
- JGUWRQWULDWNCM-FXQIFTODSA-N Ser-Val-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O JGUWRQWULDWNCM-FXQIFTODSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- AIISTODACBDQLW-WDSOQIARSA-N Trp-Leu-Arg Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)=CNC2=C1 AIISTODACBDQLW-WDSOQIARSA-N 0.000 description 2
- MUPFEKGTMRGPLJ-UHFFFAOYSA-N UNPD196149 Natural products OC1C(O)C(CO)OC1(CO)OC1C(O)C(O)C(O)C(COC2C(C(O)C(O)C(CO)O2)O)O1 MUPFEKGTMRGPLJ-UHFFFAOYSA-N 0.000 description 2
- 108010050025 alpha-glutamyltryptophan Proteins 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000002079 cooperative effect Effects 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000000849 parathyroid Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- MUPFEKGTMRGPLJ-ZQSKZDJDSA-N raffinose 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[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)O1 MUPFEKGTMRGPLJ-ZQSKZDJDSA-N 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 239000008223 sterile water Substances 0.000 description 2
- WPRAXAOJIODQJR-UHFFFAOYSA-N 1-(3,4-dimethylphenyl)ethanone Chemical compound CC(=O)C1=CC=C(C)C(C)=C1 WPRAXAOJIODQJR-UHFFFAOYSA-N 0.000 description 1
- 241000238876 Acari Species 0.000 description 1
- MNZHHDPWDWQJCQ-YUMQZZPRSA-N Ala-Leu-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O MNZHHDPWDWQJCQ-YUMQZZPRSA-N 0.000 description 1
- NINQYGGNRIBFSC-CIUDSAMLSA-N Ala-Lys-Ser Chemical compound NCCCC[C@H](NC(=O)[C@@H](N)C)C(=O)N[C@@H](CO)C(O)=O NINQYGGNRIBFSC-CIUDSAMLSA-N 0.000 description 1
- MAZZQZWCCYJQGZ-GUBZILKMSA-N Ala-Pro-Arg Chemical compound [H]N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(O)=O MAZZQZWCCYJQGZ-GUBZILKMSA-N 0.000 description 1
- ADSGHMXEAZJJNF-DCAQKATOSA-N Ala-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N ADSGHMXEAZJJNF-DCAQKATOSA-N 0.000 description 1
- WKPXXXUSUHAXDE-SRVKXCTJSA-N Arg-Pro-Arg Chemical compound NC(N)=NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCN=C(N)N)C(O)=O WKPXXXUSUHAXDE-SRVKXCTJSA-N 0.000 description 1
- OMSMPWHEGLNQOD-UWVGGRQHSA-N Asn-Phe Chemical compound NC(=O)C[C@H](N)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 OMSMPWHEGLNQOD-UWVGGRQHSA-N 0.000 description 1
- UYCPJVYQYARFGB-YDHLFZDLSA-N Asn-Phe-Val Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C(C)C)C(O)=O UYCPJVYQYARFGB-YDHLFZDLSA-N 0.000 description 1
- JZLFYAAGGYMRIK-BYULHYEWSA-N Asn-Val-Asp Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O JZLFYAAGGYMRIK-BYULHYEWSA-N 0.000 description 1
- HPNDBHLITCHRSO-WHFBIAKZSA-N Asp-Ala-Gly Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)NCC(O)=O HPNDBHLITCHRSO-WHFBIAKZSA-N 0.000 description 1
- RDRMWJBLOSRRAW-BYULHYEWSA-N Asp-Asn-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O RDRMWJBLOSRRAW-BYULHYEWSA-N 0.000 description 1
- LIVXPXUVXFRWNY-CIUDSAMLSA-N Asp-Lys-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O LIVXPXUVXFRWNY-CIUDSAMLSA-N 0.000 description 1
- 101001135732 Bos taurus Parathyroid hormone Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-N Caprylic acid Natural products CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 1
- MOJKRXIRAZPZLW-WDSKDSINSA-N Gly-Glu-Ala Chemical compound [H]NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O MOJKRXIRAZPZLW-WDSKDSINSA-N 0.000 description 1
- 208000013038 Hypocalcemia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 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
- AIMGJYMCTAABEN-GVXVVHGQSA-N Leu-Val-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O AIMGJYMCTAABEN-GVXVVHGQSA-N 0.000 description 1
- UQRZFMQQXXJTTF-AVGNSLFASA-N Lys-Lys-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O UQRZFMQQXXJTTF-AVGNSLFASA-N 0.000 description 1
- IOQWIOPSKJOEKI-SRVKXCTJSA-N Lys-Ser-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O IOQWIOPSKJOEKI-SRVKXCTJSA-N 0.000 description 1
- HMRAQFJFTOLDKW-GUBZILKMSA-N Ser-His-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(O)=O HMRAQFJFTOLDKW-GUBZILKMSA-N 0.000 description 1
- SYSWVVCYSXBVJG-RHYQMDGZSA-N Val-Leu-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)N)O SYSWVVCYSXBVJG-RHYQMDGZSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 108010024078 alanyl-glycyl-serine Proteins 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 238000011001 backwashing Methods 0.000 description 1
- UDEWPOVQBGFNGE-UHFFFAOYSA-N benzoic acid n-propyl ester Natural products CCCOC(=O)C1=CC=CC=C1 UDEWPOVQBGFNGE-UHFFFAOYSA-N 0.000 description 1
- GONOPSZTUGRENK-UHFFFAOYSA-N benzyl(trichloro)silane Chemical compound Cl[Si](Cl)(Cl)CC1=CC=CC=C1 GONOPSZTUGRENK-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 230000008468 bone growth Effects 0.000 description 1
- 239000001273 butane Substances 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 238000002309 gasification Methods 0.000 description 1
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 1
- 108010050848 glycylleucine Proteins 0.000 description 1
- 108010083224 human transframe polypeptide Proteins 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000000705 hypocalcaemia Effects 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 108010044348 lysyl-glutamyl-aspartic acid Proteins 0.000 description 1
- 125000003717 m-cresyl group Chemical group [H]C1=C([H])C(O*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- FJQXCDYVZAHXNS-UHFFFAOYSA-N methadone hydrochloride Chemical compound Cl.C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 FJQXCDYVZAHXNS-UHFFFAOYSA-N 0.000 description 1
- OLXYLDUSSBULGU-UHFFFAOYSA-N methyl pyridine-4-carboxylate Chemical compound COC(=O)C1=CC=NC=C1 OLXYLDUSSBULGU-UHFFFAOYSA-N 0.000 description 1
- 238000005065 mining Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N n-hexanoic acid Natural products CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 235000020610 powder formula Nutrition 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 208000006078 pseudohypoparathyroidism Diseases 0.000 description 1
- 230000000541 pulsatile effect Effects 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 230000010410 reperfusion Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 210000002700 urine Anatomy 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
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/29—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-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
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—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
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Physical Education & Sports Medicine (AREA)
- Endocrinology (AREA)
- General Chemical & Material Sciences (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Rheumatology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Zoology (AREA)
- Dermatology (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Silver Salt Photography Or Processing Solution Therefor (AREA)
Description
570811 A7 B7 五、發明説明〇 技術範疇 本發明係關於含有副甲狀腺素之醫藥組合物。更特別 地,本發明係關於泰瑞帕拉肽,PTH( 1-34),安定溶液處 方。 發明背景 副甲狀腺素(PTH)係哺乳類副甲狀腺分泌之84個胺基酸 的產物,其經由對不同的組織包括骨骼之作用控制血清鈣 濃度。以某型式PTH對人所作之研究顯示其對骨骼具同化 效益,並促成吾人對其治療骨質疏鬆與相關骨骼症候強烈 興趣。 以牛與人的激素N-端34個胺基酸爲例,其在所有出版文 獻中皆視同全長激素之生物相等物,經顯示在人體中副甲 狀腺素可增強骨骼生長,特別係在採皮下途徑以搏動型式 施用時。型式略異之PTH,人類ΡΤΗ(1-38)顯示類似結 經濟部中央標準局員工消費合作社印製 吾人已由新鮮或冷凍乾燥之激素合併不同型式之載體、 賦型劑與載劑回沖PTH製劑。多數以水基載劑諸如鹽液製 式,或是水典型地經乙酸酸化俾溶解激素。多數經報導之 處方亦合併白蛋白作爲安定劑(參照例如Reeve等.,Br. Med. J·,1980,280 ·· 6228 ; Reeve 等·,Lancet,1976,1 ·· 1035 ; Reeve 等·,Calcif. Tissue Res·,1976,21 : 469 ; Hodsman 等·, Bone Miner ; 1990, 9(2) : 13 7 ; Tsai 等· J. Clin. Endocrinol
Metab·, 1989,69(5) ·· 1024 ; Isaac 等.,Horm. Metab. Res·, 1980,12(9) : 487 ; Law 等·,J. Clin Invest. 1983,72(3): -4- ‘紙張尺度適用中國國家標準(CNS ) A4規格(210 X 297公釐) 570811 A7 _____________— ______B7 五、發明説明(2 ) 1106 ;與 Hulter,J· Clin Hypertens,1986,2(4) : 360)。其他 經報導之處方併用諸如甘露醇之賦型劑,其若非與冷凍乾 燥之激素併存即是存於回沖載劑中。用於人類研究之代表 性處方包括如下之人類PTH( 1-34)(序列辨識號碼:2)製 劑,其包括經回沖後,甘露醇、熱抑制人類血清白蛋白與 己酸(蛋白酶抑制劑)作爲吸收增強劑(參照Reeve等.,1976, Calcif· Tissue Res.,21,補篇·,469-477); —種回沖以鹽液 載劑之人類ΡΤΗ(1·38)製劑(參照Hodsman等·,1991,14(1), 67·83 );與經乙酸調p Η並含白蛋白之以水爲載劑之牛 ΡΤΗ(1·3 4)製劑,亦有一種國際參考製劑,其對人的 ΡΤΗ(1-84)(序列辨識號碼:1)包含1〇〇毫微克激素且裝於 含250微克人類血清白蛋白與ι·25毫克乳糖(1981)之安瓶 中,對牛之ΡΤΗ則包含溶於0.01莫耳濃度乙酸與〇.1%重量 /體積甘露醇之1 0微克的冷凍乾燥激素(參照Martindale, The Extra Pharmacoepia, The Pharmaceutical Press, London, 第 29 版,1989,1338 頁)。 £卩619119報告一種改善11_?1^(1-3 4)(序列辨識號碼: 2 )冷凍乾燥製劑之新嚐試,其係混合糖與氣化鈉。而且美 國專利號碼5,496,801説明一種天然激素PTH(l-84)之冷束 乾燥組合物,其以甘露醇做爲賦型劑而擰檬酸鹽做爲非-揮 發性緩衝劑。 副甲狀腺激素之商業開發必須發展具可接受之貯存安定 性與易操作之處方。因其爲蛋白質因此比傳統小分子量之 藥物益發不安定,然而副甲狀腺素之處方帶給製藥業不常 (請先閱讀背面之注意事項再填寫本頁)
-5-
A7 B7 570811 五、發明説明(3 遭遇之挑戰。甚且,正如已經成功製成處方之蛋白般, PTH對氧化、去醯胺及水解作用特別敏感,故需要保持N-端與C -端序列之完整俾維持其生物活性。 提供具醫藥用途之PTH製劑係本發明目的之一,特別是 包括態^帕拉肽、P T H ( b 3 4 )(序列辨識號碼:2 )作爲活 性成份者。 發明搞沭 本發明提供一種安定溶液型式之包含醫療有效量之副甲 狀腺素(Ρ Τ Η )之醫藥組合物。該溶液具貯存安定性而且係 典囷型式,得貯存於小瓶或匣中以便供病人之非經腸施 用。本溶液之優點在省去冷凍燥之麻煩。 據此’本發明係副甲狀腺素溶液,包括: (a)醫療有效量之副甲狀腺素; (b )有效量之安定劑; (c)足以維持該組合物於約pH 3〜7範園之量的緩衝劑;與 (d )餘量爲水。 必要時,可將本溶液冷凍乾燥製成含2%以下的水之冷凍 乾燥粉末。 本發明另一方面係一種副甲狀腺素溶液,包括: (a) 醫療有效量之副甲狀腺素; (b) 約1-20重量%之安定劑; (c) 足以維持該組合物於約pH 3〜7範園之量的緩衝劑, 並且是選自乙酸鹽或酒石酸鹽者; (d) 由約(M〜2重量%之非經腸可接受之防腐劑;與 本紙張尺心 (請先閲讀背面之注意事項再填寫本頁) 、11 570811 A7
(e)餘量爲水。 又’本發明另一方面係回沖前爲冷凍乾燥粉末型式之醫 藥組合物,包括: U)醫療有效量之選自ΡΤΗ(1-34),ΡΤΗ(1_37), ρΤΗ(1·38)與ΡΤΗ(1-41)之副甲狀腺素之片段; (b)有效量之安定劑; (c )足以維持該組合物於約pjj 3〜7範圍之量的緩衝劑;與 (d)低於2%重量之水。 發明詳沭 本發明係關於依激素組成份與活性而展現胖存安定性之 副曱狀腺素溶液。 以活性成分言,該組合物或溶得合併8 4個胺基酸型式, 全長之副甲狀腺素,特別是人類者,hPTH( 1-84)(序列辨 識號碼:1 )不論其係經肽合成之重組物或由人類體液萃取 者。其例參照美國專利號碼5,208,041,併列本文供參考。 hPTH(l-84)的胺基敗之報告请見Kimura等Biochem. Biophys. Res. Comm·,114(2) : 493 (序列辨識號碼:1)。 經濟部中央標準局員工消費合作社印製 該組合物或溶液亦得合併如Kimmel等.,Endocrinology, 1993, 32(4) : 1577所報告之骨質疏鬆症的切除卵巢大鼠模 式所定出具人類PTH活性之人類PTH或大鼠豬或牛PTH之 片段或片段之變體作爲活性成份。 所併用之副甲狀腺片段至少係N ·端前3 4個殘基,諸如 ΡΤΗ(1·34)(序列辨識號碼:2),ΡΤΗ(1·37),ΡΤΗ(1· 38)與ΡΤΗ(1-41)。替代地在PTH變體中得採用1至5個胺 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 570811 A7
570811 A7 B7 五、發明説明(6 II——.----0|丨 (請先閱讀背面之注意事項再填寫本頁j 苯酸丙酯,硫柳汞,與苯基硝酸汞及乙酸。較佳之防腐劑 爲間-甲苯酚或芊醇,又以間-甲苯酚最佳。使用的防腐劑 之範園爲總溶液之約〇. 1〜約2重量%,以約0.3〜約1 ·〇重量 %較佳。 因此,本發明提供例如含有甘露醇、乙酸鹽與間-甲苯酚 之泰瑞帕拉肽溶液且在5 °C時預測其貯存期逾1 5個月。 本發明之副甲狀腺素組合物必要時得以含不逾2 %水份重 之粉末型式供應,其係得自選用之副甲狀腺素,缓衝劑與 上述之安定劑混合製成之無菌,激素水溶液的冷凍乾燥產 品。製備冷凍乾燥粉末時特佳之緩衝劑爲酒石酸。特別有 用之安定劑包括甘胺酸,甘露醇,蔗糖,繭糖,棉子糖或 其混合物。 訂 本發明之PTH溶液與組合物併用醫藥有效量之pth,關 於有用量之用語意指醫療或醫學診斷方面。製劑中併用之 副甲狀腺素之特定量得根據選用之PTH型式及製劑之目標 終用法而預先定之。某種用法中,所開發之該製劑係供醫 療用途’特別是治療骨質疏鬆症。骨質疏鬆症之治療需要 注射該回沖製劑,以皮下注射較佳,其係可反應處方之療 程的單位劑量,但以實例言,人的ΡΊΓΗ( 1-3 4)(序列辨識 號碼:2)其注射溶液之範圍爲由25微克PTH/毫升注射液 至1000微克/毫升注射液,注射量以0 02〜13毫升較佳。 據此,該純化P T Η右*合併緩衝劑與賦型劑形式含ρ τ η渡户 範圍爲25〜1000微克/毫升較佳,又以1〇〇〜5〇〇微克/毫升 較佳,然後將之過爐除菌並充入小瓶或匿中備用。 _________-9- "iS尺度ϋ中國國家標準「CNS ) Α4規格(------ 經濟部中央標準局員工消費合作社印製 570811 A7 B7 五、發明説明(7 ) 一 ' - 一旦取得孩含所需量與濃度之缓衝劑、賦型劑與PTH之 水〉谷液製劑’便將所需體積之該溶劑充入小瓶中。本發明 之優·沾係上it 液得以無菌水製備而不需冷滚乾燥過程。 本發明是一種具體實施例中,其所提供之製劑型式係在 沖泡於1 Φ升(0·8-1.2毫升)沖泡載體時含有100-500微克人 類ΡΤΗ(1-34)(序列辨識號碼:2)之單位容器,而且該小瓶 據此充入約1亳升ΡΤΗ水性製劑俾進行後續之冷凍乾燥。 在一種較佳之本發明的具體實施例中,該付諸冷凍乾燥 之ΡΤΗ製劑包括25〜1〇〇〇微克/毫升之人類ΡΤΗ(1_34)(序 列辨識號碼:2 ),2〜8 %重之甘露醇,與足以缓衝該製劑 經無菌水回沖時維持pH範圍3.0〜6.5之量的酒石酸。在本 發明之特定具體實施例中,所合併之酒石酸緩衝劑的量足 以緩衝pH於3.5〜5.5。 除醫療用途外,本發明之PTH組合物得處方並施用於醫 學診斷,特別是幫助建立對低血鈣病人之低副甲狀腺症與 僞低副甲狀腺症之診斷。除了 P T Η劑量,該P T Η製劑之組 成份與本文所述之醫療用途者同。爲此診斷目的,相當於 Ρ Τ Η活性之200個國際單位之靜脈内浸潤,單一劑量之人 類ΡΤΗ( 1·34)(序列辨識號碼:2)係適當的。然後經由施 用的ΡΤΗ之效果或尿中cAMP量之決定進行診斷,因c AMP 而非其僞型之升高係低副甲狀腺症之指標。 下列實例係説明本發明而非其限制之用。 實例 實例1 _________ - 10 - 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) (請先聞讀背面之注意事項再填寫本頁) -訂 570811 A7 B7 五、發明説明(8 ) 將〇·1毫克rhPTH(l-3 4)(序列辨識號碼:2),50毫克甘 露醇,2.5毫克間甲苯酚,0.52亳克乙酸與0.12毫克乙酸鈉 和1亳升蒸餾水混合成溶液。 將〇.25毫克1^丁11(1-34)(序列辨識號碼1),45.4毫克 甘露醇,3毫克間甲苯酚,0.41毫克乙酸與〇.1毫克乙酸鈉 和1毫升蒸餾水混合成溶液。 本發明之處方、實例1與實例2與不含安定劑,或含0.9% NaCn,20毫莫耳濃度乙酸鹽與1〇毫莫耳濃度乙酸鹽等初級 安定劑之溶液比較。安定性係利用決定某段時間後 rhPTH( 1-3 4)(序列辨識號碼:2)剩餘之量而測之。該測量 係利用HPLC。其結果列於表1與2。 請 先 閲 讀 背 Λ 之 注 意 事 項 再 填 寫 本 頁 經濟部中央標準局員工消費合作社印製 表1 水 0.9%NaCl 20毫莫耳濃度乙酸鹽 10毫莫耳濃度乙酸鹽 時間,日 %剩餘量 初始 100 100 100 100 7 74 81 84 80 14 55 58 67 71 -11 - 本紙張尺度適用中國國家標準(CNS ) Α4規格(210 X 297公釐) 570811 五 、發明説明(9 ) A7 B7
(請先閱讀背面之注意事項再填寫本頁j 訂 下列實例之進行係在顯示由本發明之安定化溶液製成之 冷凍乾燥粉末處方比單獨由PTH(1-34)與甘露醇製成之對 照組安定。 蜱 根據表3所示之成份與濃度如前述般製成對照組溶液及樣 本A至〇之溶液。然後將這些溶液冷凍乾燥並將生成之冷凍 乾燥粉末處方貯存於4 〇 °C 1個月。然後利用HPLC測定每一 樣本中剩餘之ΡΤΗ(1-34)量。結果列於表3。 -12- 本紙張尺度適财_家縣(CNS )以規格(21()χ297公菱) 570811 A7 _________________B7 五、發明説明(10 ) 表3 PTH(1_34)冷凍乾燥處理貯存於40°C—個月後之安定性 樣本 ΡΤΗ(1-34) 毫克/毫升 充量劑 充量劑濃度 毫克/毫升 緩衝劑 緩衝液濃度 毫莫耳濃度 剩餘 %PTH 對照組 0.2 甘露醇 40 __ 78 A 0.5 甘露醇 30 乙酸鹽 5 90 B 0.5 甘胺酸 30 乙酸鹽 5 98 C 0.5 蔗糖 30 乙酸鹽 5 98 D 0.5 繭糖 30 乙酸鹽 5 97 E 0.5 棉子糖 30 乙酸鹽 5 99 F 0.75 甘露醇 30 酒石酸鹽 15 95 G 1.5 蔗糖與甘 露醇 5/25 酒石酸鹽 5 99 Η 0.75 蔗糖與甘 露醇 5/25 酒石酸鹽 15 99 I 1.5 甘露醇 30 酒石酸鹽 5 96 J 1.5 蔗糖 30 酒石酸鹽 15 100 K 1.5 甘露醇 30 酒石酸鹽 15 99 L 0.75 蔗糖 30 酒石酸鹽 15 100 Μ 0.75 蔗糖 30 酒石酸鹽 5 100 N 1.5 蔗糖與甘 露醇 5/25 酒石酸鹽 15 99 0 1.5 蔗糖與甘 露醇 5/25 乙酸鹽 5 91* *2個月後之安定性爲96% (請先閱讀背面之注意事項再楨寫本頁)
、1T ___ -13· 本紙張尺度適用T國國家標準(CNS ) A4規格(210X297公釐) 570811 A7 _____ _______B7 五、發明説明(11 ) 序列表列 (請先閱讀背面之注意事項再填寫本頁) <110>Eli Lilly and Company < 120 >安定肽瑞帕拉泰溶液 <130>3797.16WO01 <140>新建檔 <141> 1998-12-08 <150>60/069?075 <151>1997-12-09 <160>2 < 170>PatentIn Ver. 2.0 <210>1 <211>84 <212>PRT <213>人類 <400>1
Ser Val Ser Glu lie Gin Leu Met His Asn Leu Gly Lys His Leu Asn 15 10 15
Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gin Asp Val His 20 25 30
Asn Phe Val Ala Leu Gly Ala Pro Leu Ala Pro Arg Asp Ala Gly Ser 35 40 45
Gin Arg Pro Arg Lys Lys Glu Asp Asn Val Leu Val Glu Ser His Glu 50 55 60
Lys Ser Leu Gly Glu Ala Asp Lys Ala Asn Val Asp Val Leu Thr Lys 65 70 75 80 -14- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 570811 A7 B7 五、發明説明(12 )
Ala Lys Ser Gin <210>2 <211>34 <212>PRT <213〉人類 <400>2
Ser Val Ser Glu He Gin Leu Met His Asn Leu Gly Lys His Leu Asn 15 10 15
Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gin Asp Val His 20 25 30
Asn Phe -15- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) (請先閱讀背面之注意事項再填寫本頁)
Claims (1)
- 8 70 5 中1. 2. 3. 4. 一種準備供非經腸施用之溶液形式 1 1 一 〈餐藥組合物,並句 括人類副甲狀腺素、選自乙酸鹽、涵 a 八 夕雉姓w古、“ s ''石馱鹽或擰檬酸鹽 之、准持pH同於3至7之緩衝液,及安定南丨 、虫,土二 &釗,其中該溶液在 病患使用丽無須經冷凍乾燥或回沖步驟。 根據申請專利範圍第1項之醫藥組合物,、、、 τ琢安定齋 係選自多元醇或糖醇。 ' 根據申請專利範圍第丨至2項中任一項之醫藥組合物, 其中該人類副甲狀腺素係選自PTH (1·34)、p丁h(i_37)、 PTH (1-3 8)、PTH(1-41)及PTH (1-84)所組成之群。 根據中凊專利範圍第1至2項中任一項之醫藥組合物, 其中該安定劑為甘露醇。 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) '""""' ' ----
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US6907597P | 1997-12-09 | 1997-12-09 |
Publications (1)
Publication Number | Publication Date |
---|---|
TW570811B true TW570811B (en) | 2004-01-11 |
Family
ID=22086574
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW087120429A TW570811B (en) | 1997-12-09 | 1998-12-09 | Stabilized teriparatide solutions |
Country Status (32)
Country | Link |
---|---|
EP (2) | EP0920873B1 (zh) |
JP (1) | JP4405666B2 (zh) |
KR (1) | KR100482703B1 (zh) |
CN (1) | CN1198644C (zh) |
AR (1) | AR018526A1 (zh) |
AT (1) | ATE260113T1 (zh) |
AU (1) | AU759726B2 (zh) |
BR (1) | BR9813463A (zh) |
CA (1) | CA2314313C (zh) |
CY (1) | CY1114000T1 (zh) |
CZ (1) | CZ302401B6 (zh) |
DE (1) | DE69821872T2 (zh) |
DK (2) | DK1417972T4 (zh) |
EA (1) | EA004761B1 (zh) |
EG (1) | EG23675A (zh) |
ES (2) | ES2405994T5 (zh) |
HK (1) | HK1021798A1 (zh) |
HU (1) | HU230784B1 (zh) |
ID (1) | ID27741A (zh) |
IL (1) | IL136662A (zh) |
MY (1) | MY120063A (zh) |
NO (1) | NO327302B1 (zh) |
NZ (1) | NZ505222A (zh) |
PE (1) | PE20000001A1 (zh) |
PL (1) | PL194268B1 (zh) |
PT (2) | PT920873E (zh) |
SK (1) | SK288203B6 (zh) |
TR (1) | TR200002134T2 (zh) |
TW (1) | TW570811B (zh) |
UA (1) | UA72884C2 (zh) |
WO (1) | WO1999029337A1 (zh) |
ZA (1) | ZA9811127B (zh) |
Families Citing this family (59)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP4719357B2 (ja) * | 1998-07-23 | 2011-07-06 | アレス トレイディング ソシエテ アノニム | Fsh及びfsh変異体の製剤、製品及び方法 |
US20030166525A1 (en) | 1998-07-23 | 2003-09-04 | Hoffmann James Arthur | FSH Formulation |
DZ2873A1 (fr) | 1998-08-19 | 2003-12-15 | Lilly Co Eli | Procédé pour augmenter la dureté et la rigidité osseuse. |
US7022674B2 (en) | 1999-12-16 | 2006-04-04 | Eli Lilly And Company | Polypeptide compositions with improved stability |
WO2001087322A2 (en) * | 2000-05-17 | 2001-11-22 | Bionebraska, Inc. | Peptide pharmaceutical formulations |
JP2004513069A (ja) * | 2000-05-19 | 2004-04-30 | レストラゲン,インコーポレイテッド | ペプチド医薬処方 |
US20040156835A1 (en) * | 2001-05-30 | 2004-08-12 | Taiji Imoto | Protein preparation |
EP1767213A3 (en) * | 2001-11-05 | 2007-04-25 | Eli Lilly & Company | Method for improving stability of a bone-connecting implant |
AU2002363412A1 (en) * | 2001-11-05 | 2003-05-19 | Eli Lilly And Company | Method for improving stability of a bone-connecting implant |
US8088734B2 (en) | 2003-01-21 | 2012-01-03 | Unigene Laboratories Inc. | Oral delivery of peptides |
EA012565B1 (ru) | 2003-04-02 | 2009-10-30 | Арес Трейдинг С.А. | Жидкие фармацевтические композиции фолликулостимулирующего гормона (фсг) и лютеинизирующего гормона (лг), содержащие неионогенное поверхностно-активное вещество |
CA2526099C (en) | 2003-06-20 | 2013-02-05 | Ares Trading Sa | Freeze-dried fsh / lh formulations |
US7329725B1 (en) | 2003-10-29 | 2008-02-12 | Nastech Pharmaceutical Company Inc. | Phage displayed Trp cage ligands |
HUE043210T2 (hu) | 2003-11-20 | 2019-08-28 | Novo Nordisk As | Injekciós eszközök elõállítására optimális propilénglikol-tartalmú peptidkészítmények |
CN102643233B (zh) | 2003-12-23 | 2015-11-25 | 无限发现公司 | 用于治疗癌症的包含苯醌的安沙霉素类似物 |
US8268791B2 (en) | 2004-08-25 | 2012-09-18 | Aegis Therapeutics, Llc. | Alkylglycoside compositions for drug administration |
WO2006025882A2 (en) * | 2004-08-25 | 2006-03-09 | The Uab Research Foundation | Absorption enhancers for drug administration |
US20140162965A1 (en) | 2004-08-25 | 2014-06-12 | Aegis Therapeutics, Inc. | Compositions for oral drug administration |
US8642564B2 (en) | 2004-08-25 | 2014-02-04 | Aegis Therapeutics, Llc | Compositions for drug administration |
US9895444B2 (en) | 2004-08-25 | 2018-02-20 | Aegis Therapeutics, Llc | Compositions for drug administration |
US20060046962A1 (en) | 2004-08-25 | 2006-03-02 | Aegis Therapeutics Llc | Absorption enhancers for drug administration |
US9114069B2 (en) | 2004-08-25 | 2015-08-25 | Aegis Therapeutics, Llc | Antibacterial compositions for drug administration |
KR100700869B1 (ko) * | 2005-06-03 | 2007-03-29 | 재단법인 목암생명공학연구소 | Pth, 완충제 및 안정제를 포함하는 안정한 pth조성물 |
BRPI0618469A2 (pt) | 2005-11-10 | 2011-08-30 | Univ Michigan Tech | hormÈnio paratiróide de urso preto e métodos de uso de hormÈnio paratiróide de urso preto |
US8226949B2 (en) | 2006-06-23 | 2012-07-24 | Aegis Therapeutics Llc | Stabilizing alkylglycoside compositions and methods thereof |
USRE49444E1 (en) | 2006-10-03 | 2023-03-07 | Radius Health, Inc. | Method of treating osteoporosis comprising administration of PTHrP analog |
US7803770B2 (en) | 2006-10-03 | 2010-09-28 | Radius Health, Inc. | Method of treating osteoporosis comprising administration of PTHrP analog |
ES2739459T3 (es) * | 2006-10-03 | 2020-01-31 | Radius Health Inc | Una composición estable que comprende una proteína anabólica ósea, es decir un análogo de PTHrP y usos de la misma |
EP1958618A1 (de) | 2007-02-15 | 2008-08-20 | Octapharma AG | Verfahren zur Gefriertrocknung mit optimierter Rekonstitution von Biopolymeren |
AU2008240179A1 (en) * | 2007-04-12 | 2008-10-23 | Infinity Discovery, Inc. | Hydroquinone ansamycin formulations |
US20080299228A1 (en) * | 2007-05-29 | 2008-12-04 | Alan Gerald Harris | Topical compositions comprising a macromolecule and methods of using same |
AU2008269086B2 (en) | 2007-06-25 | 2014-06-12 | Amgen Inc. | Compositions of specific binding agents to hepatocyte growth factor |
CA2756690C (en) | 2008-03-28 | 2016-08-16 | Hale Biopharma Ventures, Llc | Administration of benzodiazepine compositions |
EP2348845A4 (en) | 2008-10-15 | 2013-01-23 | Infinity Pharmaceuticals Inc | ANSAMYCIN HYDROQUINONE COMPOSITIONS |
US8440631B2 (en) | 2008-12-22 | 2013-05-14 | Aegis Therapeutics, Llc | Compositions for drug administration |
IN2012DN00857A (zh) * | 2009-09-09 | 2015-07-10 | Asahi Kasei Pharma Corp | |
JP2013512688A (ja) | 2009-12-07 | 2013-04-18 | ミシガン テクノロジカル ユニバーシティ | クロクマの副甲状腺ホルモン及びクロクマの副甲状腺ホルモンを使用する方法 |
EP4085899A1 (en) | 2011-06-14 | 2022-11-09 | Neurelis, Inc. | Administration of benzodiazepine |
CN102731643A (zh) * | 2012-06-26 | 2012-10-17 | 深圳翰宇药业股份有限公司 | 一种治疗骨质疏松多肽的制备方法 |
CN103301058A (zh) * | 2013-06-17 | 2013-09-18 | 深圳翰宇药业股份有限公司 | 一种特立帕肽注射用组合物及其制备方法和制剂 |
EP4039253A1 (en) | 2015-04-29 | 2022-08-10 | Radius Pharmaceuticals, Inc. | Methods of treating cancer |
CN106309358A (zh) * | 2015-06-29 | 2017-01-11 | 成都金凯生物技术有限公司 | 含有人甲状旁腺激素的药物组合物及其制备方法与用途 |
JP6634758B2 (ja) * | 2015-09-25 | 2020-01-22 | ニプロ株式会社 | 液体組成物及び凍結乾燥製剤 |
KR20230015517A (ko) | 2016-03-01 | 2023-01-31 | 아센디스 파마 본 디지즈 에이/에스 | Pth 프로드럭 |
EP3518961B1 (en) | 2016-09-29 | 2023-02-22 | Ascendis Pharma Bone Diseases A/S | Pth compounds with low peak-to-trough ratios |
HUE063235T2 (hu) | 2016-09-29 | 2024-01-28 | Ascendis Pharma Bone Diseases As | Adagolási rendszer szabályozott leadású PTH vegyülethez |
US10385008B2 (en) | 2017-01-05 | 2019-08-20 | Radius Pharmaceuticals, Inc. | Polymorphic forms of RAD1901-2HCL |
US10996208B2 (en) | 2017-04-28 | 2021-05-04 | Radius Health, Inc. | Abaloparatide formulations and methods of testing, storing, modifying, and using same |
AU2018321157B2 (en) | 2017-08-24 | 2024-03-28 | Novo Nordisk A/S | GLP-1 compositions and uses thereof |
JP6577683B2 (ja) * | 2017-09-22 | 2019-09-18 | 旭化成ファーマ株式会社 | 安定性に優れるテリパラチド含有液状医薬組成物 |
JP2019060866A (ja) * | 2017-09-22 | 2019-04-18 | 旭化成ファーマ株式会社 | 液状医薬組成物の体内動態を予測する方法 |
CA3075984A1 (en) * | 2017-09-22 | 2019-03-28 | Asahi Kasei Pharma Corporation | Teriparatide-containing liquid pharmaceutical composition having excellent pharmacokinetics and/or safety |
CN108159404B (zh) * | 2018-01-05 | 2019-08-27 | 北京博康健基因科技有限公司 | 重组人甲状旁腺激素制剂及其制备方法 |
WO2019220654A1 (ja) * | 2018-05-17 | 2019-11-21 | 旭化成ファーマ株式会社 | N-ホルミルピぺリジン含有量が低減されている、及び/又は、凍結乾燥ケーキの崩潰又は収縮が抑制されている、製剤 |
CN113423383A (zh) * | 2019-02-11 | 2021-09-21 | 阿森迪斯药物骨疾病股份有限公司 | Pth缀合物的液体药物制剂 |
CN112439054B (zh) * | 2019-08-28 | 2023-05-16 | 深圳翰宇药业股份有限公司 | 一种特立帕肽缓释凝胶注射液及其制备方法 |
IL294521A (en) | 2020-02-18 | 2022-09-01 | Novo Nordisk As | glp-1 compounds and their uses |
EP4110370A4 (en) * | 2020-03-30 | 2023-06-07 | Sichuan Luzhou Buchang Bio-Pharmaceutical Co., Ltd. | FORMULATIONS OF HUMAN PARATHYROID HORMONE (PTH) AND METHODS OF MANUFACTURE THEREOF |
CN113967249A (zh) * | 2021-12-10 | 2022-01-25 | 深圳先进技术研究院 | 甲状旁腺激素在制备治疗男性抑郁症的药物或保健品中的应用 |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6360940A (ja) * | 1986-09-01 | 1988-03-17 | Toyo Jozo Co Ltd | 白内障の予防または治療剤 |
JP2505812B2 (ja) * | 1987-07-10 | 1996-06-12 | 旭化成工業株式会社 | h―PTH(1―34)凍結乾燥組成物 |
US5059587A (en) * | 1987-08-03 | 1991-10-22 | Toyo Jozo Company, Ltd. | Physiologically active peptide composition for nasal administration |
DE3935738A1 (de) * | 1989-10-27 | 1991-05-08 | Forssmann Wolf Georg | Arzneimittel, enthaltend das humane parathormon-fragment (1-37) als aktiven wirkstoff |
GB9020544D0 (en) * | 1990-09-20 | 1990-10-31 | Sandoz Ltd | Improvements in or relating to organic compounds |
WO1993011785A1 (en) * | 1991-12-09 | 1993-06-24 | Asahi Kasei Kogyo Kabushiki Kaisha | Stabilized parathyroid hormone composition |
ES2179831T3 (es) | 1992-09-29 | 2003-02-01 | Inhale Therapeutic Syst | Liberacion en los pulmones de fragmentos activos de hormona paratiroidiana. |
IT1255723B (it) † | 1992-10-09 | 1995-11-13 | Uso di paratormone,suoi frammenti biologicamente attivi e peptidi correlati, per la preparazione di composizioni farmaceutiche utili nella prevenzione e terapia dell'aborto e del parto pretermine ed in generale per il trattamento della gestazione | |
US5496801A (en) * | 1993-12-23 | 1996-03-05 | Allelix Biopharmaceuticals Inc. | Parathyroid hormone formulation |
DE19538687A1 (de) † | 1995-10-17 | 1997-04-24 | Boehringer Mannheim Gmbh | Stabile pharmazeutische Darreichungsformen enthaltend Parathormon |
-
1998
- 1998-12-04 MY MYPI98005507A patent/MY120063A/en unknown
- 1998-12-04 ZA ZA9811127A patent/ZA9811127B/xx unknown
- 1998-12-07 AT AT98123225T patent/ATE260113T1/de not_active IP Right Cessation
- 1998-12-07 DK DK03104219.5T patent/DK1417972T4/en active
- 1998-12-07 PT PT98123225T patent/PT920873E/pt unknown
- 1998-12-07 EG EG151498A patent/EG23675A/xx active
- 1998-12-07 DE DE69821872T patent/DE69821872T2/de not_active Revoked
- 1998-12-07 AR ARP980106213A patent/AR018526A1/es active IP Right Grant
- 1998-12-07 ES ES03104219T patent/ES2405994T5/es not_active Expired - Lifetime
- 1998-12-07 DK DK98123225T patent/DK0920873T3/da active
- 1998-12-07 PT PT3104219T patent/PT1417972E/pt unknown
- 1998-12-07 ES ES98123225T patent/ES2215268T3/es not_active Expired - Lifetime
- 1998-12-07 EP EP98123225A patent/EP0920873B1/en not_active Revoked
- 1998-12-07 EP EP03104219.5A patent/EP1417972B2/en not_active Expired - Lifetime
- 1998-12-08 HU HU0004447A patent/HU230784B1/hu unknown
- 1998-12-08 ID IDW20001318A patent/ID27741A/id unknown
- 1998-12-08 WO PCT/US1998/026043 patent/WO1999029337A1/en active IP Right Grant
- 1998-12-08 JP JP2000524006A patent/JP4405666B2/ja not_active Expired - Lifetime
- 1998-12-08 AU AU17177/99A patent/AU759726B2/en not_active Expired
- 1998-12-08 NZ NZ505222A patent/NZ505222A/en not_active IP Right Cessation
- 1998-12-08 CZ CZ20002115A patent/CZ302401B6/cs not_active IP Right Cessation
- 1998-12-08 PL PL98340902A patent/PL194268B1/pl unknown
- 1998-12-08 KR KR10-2000-7006211A patent/KR100482703B1/ko not_active IP Right Cessation
- 1998-12-08 CN CNB988119641A patent/CN1198644C/zh not_active Ceased
- 1998-12-08 BR BR9813463-9A patent/BR9813463A/pt not_active Application Discontinuation
- 1998-12-08 EA EA200000629A patent/EA004761B1/ru not_active IP Right Cessation
- 1998-12-08 CA CA002314313A patent/CA2314313C/en not_active Expired - Lifetime
- 1998-12-08 IL IL13666298A patent/IL136662A/en not_active IP Right Cessation
- 1998-12-08 SK SK1532-2000A patent/SK288203B6/sk not_active IP Right Cessation
- 1998-12-08 UA UA2000074034A patent/UA72884C2/uk unknown
- 1998-12-08 TR TR2000/02134T patent/TR200002134T2/xx unknown
- 1998-12-09 PE PE1998001200A patent/PE20000001A1/es not_active IP Right Cessation
- 1998-12-09 TW TW087120429A patent/TW570811B/zh not_active IP Right Cessation
-
1999
- 1999-12-09 HK HK99105809A patent/HK1021798A1/xx not_active IP Right Cessation
-
2000
- 2000-06-08 NO NO20002945A patent/NO327302B1/no not_active IP Right Cessation
-
2013
- 2013-05-17 CY CY20131100405T patent/CY1114000T1/el unknown
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TW570811B (en) | Stabilized teriparatide solutions | |
US7550434B2 (en) | Stabilized teriparatide solutions | |
JP4689833B2 (ja) | グルカゴン様ペプチド−1の貯蔵安定性製剤 | |
EP1506786B1 (en) | Medicinal compositions containing ghrelin | |
EP0926158B1 (en) | Crystalline parathyroid hormone | |
JP5973918B2 (ja) | Glp−1アゴニスト及びメチオニンを含む薬学的組成物 | |
RU2467762C2 (ru) | Составы паратиреоидного гормона и их применение | |
US6541450B1 (en) | Parathyroid hormone analogues for the treatment of osteoporosis | |
US20120184488A1 (en) | Insulin analogues of enhanced receptor-binding specificity | |
US20100048462A1 (en) | Truncated pth peptides with a cyclic conformation | |
JP2002511103A (ja) | アミリン作動薬ペプチド用製剤 | |
CN118103391A (zh) | Glp-1受体和gip受体双重激动剂的药物组合物及其用途 | |
MXPA00005655A (en) | Stabilized teriparatide solutions | |
AU2003213511A1 (en) | Stabilized Teriparatide Solutions | |
EP1352912A1 (en) | Parathyroid hormone analogues for the treatment of osteoporosis |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
GD4A | Issue of patent certificate for granted invention patent | ||
MK4A | Expiration of patent term of an invention patent |