CN1190896A - 包括生长激素和包括至少一种碱性氨基酸残基和至少一种酸性氨基酸残基肽的稳定的药物制剂 - Google Patents
包括生长激素和包括至少一种碱性氨基酸残基和至少一种酸性氨基酸残基肽的稳定的药物制剂 Download PDFInfo
- Publication number
- CN1190896A CN1190896A CN96195465A CN96195465A CN1190896A CN 1190896 A CN1190896 A CN 1190896A CN 96195465 A CN96195465 A CN 96195465A CN 96195465 A CN96195465 A CN 96195465A CN 1190896 A CN1190896 A CN 1190896A
- Authority
- CN
- China
- Prior art keywords
- amino acid
- acid residue
- growth hormone
- peptide
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 102000018997 Growth Hormone Human genes 0.000 title claims abstract description 59
- 108010051696 Growth Hormone Proteins 0.000 title claims abstract description 59
- 239000000122 growth hormone Substances 0.000 title claims abstract description 56
- 125000000539 amino acid group Chemical group 0.000 title claims abstract description 51
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 24
- 239000002253 acid Substances 0.000 title abstract description 7
- 239000008194 pharmaceutical composition Substances 0.000 title abstract description 3
- 239000000203 mixture Substances 0.000 claims abstract description 14
- 238000009472 formulation Methods 0.000 claims abstract description 9
- 238000002360 preparation method Methods 0.000 claims description 47
- 230000002378 acidificating effect Effects 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 17
- 239000000243 solution Substances 0.000 claims description 17
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 230000002421 anti-septic effect Effects 0.000 claims description 6
- 150000001720 carbohydrates Chemical class 0.000 claims description 3
- 201000010099 disease Diseases 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 239000012062 aqueous buffer Substances 0.000 claims description 2
- 239000008367 deionised water Substances 0.000 claims description 2
- 229910021641 deionized water Inorganic materials 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 abstract description 5
- 238000007254 oxidation reaction Methods 0.000 abstract description 5
- 239000000654 additive Substances 0.000 abstract description 3
- 230000000996 additive effect Effects 0.000 abstract description 3
- 239000006172 buffering agent Substances 0.000 abstract 1
- 238000003776 cleavage reaction Methods 0.000 abstract 1
- 230000006240 deamidation Effects 0.000 abstract 1
- 230000007017 scission Effects 0.000 abstract 1
- 239000000854 Human Growth Hormone Substances 0.000 description 38
- 108010000521 Human Growth Hormone Proteins 0.000 description 38
- 102000002265 Human Growth Hormone Human genes 0.000 description 38
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 18
- 150000001412 amines Chemical class 0.000 description 11
- 235000001014 amino acid Nutrition 0.000 description 10
- 150000001413 amino acids Chemical class 0.000 description 9
- 230000006641 stabilisation Effects 0.000 description 8
- 238000011105 stabilization Methods 0.000 description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 7
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 7
- 239000008363 phosphate buffer Substances 0.000 description 7
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 6
- 235000019445 benzyl alcohol Nutrition 0.000 description 6
- 150000005846 sugar alcohols Polymers 0.000 description 6
- 229920001503 Glucan Polymers 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 5
- 238000003860 storage Methods 0.000 description 5
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 206010062767 Hypophysitis Diseases 0.000 description 4
- 229930195725 Mannitol Natural products 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 230000000968 intestinal effect Effects 0.000 description 4
- TWNIBLMWSKIRAT-VFUOTHLCSA-N levoglucosan Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@H]2CO[C@@H]1O2 TWNIBLMWSKIRAT-VFUOTHLCSA-N 0.000 description 4
- 239000008176 lyophilized powder Substances 0.000 description 4
- 239000000594 mannitol Substances 0.000 description 4
- 235000010355 mannitol Nutrition 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 239000003381 stabilizer Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000004471 Glycine Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 229960001231 choline Drugs 0.000 description 3
- -1 choline citrates Chemical class 0.000 description 3
- 239000000539 dimer Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 210000003635 pituitary gland Anatomy 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 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 2
- 239000004475 Arginine Substances 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 206010013883 Dwarfism Diseases 0.000 description 2
- 229920001917 Ficoll Polymers 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- 206010056438 Growth hormone deficiency Diseases 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- 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 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- 108010013127 Met-human growth hormone Proteins 0.000 description 2
- FFDGPVCHZBVARC-UHFFFAOYSA-N N,N-dimethylglycine Chemical compound CN(C)CC(O)=O FFDGPVCHZBVARC-UHFFFAOYSA-N 0.000 description 2
- 241000277331 Salmonidae Species 0.000 description 2
- 208000020221 Short stature Diseases 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 235000003704 aspartic acid Nutrition 0.000 description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 2
- 150000002989 phenols Chemical class 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 150000003248 quinolines Chemical class 0.000 description 2
- 238000010188 recombinant method Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000002269 spontaneous effect Effects 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- FSJVVVCZSRCTBM-RXSVEWSESA-N (2S)-2-[(2R)-3,4-dihydroxy-5-oxo-2H-furan-2-yl]-2-hydroxyethanolate 2-hydroxyethyl(trimethyl)azanium Chemical compound C[N+](C)(C)CCO.O[C@@H](C[O-])[C@H]1OC(=O)C(O)=C1O FSJVVVCZSRCTBM-RXSVEWSESA-N 0.000 description 1
- QZNNVYOVQUKYSC-JEDNCBNOSA-N (2s)-2-amino-3-(1h-imidazol-5-yl)propanoic acid;hydron;chloride Chemical compound Cl.OC(=O)[C@@H](N)CC1=CN=CN1 QZNNVYOVQUKYSC-JEDNCBNOSA-N 0.000 description 1
- NAOLWIGVYRIGTP-UHFFFAOYSA-N 1,3,5-trihydroxyanthracene-9,10-dione Chemical compound C1=CC(O)=C2C(=O)C3=CC(O)=CC(O)=C3C(=O)C2=C1 NAOLWIGVYRIGTP-UHFFFAOYSA-N 0.000 description 1
- YHHSONZFOIEMCP-UHFFFAOYSA-N 2-(trimethylazaniumyl)ethyl hydrogen phosphate Chemical class C[N+](C)(C)CCOP(O)([O-])=O YHHSONZFOIEMCP-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- WEZNMMBMSZOXAZ-UHFFFAOYSA-N 2-boronooxyethyl(trimethyl)azanium Chemical compound C[N+](C)(C)CCOB(O)O WEZNMMBMSZOXAZ-UHFFFAOYSA-N 0.000 description 1
- 239000001763 2-hydroxyethyl(trimethyl)azanium Substances 0.000 description 1
- UJWRGESBUBDIIB-JJKGCWMISA-M 2-hydroxyethyl(trimethyl)azanium;(2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanoate Chemical compound C[N+](C)(C)CCO.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O UJWRGESBUBDIIB-JJKGCWMISA-M 0.000 description 1
- KZSXRDLXTFEHJM-UHFFFAOYSA-N 5-(trifluoromethyl)benzene-1,3-diamine Chemical class NC1=CC(N)=CC(C(F)(F)F)=C1 KZSXRDLXTFEHJM-UHFFFAOYSA-N 0.000 description 1
- 241000972773 Aulopiformes Species 0.000 description 1
- DHHFDKNIEVKVKS-FMOSSLLZSA-N Betanin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC(C(=C1)O)=CC(C[C@H]2C([O-])=O)=C1[N+]2=C\C=C\1C=C(C(O)=O)N[C@H](C(O)=O)C/1 DHHFDKNIEVKVKS-FMOSSLLZSA-N 0.000 description 1
- DHHFDKNIEVKVKS-MVUYWVKGSA-N Betanin Natural products O=C(O)[C@@H]1NC(C(=O)O)=C/C(=C\C=[N+]/2\[C@@H](C(=O)[O-])Cc3c\2cc(O)c(O[C@H]2[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O2)c3)/C1 DHHFDKNIEVKVKS-MVUYWVKGSA-N 0.000 description 1
- 235000019743 Choline chloride Nutrition 0.000 description 1
- 239000004381 Choline salt Substances 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- KDXKERNSBIXSRK-RXMQYKEDSA-N D-lysine Chemical compound NCCCC[C@@H](N)C(O)=O KDXKERNSBIXSRK-RXMQYKEDSA-N 0.000 description 1
- 201000010374 Down Syndrome Diseases 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- 208000002720 Malnutrition Diseases 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229920000805 Polyaspartic acid Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 108010020346 Polyglutamic Acid Proteins 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 108010077895 Sarcosine Proteins 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- 206010044688 Trisomy 21 Diseases 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 125000003275 alpha amino acid group Chemical group 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- 235000012677 beetroot red Nutrition 0.000 description 1
- 239000001654 beetroot red Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000002185 betanin Nutrition 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000023852 carbohydrate metabolic process Effects 0.000 description 1
- 229960003178 choline chloride Drugs 0.000 description 1
- SGMZJAMFUVOLNK-UHFFFAOYSA-M choline chloride Chemical group [Cl-].C[N+](C)(C)CCO SGMZJAMFUVOLNK-UHFFFAOYSA-M 0.000 description 1
- 229950002847 choline gluconate Drugs 0.000 description 1
- 235000019417 choline salt Nutrition 0.000 description 1
- WXCQAWGXWVRCGP-UHFFFAOYSA-N choline sulfate Chemical compound C[N+](C)(C)CCOS([O-])(=O)=O WXCQAWGXWVRCGP-UHFFFAOYSA-N 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 108700003601 dimethylglycine Proteins 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- DQKGOGJIOHUEGK-UHFFFAOYSA-M hydron;2-hydroxyethyl(trimethyl)azanium;carbonate Chemical compound OC([O-])=O.C[N+](C)(C)CCO DQKGOGJIOHUEGK-UHFFFAOYSA-M 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000001071 malnutrition Effects 0.000 description 1
- 235000000824 malnutrition Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 229940078490 n,n-dimethylglycine Drugs 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 208000015380 nutritional deficiency disease Diseases 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 229940059574 pentaerithrityl Drugs 0.000 description 1
- WXZMFSXDPGVJKK-UHFFFAOYSA-N pentaerythritol Chemical compound OCC(CO)(CO)CO WXZMFSXDPGVJKK-UHFFFAOYSA-N 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 230000036417 physical growth Effects 0.000 description 1
- 229920000724 poly(L-arginine) polymer Polymers 0.000 description 1
- 108010011110 polyarginine Proteins 0.000 description 1
- 108010064470 polyaspartate Proteins 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002643 polyglutamic acid Polymers 0.000 description 1
- 229920002704 polyhistidine Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 108010055896 polyornithine Proteins 0.000 description 1
- 229920002714 polyornithine Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 235000019515 salmon Nutrition 0.000 description 1
- 229940043230 sarcosine Drugs 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000007391 self-medication Methods 0.000 description 1
- 210000002356 skeleton Anatomy 0.000 description 1
- 238000003307 slaughter Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000006277 sulfonation reaction Methods 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 230000029663 wound healing Effects 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
- A61K38/27—Growth hormone [GH], i.e. somatotropin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- 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
- A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Endocrinology (AREA)
- Physical Education & Sports Medicine (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Urology & Nephrology (AREA)
- Zoology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Peptides Or Proteins (AREA)
Abstract
包括生长激素和包括至少一种碱性氨基酸残基和至少一种酸性氨基酸残基的肽作为添加剂或缓冲物质的药物制剂对脱酰胺作用,氧化作用和肽键的断裂显示出很高的稳定性。该产品的稳定性允许以冻干的状态或在周围温度中以溶解或重新溶解制剂的形式贮存及其运输。
Description
发明领域
本发明涉及包括生长激素的稳定的药物制剂,制备这种制剂的方法,用于稳定生长激素制剂的包括至少一种碱性氨基酸残基和至少一种酸性氨基酸残基肽的用途和用于治疗易受生长激素影响的疾病的方法。
发明背景
人和常见家养动物的生长激素是垂体腺前页合成和分泌的约191个氨基酸的蛋白。人类生长激素由191个氨基酸所组成。
生长激素是涉及不仅身体生长的调节,而且蛋白、碳水化合物和脂类代谢调节的一种关键性激素。生长激素的主要作用是促进生长。
生长激素影响的器官系统包括骨骼、结缔组织、肌肉和内脏如肝脏、肠及肾脏。
直到现在的导致如人类生长激素(hGH)和Met-hGH以工业规模生产的重组技术和生长激素基因的克隆开发以前,人类生长激素仅可从人类尸体的垂体腺中提取而获得。生长激素很有限的供应限制其用于童年和青春期侏儒症治疗中的纵向生长促进中,尽管已提议其特别用于治疗矮的身材(由于生长激素缺乏,正常的矮身材及唐氏综合症)、成年人生长激素缺乏、不育、烧伤治疗、伤口愈合、营养不良、骨头接合、骨质疏松症、迷散性胃出血以及伪关节(psendoarthrosis)。
此外,生长激素已被提议用于增加家养动物的生长速度或降低人类消费的宰杀动物的脂肪比例。
生长激素的药物制剂趋于不稳定。产生了降解产物如脱酰胺或磺化(sulfoxydated)产物以及二聚体或多聚体形式-尤其在生长激素溶液中。
hGH显著的降解反应为1)通过直接的水解的脱酰胺作用或通过环状的琥珀酰亚胺中间体以形成不同量的L-asp-hGH、L-iso-asp-hGH、D-asp-hGH和D-iso-asp-hGH(参考1-3),和2)位置14和位置125甲硫氨酸残基的氧化作用(参考4-9)。在冻干状态及溶液中hGH的主要降解产物为脱酰胺的hGH。
脱酰胺作用尤其发生于位置149的天冬酰胺并以较少的程度发生于位置152的天冬酰胺。
位置14和125的hGH也很容易被氧化,尤其在溶液中(4-8)。
hGH在溶液中形成磺化物(sulfoxides)的氧化一般是由于溶于制剂中的氧气。氧气在蒸馏水中的溶解性约200μM(9)。由于在制剂中包括4IU/ml的hGH的浓度相应于60nm的hGH为1.3mg/ml,故在正常的贮存条件下,氧气将以超过约3000倍用于hGH氧化的化学计量的量存在。在封闭(taping)和包装制剂以前通过去除缓冲液中的气体以试图解决此问题是不切合实际的。
目前,认为这些脱酰胺形式和氧化形式的hGH应该具有无毒或没有改变的生物学活性或受体结合特性,但有迹象表明磺化物的构型稳定性较天然hGH降低。
为了开发包括hGH的稳定、溶解的制剂,知道脱酰胺和磺化物形成速度以及控制反应的方法是至关重要的。
降解的动力学依赖于hGH配方中的温度、pH和不同的添加剂或佐剂。
由于不稳定性,为了最大限度地减少降解,目前,生长激素被冻干并于4℃以冻干形式贮存直至重新调配使用。
目前,包括hGH的冻干药物制剂由病人重新调配且然后在达14天的使用期内于4℃作为溶液贮存,这其中将发生部分降解。
此外,冻干生长激素重新调配的方法让病人为难。因此,目前优选在使用前尽可能晚地重新调配生长激素并以冻干状态贮存和运输制剂。从生产商到用药的环节适宜于在控制的低温如4℃处理制剂,在此温度下允许达2年的长时间保存寿命(shelflife)。
然而,用于自我疗法的笔式系统(pen systems for self-medication)的扩展使用和使用的扩展领域要求在终末使用者不可总得到“足够”冷却的条件下稳定足够长时间的制剂。
优选地,对于终末使用者,制剂应以冻干状态稳定约一种月并且在盒式使用的试用期(the intended period of use of a cartridge)在笔式装置(in a pen device)以重新调配的状态额外稳定一种月。
因此,需要更为稳定的生长激素制剂,其在冻干状态在相对较高的温度时稳定一段时间并且在溶液中相对较高的温度时额外稳定一段使用期。当将生长激素的施用从诊所转移到不可得到上述最佳贮存的待治疗个体家中时这种稳定作用是非常重要的。
此外,为了利于病人进行处理,生长激素施用方式换成使用笔式装置要求包括生长激素的稳定的溶解制剂。可制备包括生长激素稳定的溶解制剂,病人易于使用的适于笔式装置的小盒形式(in the form ofcartridges fitting into the pendevice),然后病人可避免重新调配制剂并且,因此,将不必具有冻干的制剂,用于重新调配的合适赋形剂(vehicle)以及用于制剂无菌调配的必需技巧和无菌设备。
为了安全的原因,避免刚好制剂使用前重新调配冻干的制剂也将是必需的。
此外,避免生长激素制剂制备中的冻干步骤也将是个优势。冻干是一种耗时且昂贵的方法并且由于冷冻干燥器有限的容量也经常是制备中的“瓶颈”。
因此,为了使溶解hGH的制剂在保存期和达一种月的使用期稳定需要降低降解过程的速度。
稳定hGH的以前尝试在防止二聚体形成中没有完全成功。Becker,G.W.,生物技术和应用生化9,478(1987)中记录了与二聚体形成有关的问题。
国际专利公开No.WO89/09614和澳大利亚专利申请No.30771/89公布了一种含有人类生长激素甘氨酸和甘露醇的稳定药物制剂。这种制剂在冻干状态的正常处理和贮存过程中以及重新调配后的使用期内显现出提高的稳定性。
公开的欧洲专利申请No.303 746公开了动物生长激素可以不同的稳定剂稳定以导致不溶物减少的形成和水环境中可溶性活性的保存,这种稳定剂包括某些多元醇、氨基酸、在生理pH时具有带电侧基的氨基酸聚合物和胆碱盐。多元醇选自非还原性糖、糖醇、糖酸、季戊四醇、乳糖、水溶性葡聚糖和Ficoll;氨基酸选自甘氨酸、肌氨酸、赖氨酸或其盐、丝氨酸、精氨酸或其盐、甜菜碱、N,N-二甲基-甘氨酸、天冬氨酸或其盐、谷氨酸或其盐;在生理pH时具有带电侧基的氨基酸聚合物选自多聚赖氨酸、多聚天冬氨酸、多聚谷氨酸、多聚精氨酸、多聚组氨酸、多聚乌氨酸及其盐;且胆碱衍生物选自胆碱氯化物、胆碱柠檬酸二氢盐、胆碱酒石酸氢盐、胆碱碳酸氢盐、三胆碱柠檬酸盐、胆碱抗坏血酸盐、胆碱硼酸盐、胆碱葡萄糖酸盐、胆碱磷酸盐、二(胆碱)硫酸盐和胆碱mucate。
美国专利说明No.4,917,685公开了一种设计待输入(implanted)的包括用与EP303746中提到的相同稳定剂稳定的生长激素的运载系统。
公开的欧洲专利申请No.374,120公开了一种包括hGH和具有三个羟基多元醇的稳定制剂。提到甘油和三(羟甲基)氨基甲烷。此外,公开了组氨酸盐酸盐与多元醇一起作为缓冲液的存在。
国际专利公开No.WO93/12811公开了以冻干粉形式或包括天冬酰胺水溶液形式的生长激素稳定制剂。
国际专利公开No.WO93/12812公开了以冻干粉形式或包括组氨酸水溶液形式的生长激素稳定制剂。在这种制剂中脱酰胺作用与相应的包括磷酸盐缓冲液生长激素的制剂相比降低了25-30%。
国际专利公开No.WO93/19776公开了包括柠檬酸盐作为缓冲液的包括生长激素的蛋白制剂,其较包括磷酸盐缓冲液的制剂更为稳定。该制剂也可包括氨基酸如甘氨酸和丙氨酸和/或甘露醇或其它糖醇和/或甘油和/或其它碳水化合物及任选包括防腐剂如苯甲醇。
国际专利公开No.WO94/03198公开了一种稳定的水溶液,其中含有人类生长激素、缓冲液、非离子性表面活性剂,和任选含有中性盐、甘露醇、或防腐剂。
发明简述
现已令人惊奇地发现包括至少一种碱性氨基酸残基和至少一种酸性氨基酸残基的肽作为添加剂的人类生长激素制剂对脱酰胺作用和氧化作用显示出很高的稳定性。该产品的稳定性允许以冻干状态或以溶解或重新溶解制剂的形式对其贮存和运输。
根据本发明待用的包括至少一种碱性氨基酸残基和至少一种酸性氨基酸残基的肽可以是包括10到20个氨基酸残基的肽,优选包括3到10个氨基酸残基,更优选包括3到6个氨基酸残基如3或4个氨基酸残基。根据本发明的一种方面,较短肽的碱性和酸性氨基酸残基由1个或2个氨基酸残基所分离。
本发明的药物制剂可配制用于任何合适方式的施用,如通过肠道外或口腔施用或施用于粘膜,如鼻腔施用。药物制剂可以包括在小瓶(vial)或小室(cartridge)或任何其它合适的容器如预先填满的注射器或笔式装置(pen device)中的剂量形式存在。
因此,本发明的制剂可以是冻干粉的形式,该冻干粉后来用常规的赋形剂如蒸馏水或注射用水重新调配,或者是包括生长激素的溶液形式。这种赋形剂可包括常规的防腐剂如苯甲醇和酚类(phenoles),如苯酚或间-甲酚或其混合物。
本发明的优选实施方案是人类生长激素的药物制剂形式,其中包括至少一种碱性氨基酸残基和至少一种酸性氨基酸残基的肽并进一步包括以生长激素缓冲水溶液形式的载体。这种制剂是现成的(ready-to-use)形式并且可作为水溶液贮存和运输而无任何重要的降解。
待用于生长激素溶液的缓冲液可以是,如,组氨酸、柠檬酸盐、酒石酸盐或磷酸盐缓冲液。
为了稳定性的原因,溶液pH优选调至约2到8之间,优选从约5到7,更优选从约6.0到7.0,甚至更为优选从约6.0到6.8。
为了获得稳定作用优选加入包括至少一种碱性氨基酸残基和至少一种酸性氨基酸残基的肽,其量达100mM,更为优选其量约1-10mM,优选约2-6mM,最优选约3-5mM。
此外,为了便于使用前重新调配制剂时对其处理,如,冻干和冻干制剂快速而完全的溶解,本发明的药物制剂可包括用于调整增强性(tonicity)的盐和任选地包括赋形剂。
赋形剂可选自二糖如乳糖茧密糖二霉菌酸酯(trehalose)和蔗糖,糖醇如山梨醇或甘露醇,多糖如作为葡聚糖产品的商品化聚合物如葡聚糖40,葡聚糖70或葡聚糖75以及Ficoll和多价醇如聚乙二醇或聚乙烯醇或这些物质中2种或更多种的组合。
本发明的进一步方面涉及制备包括生长激素和包括至少一种碱性氨基酸残基和至少一种酸性氨基酸残基肽的药物制剂的方法,其中的生长激素通过以下方法溶于包括至少一种碱性氨基酸残基和至少一种酸性氨基酸残基肽的溶液中,包括溶解包括至少一种碱性氨基酸残基和至少一种酸性氨基酸残基的肽于任选含有苯甲醇的去离子水中,加入生长激素并且任选调节pH至约2到约8。
pH可通过加入酸而调节,该酸对生长激素无副作用,优选为生理上可接受的酸如无机酸,如盐酸、硫酸或硝酸或有机酸如醋酸。
在本发明方法的实施方案中,任选加入盐和赋形剂,之后将溶液装入容器并冻干。
本发明的另一方面涉及包括至少一种碱性氨基酸残基和至少一种酸性氨基酸残基肽用于生长激素稳定制剂配制的用途。
本发明的另一方面涉及用于治疗易受生长激素影响的疾病的方法,包括施用包括生长激素和包括至少一种碱性氨基酸残基和至少一种酸性氨基酸残基肽的制剂。
在本文中“生长激素”可以是任何来源的生长激素,如鸟、牛、马、人类、羊、猪、鲑鱼、真鳟(trout)或金枪鱼的生长激素,优选为牛、人类或猪的生长激素,人类生长激素最为优选。用于本发明的生长激素可以是分离自自然来源的,如通过以常规方式提取垂体腺的天然生长激素,或者是通过重组技术,如E.B.Jensen和S.Carlsen在生物技术和生物工程。36,1-11(1990)中所描述而制备的生长激素。“生长激素”也可是截短形式的生长激素,其中的一种或更多个氨基酸残基被删除;其类似物,只要替代不具有任何副作用如抗原性或降低的功能,天然分子中的一种或更多个氨基酸残基被别的氨基酸残基,优选天然氨基酸残基所替代;或者其衍生物,如具有N-或者C-末端延伸如Met-hGH。优选的生长激素为hGH。
术语生长激素“剂量”指在施用方案(regimen)中产生治疗效应的量。制备其制剂,根据现成的制剂计算,其中含有至少约0.1mg/ml的hGH量,优选向上约10mg/ml的hGH量,优选从约1mg/ml到约40mg/ml,更优选从约1mg/ml至约40mg/ml,更优选从约1mg/ml到约25mg/ml,如从1mg/ml到约5mg/ml的hGH量。例如,对于使用这些施用组合物至患垂体机能不良侏儒症的人类,这些制剂含有从约0.1mg/ml到约10mg/ml,相应于用于试图治疗(intended treatment)的当前期望的剂量方案(dosage regimen)。浓度范围对本发明并不至关重要且可通过监督施用的内科医生加以改变。
包括至少一种碱性氨基酸残基和至少一种酸性氨基酸残基的待用于本发明的肽优选包括自然产生的α氨基酸残基。氨基酸可以为1个或d个氨基酸或其混合物。
“酸性氨基酸残基”为如谷氨酸或天冬氨酸,且“碱性氨基酸残基”为如赖氨酸或精氨酸。
在本文中当制剂较包括磷酸缓冲液的常规制剂更为稳定并优选与包括组氨酸作为稳定剂的相应配方一样稳定,且其中的hGH脱酰胺作用与WO93/12812中公开的磷酸缓冲液相比减少约20%时,“高度稳定性”便获得。
用于本发明方法的溶剂可以是水,醇如乙醇,n-丙醇或异丙醇、丁醇或其混合物。溶剂可以包括防腐剂如苯甲醇和酚类,如苯酚或m-甲酚或其混合物。
发明详述
本发明在下面的说明本发明的实施例中更为详细地加以解释。它们没有被认为是限制了附属权利要求所定义的本发明范围。实验部分实施例脱酰胺作用的减少
在5mM包括至少一种碱性氨基酸残基和至少一种酸性氨基酸残基肽(Lys-Gly-Asp-Ser)的存在时于37℃测定pH6.8的包括4mg/ml hGH的hGH制剂的脱酰胺作用速度。
通过溶解8mg hGH于2ml 10mM的Lys-Gly-Asp-Ser或组氨酸溶液中而制备hGH制剂。因此,加入2ml 3.0%的苯甲醇以得到4mg/mlhGH、5mM Lys-Gly-Asp-Ser或组氨酸、1.5%苯甲醇、pH6-8(加入HCl或NaOH调节)的最终制剂。
下表中所述的hGH制剂于37℃贮存7天,并通过IE-HPLC分析脱酰胺的hGH含量。结果显示于下表。
表
制剂 | 起始pH/最终pH/%脱酰胺 | 校正的脱酰胺hGH的含量* | 与His相比脱酰胺hGH的含量 |
Lys-Gly-Asp-Ser | 6.8/6.8/13.6 | 13.6 | 83 |
组氨酸 | 6.8/6.8/16.4 | 16.4 | 100 |
*偏离6.8每0.1个pH单位校正1%的脱酰胺(desamido)
在起始物质中脱酰胺hGH的含量为2.0%
从上表,似乎通过加入Lys-Gly-Asp-Ser,hGH的脱酰胺作用降低到至少与通过加入组氨酸而获得的相同水平(与磷酸缓冲液相比25-30%,参考上面的WO93/12812)。
上面的结果表明通过加入达100mM,优选1-10mM,更优选2-6mM且最优选约3-5mM低浓度的Lys-Gly-Asp-Ser,脱酰胺作用的速度降低至很大的程度。因此,通过以Lys-Gly-Asp-Ser替代磷酸缓冲液,脱酰胺作用的速度可降低超过30%。
作为防腐剂的苯甲醇的使用似乎对脱酰胺速度没有影响。
参考文献
1)Y.-C.J.Wang和M.A.Hanson蛋白和肽的肠道外制剂:稳定性和稳定剂。肠道外科学和技术杂志42(增刊)(1988)53-525。
2)M.C.Manning,K.Patel,R.T.Borchardt.蛋白药物的稳定性。药物研究6(11)(1989)903-918。
3)B.A.Johnson,J.M.Shirokawa,W.S.Hancock,M.W.Spellman,L.J.Basa和D.W.Asward生物化学杂志。264,1462-71(1989)。
4)L.C.Teh等,生物化学杂志,262,785-794(1987)。
5)G.W.Becker等,生物技术,应用,生化,10,326-337(1988)。
6)R.A.Houghten等.,建筑(Arch),生化,生物物理.,178,350-355(1977)。
7)R.M.Riggin等.,生化年鉴.,167,199-209(1987)。
8)P.Gellerfors等.,Acta Pacdiatr.Scand(增刊),370,93100(1990)。
9)M.J.Kaufman,药物研究.,7(3)289-292.(1990)。
Claims (10)
1.包括生长激素和包括至少一种碱性氨基酸残基和至少一种酸性氨基酸残基肽的药物制剂。
2.权利要求1的药物制剂,进一步包括以生长激素缓冲水溶液形式的载体,生长激素中含有包括至少一种碱性氨基酸残基和至少一种酸性氨基酸残基的肽。
3.权利要求1或2的药物制剂,其中的pH调至从约2到约8之间的值。
4.以前权利要求中任一权利要求的药物制剂,其中包括至少一种碱性氨基酸残基和至少一种酸性氨基酸残基的肽的浓度达到约100mM。
5.以前权利要求中任一权利要求的药物制剂,进一步包括盐和/或糖类。
6.权利要求1-5中任一权利要求的药物制剂,其中的生长激素为hGH。
7.制备包括生长激素和包括至少一种碱性氨基酸残基和至少一种酸性氨基酸残基肽的药物制剂的方法,该方法包括(a)将肽溶解于任选含有防腐剂的去离子水中以形成溶液,和(b)向该溶液中加入生长激素,和(c)任选调节pH至pH2到约pH8。
8.根据权利要求7的方法,任选向其中加入盐和/或赋形剂,之后将溶液装入容器中并冻干。
9.包括至少一种碱性氨基酸残基和至少一种酸性氨基酸残基肽用于制备稳定的生长激素制剂的用途。
10.治疗易受生长激素影响的疾病的方法,包括施用权利要求1-6中任何一个权利要求的制剂。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US88195P | 1995-07-12 | 1995-07-12 | |
US60/000,881 | 1995-07-12 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1190896A true CN1190896A (zh) | 1998-08-19 |
Family
ID=21693419
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN96195465A Pending CN1190896A (zh) | 1995-07-12 | 1996-06-28 | 包括生长激素和包括至少一种碱性氨基酸残基和至少一种酸性氨基酸残基肽的稳定的药物制剂 |
Country Status (14)
Country | Link |
---|---|
EP (1) | EP0837690A1 (zh) |
JP (1) | JPH11510483A (zh) |
KR (1) | KR19990028908A (zh) |
CN (1) | CN1190896A (zh) |
AU (1) | AU699850B2 (zh) |
BR (1) | BR9609573A (zh) |
CA (1) | CA2226553A1 (zh) |
CZ (1) | CZ6198A3 (zh) |
HU (1) | HUP9802286A3 (zh) |
IL (1) | IL122519A0 (zh) |
NO (1) | NO980103D0 (zh) |
PL (1) | PL324386A1 (zh) |
WO (1) | WO1997002833A1 (zh) |
ZA (1) | ZA965367B (zh) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR100236393B1 (ko) * | 1996-02-02 | 1999-12-15 | 나까니시 히로유끼 | 사람성장호르몬을 함유하는 의약제제 |
US6566329B1 (en) | 1999-06-28 | 2003-05-20 | Novo Nordisk A/S | Freeze-dried preparation of human growth hormone |
TWI283182B (en) | 2000-08-07 | 2007-07-01 | Nektar Therapeutics | Inhalable spray dried 4-helix bundle protein powders having minimized aggregation |
WO2004052403A1 (ja) * | 2002-12-11 | 2004-06-24 | Santen Pharmaceutical Co., Ltd. | 眼科用保存剤 |
CN103751769B (zh) * | 2013-12-25 | 2015-08-19 | 楼秀余 | 一种冻干重组人生长激素胶囊及其制备方法 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4816568A (en) * | 1986-05-16 | 1989-03-28 | International Minerals & Chemical Corp. | Stabilization of growth hormones |
DK204791D0 (da) * | 1991-12-20 | 1991-12-20 | Novo Nordisk As | Hidtil ukendt farmaceutisk praeparat |
WO1993012812A1 (en) * | 1991-12-20 | 1993-07-08 | Novo Nordisk A/S | A stabilized pharmaceutical formulation comprising growth hormone and histidine |
KR19980701351A (ko) * | 1995-01-13 | 1998-05-15 | 슈타르 피아 | 성장호르몬 및 X-Lys를 함유하는 안정화된 약제조제물(A STABILIZED PHARMACEUTICAL FORMULATION COMPRISING A GROWTH HORMONE AND X-Lys |
-
1996
- 1996-06-25 ZA ZA965367A patent/ZA965367B/xx unknown
- 1996-06-28 PL PL96324386A patent/PL324386A1/xx unknown
- 1996-06-28 CN CN96195465A patent/CN1190896A/zh active Pending
- 1996-06-28 JP JP9505422A patent/JPH11510483A/ja active Pending
- 1996-06-28 HU HU9802286A patent/HUP9802286A3/hu unknown
- 1996-06-28 EP EP96922774A patent/EP0837690A1/en not_active Withdrawn
- 1996-06-28 WO PCT/DK1996/000290 patent/WO1997002833A1/en not_active Application Discontinuation
- 1996-06-28 KR KR1019980700210A patent/KR19990028908A/ko not_active Application Discontinuation
- 1996-06-28 AU AU63533/96A patent/AU699850B2/en not_active Ceased
- 1996-06-28 BR BR9609573A patent/BR9609573A/pt not_active Application Discontinuation
- 1996-06-28 CA CA002226553A patent/CA2226553A1/en not_active Abandoned
- 1996-06-28 CZ CZ9861A patent/CZ6198A3/cs unknown
- 1996-06-28 IL IL12251996A patent/IL122519A0/xx unknown
-
1998
- 1998-01-09 NO NO980103A patent/NO980103D0/no not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
ZA965367B (en) | 1997-01-23 |
IL122519A0 (en) | 1998-06-15 |
PL324386A1 (en) | 1998-05-25 |
WO1997002833A1 (en) | 1997-01-30 |
EP0837690A1 (en) | 1998-04-29 |
NO980103L (no) | 1998-01-09 |
NO980103D0 (no) | 1998-01-09 |
HUP9802286A3 (en) | 1999-06-28 |
CZ6198A3 (cs) | 1998-06-17 |
CA2226553A1 (en) | 1997-01-30 |
BR9609573A (pt) | 1999-03-02 |
AU6353396A (en) | 1997-02-10 |
HUP9802286A2 (hu) | 1999-02-01 |
JPH11510483A (ja) | 1999-09-14 |
AU699850B2 (en) | 1998-12-17 |
KR19990028908A (ko) | 1999-04-15 |
MX9800309A (es) | 1998-07-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
RU2236250C2 (ru) | Фармацевтическая композиция, содержащая гормон роста, аминокислоту и неионогенный детергент | |
CN1190897A (zh) | 含有用锌及选择性的赖氨酸或者钙离子预处理过的生长激素的稳定药物组合物 | |
US5705482A (en) | Pharmaceutical formulation | |
US5851992A (en) | Treatment of growth hormone deficiency | |
US5654278A (en) | Composition and method comprising growth hormone and leucine | |
EP0785796B1 (en) | A pharmaceutical formulation comprising a growth hormone and isoleucine | |
EP0785795B1 (en) | A pharmaceutical formulation comprising a growth hormone and valine | |
CN1190896A (zh) | 包括生长激素和包括至少一种碱性氨基酸残基和至少一种酸性氨基酸残基肽的稳定的药物制剂 | |
JP4064455B2 (ja) | 成長ホルモンおよびロイシンを含んでなる医薬製剤 | |
US5552385A (en) | Pharmaceutical formulation | |
KR19980701351A (ko) | 성장호르몬 및 X-Lys를 함유하는 안정화된 약제조제물(A STABILIZED PHARMACEUTICAL FORMULATION COMPRISING A GROWTH HORMONE AND X-Lys | |
KR19980701350A (ko) | 성장호르몬 및 Lys-X를 함유하는 안정화된 약제조제물(A STABILIZED PHARMACEUTICAL FORMULATION COMPRISING A GROWTH HORMONE AND LYS-X) | |
KR19980701352A (ko) | 성장호르몬 및 Leu-His-Leu을 함유하는 안정화된 약제조제물(A STABILIZED PHARMACEUTICAL FORMULATION COMPRISING A GROWTH HORMONE AND LEU-HIS-LEU) | |
MXPA98000309A (en) | Stabilized pharmaceutical formulation comprising a hormone of growth and a peptide that comprises at least one residue of basic amino acid and at least one waste of aminoacido ac | |
MXPA98000358A (en) | Stabilized pharmaceutical formulation comprising a pretracted growth hormone with zincy optionally lysine or ions cal |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |