CN102233130A - Stable pharmaceutical preparation containing thymosin 1 derivatives - Google Patents
Stable pharmaceutical preparation containing thymosin 1 derivatives Download PDFInfo
- Publication number
- CN102233130A CN102233130A CN2011101121391A CN201110112139A CN102233130A CN 102233130 A CN102233130 A CN 102233130A CN 2011101121391 A CN2011101121391 A CN 2011101121391A CN 201110112139 A CN201110112139 A CN 201110112139A CN 102233130 A CN102233130 A CN 102233130A
- Authority
- CN
- China
- Prior art keywords
- pharmaceutical composition
- composition according
- sodium
- surfactant
- stabilizing agent
- 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.)
- Granted
Links
- 108010046075 Thymosin Proteins 0.000 title abstract description 11
- 102000007501 Thymosin Human genes 0.000 title abstract description 11
- LCJVIYPJPCBWKS-NXPQJCNCSA-N thymosin Chemical compound SC[C@@H](N)C(=O)N[C@H](CO)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CO)C(=O)N[C@H](CO)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@H]([C@H](C)O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@H](CCC(O)=O)C(O)=O LCJVIYPJPCBWKS-NXPQJCNCSA-N 0.000 title abstract description 11
- 239000000825 pharmaceutical preparation Substances 0.000 title abstract description 7
- 238000002360 preparation method Methods 0.000 claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 28
- 210000001541 thymus gland Anatomy 0.000 claims description 22
- OBMZMSLWNNWEJA-XNCRXQDQSA-N C1=CC=2C(C[C@@H]3NC(=O)[C@@H](NC(=O)[C@H](NC(=O)N(CC#CCN(CCCC[C@H](NC(=O)[C@@H](CC4=CC=CC=C4)NC3=O)C(=O)N)CC=C)NC(=O)[C@@H](N)C)CC3=CNC4=C3C=CC=C4)C)=CNC=2C=C1 Chemical class C1=CC=2C(C[C@@H]3NC(=O)[C@@H](NC(=O)[C@H](NC(=O)N(CC#CCN(CCCC[C@H](NC(=O)[C@@H](CC4=CC=CC=C4)NC3=O)C(=O)N)CC=C)NC(=O)[C@@H](N)C)CC3=CNC4=C3C=CC=C4)C)=CNC=2C=C1 OBMZMSLWNNWEJA-XNCRXQDQSA-N 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 15
- 239000003381 stabilizer Substances 0.000 claims description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 239000004094 surface-active agent Substances 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- 239000000872 buffer Substances 0.000 claims description 12
- 101710176384 Peptide 1 Proteins 0.000 claims description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 9
- 229920001214 Polysorbate 60 Polymers 0.000 claims description 8
- 229960003180 glutathione Drugs 0.000 claims description 8
- 229920001223 polyethylene glycol Polymers 0.000 claims description 8
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 8
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 7
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 7
- 235000019800 disodium phosphate Nutrition 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 7
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 238000012856 packing Methods 0.000 claims description 7
- 229920001993 poloxamer 188 Polymers 0.000 claims description 7
- 229940044519 poloxamer 188 Drugs 0.000 claims description 7
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 7
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 235000002639 sodium chloride Nutrition 0.000 claims description 5
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 claims description 4
- 229930064664 L-arginine Natural products 0.000 claims description 4
- 235000014852 L-arginine Nutrition 0.000 claims description 4
- 235000011054 acetic acid Nutrition 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 4
- 235000010265 sodium sulphite Nutrition 0.000 claims description 4
- 239000004475 Arginine Substances 0.000 claims description 3
- 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 claims description 3
- 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 3
- 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 claims description 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 3
- 229930195725 Mannitol Natural products 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 3
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 3
- 235000009697 arginine Nutrition 0.000 claims description 3
- 235000011187 glycerol Nutrition 0.000 claims description 3
- 229960002885 histidine Drugs 0.000 claims description 3
- 239000000594 mannitol Substances 0.000 claims description 3
- 235000010355 mannitol Nutrition 0.000 claims description 3
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 3
- 239000010452 phosphate Substances 0.000 claims description 3
- 239000011780 sodium chloride Substances 0.000 claims description 3
- 239000000600 sorbitol Substances 0.000 claims description 3
- 235000010356 sorbitol Nutrition 0.000 claims description 3
- 239000000811 xylitol Substances 0.000 claims description 3
- 235000010447 xylitol Nutrition 0.000 claims description 3
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 3
- 229960002675 xylitol Drugs 0.000 claims description 3
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 2
- 239000005695 Ammonium acetate Substances 0.000 claims description 2
- 229920001213 Polysorbate 20 Polymers 0.000 claims description 2
- 229920001219 Polysorbate 40 Polymers 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- 235000019257 ammonium acetate Nutrition 0.000 claims description 2
- 229940043376 ammonium acetate Drugs 0.000 claims description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 2
- 238000005538 encapsulation Methods 0.000 claims description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 2
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 claims description 2
- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 claims description 2
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 claims description 2
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 claims description 2
- 229940068977 polysorbate 20 Drugs 0.000 claims description 2
- 229940101027 polysorbate 40 Drugs 0.000 claims description 2
- 229940113124 polysorbate 60 Drugs 0.000 claims description 2
- 235000011056 potassium acetate Nutrition 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 2
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 claims 2
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 9
- 239000007853 buffer solution Substances 0.000 abstract 2
- 239000000463 material Substances 0.000 abstract 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 25
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 235000011121 sodium hydroxide Nutrition 0.000 description 10
- 238000005303 weighing Methods 0.000 description 10
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 229940079593 drug Drugs 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 239000003610 charcoal Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000009413 insulation Methods 0.000 description 5
- 238000011835 investigation Methods 0.000 description 5
- 239000012982 microporous membrane Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- PSWFFKRAVBDQEG-YGQNSOCVSA-N thymopentin Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 PSWFFKRAVBDQEG-YGQNSOCVSA-N 0.000 description 5
- 239000008215 water for injection Substances 0.000 description 5
- 108010078233 Thymalfasin Proteins 0.000 description 4
- 102400000160 Thymopentin Human genes 0.000 description 4
- 101800001703 Thymopentin Proteins 0.000 description 4
- 102400000800 Thymosin alpha-1 Human genes 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- NZVYCXVTEHPMHE-ZSUJOUNUSA-N thymalfasin Chemical compound CC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O NZVYCXVTEHPMHE-ZSUJOUNUSA-N 0.000 description 4
- 229960004231 thymalfasin Drugs 0.000 description 4
- 229960004517 thymopentin Drugs 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 3
- 229920001184 polypeptide Polymers 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000007951 isotonicity adjuster Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- HNUQMTZUNUBOLQ-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-(2-octadecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO HNUQMTZUNUBOLQ-UHFFFAOYSA-N 0.000 description 1
- JKXYOQDLERSFPT-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-octadecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO JKXYOQDLERSFPT-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- -1 Brij56 Chemical compound 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010067482 No adverse event Diseases 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000005211 alkyl trimethyl ammonium group Chemical group 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 239000003093 cationic surfactant Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000009514 concussion Effects 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000009615 deamination Effects 0.000 description 1
- 238000006481 deamination reaction Methods 0.000 description 1
- 238000005261 decarburization Methods 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- VICYBMUVWHJEFT-UHFFFAOYSA-N dodecyltrimethylammonium ion Chemical compound CCCCCCCCCCCC[N+](C)(C)C VICYBMUVWHJEFT-UHFFFAOYSA-N 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- SFNALCNOMXIBKG-UHFFFAOYSA-N ethylene glycol monododecyl ether Chemical compound CCCCCCCCCCCCOCCO SFNALCNOMXIBKG-UHFFFAOYSA-N 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000002411 histidines Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920001992 poloxamer 407 Polymers 0.000 description 1
- 229940044476 poloxamer 407 Drugs 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 229960005480 sodium caprylate Drugs 0.000 description 1
- FHHPUSMSKHSNKW-SMOYURAASA-M sodium deoxycholate Chemical compound [Na+].C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 FHHPUSMSKHSNKW-SMOYURAASA-M 0.000 description 1
- BYKRNSHANADUFY-UHFFFAOYSA-M sodium octanoate Chemical compound [Na+].CCCCCCCC([O-])=O BYKRNSHANADUFY-UHFFFAOYSA-M 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000000724 thymus hormone Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to a stable pharmaceutical preparation containing thymosin 1 derivatives. The preparation contains thymosin 1 derivatives, a physiologically acceptable buffer solution with the pH value of 3.0-10.0 and pharmaceutically acceptable auxiliary materials. The invention is characterized in that the chemical and physical stabilities of the preparation are enhanced by adopting the physiologically acceptable buffer solution and adding the pharmaceutically acceptable auxiliary materials.
Description
Technical field
The present invention relates to field of pharmaceutical preparations.Specifically, the present invention relates to comprise the pharmaceutical preparation of thymus peptide 1 derivative stable storing.
Technical background
Polypeptide drug has been widely used in clinical research or the therapeutic process at present.Stable, high-quality, as can industrialization to produce therapeutical peptide class pharmaceutical preparation, for research worker, still great challenge.The polypeptide drug stability of formulation comprises: chemical stability and physical stability two broad aspect; The factor that influences its chemical stability mainly is the variation of covalent bond, as hydrolysis, deamination, oxidation, racemization or crosslinked action; Influence the physics stability factor and comprise degeneration, gathering, absorption or precipitation etc.
Comprise multiple hormone in the thymus, wherein thymosin, Thymopentin, Thymosin alpha 1 all are the immunomodulators of thymic hormone, have the growth of the T of adjusting lymphocyte, differentiation and sophisticated effect, can repair impaired T lymphocyte simultaneously, in the human immune system, bringing into play important effect.Thymosin is the animal thymus extract, contain various thymosin, and Thymopentin and Thymosin alpha 1 is active component important in the human thymocyte hormone, and by synthetic, effective ingredient is definite, and clear mechanism need not skin test.1985, with trade name " Timunox " listing, in the clinical expansion process, Thymopentin was owing to purity height, steady quality, determined curative effect, the safe and reliable welcome that is subjected to numerous doctors and patients in Italy for Thymopentin; Thymosin alpha 1: in last century end, the product " Zidaxin " of Italian Sai Sheng company has entered China market, and use separately or have better curative effect with antiviral drugs and anticancer disease drug coupling, and abroad also in the listing that gets the Green Light of more than 30 countries.The safety of clinical practice proof Thymosin alpha 1 is good, almost has no adverse reaction, and need not skin test before the use.
The injection of thymosin and thymosin, in storage process, content and activity descend to some extent (Wu Ying, et al and Liu Rui, et al); At present, the commercially available thymosin of injection and the freeze-dried powder of thymosin of mostly being, this not only uses to doctors and patients has clinically increased a lot of troubles, but also makes manufacturing cost obviously improve.
Therefore, adopt different preparation technologies and attach different types of stabilizing agent, be usually used in the exploitation of polypeptide drug preparation, to improve its stability.For non-gastrointestinal preparation, the shelf life was at least 1 year or longer.Consider the variations in temperature and the concussion situation of sample transportation.Therefore, be necessary to improve the stability of thymosin and derivatives medicinal composition thereof.
Summary of the invention
The object of the present invention is to provide the pharmaceutical composition of the stable storing that comprises thymus peptide 1 derivative, pharmacy acceptable surfactant, stabilizing agent and isoosmotic adjusting agent, the pH scope of wherein said compositions is 3.0 to 10.0.
Wherein, preferably,
Described thymus peptide 1 derivative is thymus peptide 1 and the analog thereof that PEG modifies, and its concentration is selected from 0.1mg/ml to 25.6mg/ml, 0.8mg/ml to 25.6mg/ml or 1.6mg/ml to 12.8mg/ml;
Described surfactant is selected from polyoxyethylene sorbitan monoleate, polysorbate 20, polysorbate 40, polysorbate 60 or poloxamer 188, preferred polyoxyethylene sorbitan monoleate or poloxamer 188; Its consumption is 0.01% to 10%, preferred 0.05% to 5%;
Described stabilizing agent is selected from L-glutathion, L-arginine, L-histidine, arginine, sodium thiosulfate, sodium sulfite or sodium sulfite, preferred L-glutathion; Its consumption is 0.01% to 5.0%, preferred 0.02% to 0.5%;
Described isoosmotic adjusting agent is selected from sodium chloride, mannitol, sorbitol, glycerol or xylitol;
The scope of its pH is 3.0 to 10.0;
Also comprise pharmacy and can accept buffer, can be selected from phosphate or/and acetic acid and salt buffer thereof, preferred acetic acid, sodium acetate, ammonium acetate, potassium acetate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium hydrogen phosphate are or/and sodium dihydrogen phosphate.
The concentration of stabilizing agent is 0.01% to about 5.0% in one embodiment;
The concentration of stabilizing agent is 0.2% in another embodiment;
Using stabilizing agent in another embodiment is the L-glutathion;
Surfactant concentrations is 0.01% to about 10% in another embodiment;
Surfactant concentrations is 0.05% to about 2% in another embodiment;
The surfactant of using in another embodiment is a poloxamer 188;
The surfactant of using in another embodiment is Tween80;
The pH value of buffer is 3.0-10 in one embodiment;
The pH value of buffer is 5-7.5 in another embodiment;
The pH value of buffer is 6.8 in another embodiment;
Another purpose of the present invention is to provide the method for the described pharmaceutical composition of preparation, and it comprises described thymus peptide 1 derivative dissolving and mixed stabilizer and isoosmotic adjusting agent, and after decarburization, cooling, low temperature is the dissolved preparation process of drug slow again,
Wherein, preferably,
Described dissolving is to finish under cryogenic conditions, between preferred 0 ℃ and 30 ℃, more preferably between 0 ℃ and 20 ℃, more preferably between 0 ℃ and 15 ℃;
Its pH between 3.0 to 10.0, between preferred 4.5 to 8.5, more preferably between 5.0 to 7.5, more preferably 6.8,7.2 or 6.5;
It is the encapsulation of aseptic filtration packing inflated with nitrogen after pharmaceutical compositions.
Wherein,
Term used herein " pharmaceutical composition " refers to comprise the product of reactive compound or derivatives thereof and drug excipient (as buffer, antiseptic and tension regulator).This pharmaceutical composition can be used as the reagent of treatment, prevention and diagnosis.
Term used herein " pharmaceutical composition of stable storing " refers to that it stablized 1 year at least under 2～8 ℃ of conditions.Stability comprises chemical stability and physical stability.
Term used herein " pharmacy is acceptable " is made a comment or criticism and can be used in the normal drug development, i.e. application to the patient does not produce toxic and side effects.
It is constant that term used herein " pharmacy can be accepted buffer " refers to pharmaceutically to be commonly used to keep the pH value environment of medicine, and buffer comprises phosphate, acetate, Tris, histidine salt and citrate.
Term used herein " isotonic agent " refers to be used for change the chemical compound of the osmotic pressure of pharmaceutical composition in pharmaceutical composition.Isotonic agent comprises NaCl, mannitol, sorbitol, glycerol and xylitol etc.
Term used herein " stabilizing agent " refers to add in the pharmaceutical composition that comprises thymus peptide 1, has been used for the chemical compound of Stabilization.The example that is used for the stabilizing agent of pharmaceutical preparation comprises L-arginine, L-histidine, arginine and L-glutathion.
Term used herein " surfactant " refers to be meant to have fixed hydrophilic and oleophilic group, aligns at the interface energy of solution, and molecule or ion that surface tension is significantly descended.Surfactant is preferably at the interface savings, and its hydrophilic segment is towards water (aqueous favoring), and lipophilic portion is towards oil or hydrophobic phase (being glass, air, wet goods etc.).Anion surfactant commonly used has: deoxycholic acid sodium salt, dodecyl sodium sulfate, tromethane dodecyl sodium sulfate, sodium caprylate; Cationic surfactant commonly used has: alkyl trimethyl ammonium bromide, benzalkonium chloride, bromination dodecyl trimethyl ammonium etc.; Nonionic surfactant commonly used can be selected from: poloxamer, poloxamer 188, poloxamer 407, Brij35, Brij56, Brij72, Brij76 etc.
Term used herein " thymus peptide 1 derivative " refers to such an extent that be an end or two end that the C end of thymus peptide 1 is connected Polyethylene Glycol, perhaps the derivant of the thymus peptide 1 that gets with other macromolecular compounds modifications.
Term " about " used herein refers to suitable approaching of described numerical value, as adds and subtracts 10%.
The specific embodiment
The present invention further describes by following embodiment, and described embodiment is not understood to further qualification.Described ad hoc approach of those skilled in the art's easy to understand and result only are illustrative.
Embodiment 1
Taking by weighing a certain proportion of sodium hydrogen phosphate and sodium dihydrogen phosphate is dissolved in the water for injection of new system, with the pH of phosphoric acid or sodium hydrate regulator solution to about 3.0,5.0,7.0,10.0, add respectively then that 0.1% active carbon is put in 60 ℃ of water-baths insulation 15min and filtered while hot is taken off charcoal, getting subsequent filtrate puts and is cooled in the ice bath below 15 ℃, take by weighing the PEG thymus peptide 1 of recipe quantity (1.6mg/ml), slowly stirring makes it to dissolve and regulates the pH of medicinal liquid to about 3.0 with phosphoric acid or sodium hydroxide, 5.0,7.0,10.0, at last with the filtering with microporous membrane of medicinal liquid with 0.22 μ m, packing, lid is rolled in tamponade behind the inflated with nitrogen.Sample put respectively under 25 ℃ and the 40 ℃ of conditions investigate its stability, the investigation index is character, related substance, content and turbidity, the results are shown in Table 1.
Table 1
Embodiment 2
Taking by weighing a certain proportion of sodium hydrogen phosphate and sodium dihydrogen phosphate is dissolved in the water for injection of new system, with the pH of phosphoric acid or sodium hydrate regulator solution to about 7.0, add then that 0.1% active carbon is put in 60 ℃ of water-baths insulation 15min and filtered while hot is taken off charcoal, getting subsequent filtrate puts and is cooled in the ice bath below 15 ℃, the L-glutathion of adding 0.2%, take by weighing the PEG thymus peptide 1 of recipe quantity (1.6mg/ml), slowly stirring makes it to dissolve and regulates the pH of medicinal liquid to about 7.0 with phosphoric acid or sodium hydroxide, at last with the filtering with microporous membrane of medicinal liquid with 0.22 μ m, packing, lid is rolled in tamponade behind the inflated with nitrogen.Sample put respectively under 25 ℃ and the 40 ℃ of conditions investigate its stability, the investigation index is character, related substance, content and turbidity, the results are shown in Table 2.
Table 2
Embodiment 3
Taking by weighing a certain proportion of sodium hydrogen phosphate and sodium dihydrogen phosphate is dissolved in the water for injection of new system, with the pH of phosphoric acid or sodium hydrate regulator solution to about 7.0, add then that 0.1% active carbon is put in 60 ℃ of water-baths insulation 15min and filtered while hot is taken off charcoal, getting subsequent filtrate puts and is cooled in the ice bath below 15 ℃, add sweet and 0.05% the poloxamer 188 of 0.2% L-paddy Guang, take by weighing the PEG thymus peptide 1 of recipe quantity (1.6mg/ml), slowly stirring makes it to dissolve and regulates the pH of medicinal liquid to about 7.0 with phosphoric acid or sodium hydroxide, at last with the filtering with microporous membrane of medicinal liquid with 0.22 μ m, packing, lid is rolled in tamponade behind the inflated with nitrogen.Sample put respectively under 25 ℃ and the 40 ℃ of conditions investigate its stability, the investigation index is character, related substance, content and turbidity, the results are shown in Table 3.
Table 3
Embodiment 4
Taking by weighing a certain proportion of sodium hydrogen phosphate and sodium dihydrogen phosphate is dissolved in the water for injection of new system, with the pH of phosphoric acid or sodium hydrate regulator solution to about 7.0, add then that 0.1% active carbon is put in 60 ℃ of water-baths insulation 15min and filtered while hot is taken off charcoal, getting subsequent filtrate puts and is cooled in the ice bath below 15 ℃, the L-glutathion of adding 0.2% and 0.1% polyoxyethylene sorbitan monoleate, take by weighing the PEG thymus peptide 1 of recipe quantity (1.6mg/ml), slowly stirring makes it to dissolve and regulates the pH of medicinal liquid to about 7.0 with phosphoric acid or sodium hydroxide, at last with the filtering with microporous membrane of medicinal liquid with 0.22 μ m, packing, lid is rolled in tamponade behind the inflated with nitrogen.Sample put respectively under 25 ℃ and the 40 ℃ of conditions investigate its stability, the investigation index is character, related substance, content and turbidity, the results are shown in Table 4.
Table 4
Embodiment 5
Taking by weighing a certain proportion of sodium hydrogen phosphate and sodium dihydrogen phosphate is dissolved in the water for injection of new system, with the pH of phosphoric acid or sodium hydrate regulator solution to about 7.0, add then that 0.1% active carbon is put in 60 ℃ of water-baths insulation 15min and filtered while hot is taken off charcoal, getting subsequent filtrate puts and is cooled in the ice bath below 15 ℃, the L-arginine of adding 0.1% and 0.1% polyoxyethylene sorbitan monoleate, take by weighing the PEG thymus peptide 1 of recipe quantity (3.2mg/ml), slowly stirring makes it to dissolve and regulates the pH of medicinal liquid to about 7.0 with phosphoric acid or sodium hydroxide, at last with the filtering with microporous membrane of medicinal liquid with 0.22 μ m, packing, lid is rolled in tamponade behind the inflated with nitrogen.Sample put respectively under 25 ℃ and the 40 ℃ of conditions investigate its stability, the investigation index is character, related substance, content and turbidity, the results are shown in Table 5.
Table 5
Claims (29)
1. the pharmaceutical composition that comprises the stable storing of thymus peptide 1 derivative, pharmacy acceptable surfactant, stabilizing agent and isoosmotic adjusting agent, the pH scope of wherein said compositions is 3.0 to 10.0.
2. pharmaceutical composition according to claim 1, wherein said thymus peptide 1 derivative are thymus peptide 1 and the analog thereof that PEG modifies.
3. pharmaceutical composition according to claim 2, the concentration of wherein said thymus peptide 1 derivative is selected from 0.1mg/ml to 25.6mg/ml, 0.8mg/ml to 25.6mg/ml or 1.6mg/ml to 12.8mg/ml.
4. pharmaceutical composition according to claim 1, wherein said surfactant are selected from polyoxyethylene sorbitan monoleate, polysorbate 20, polysorbate 40, polysorbate 60 or poloxamer 188.
5. pharmaceutical composition according to claim 4, wherein said surfactant is selected from polyoxyethylene sorbitan monoleate.
6. pharmaceutical composition according to claim 4, wherein said surfactant is selected from poloxamer 188.
7. according to any described pharmaceutical composition of claim 4-6, wherein said dosage of surfactant is 0.01% to 10%.
8. pharmaceutical composition according to claim 7, wherein said dosage of surfactant are 0.05% to 5%.
9. pharmaceutical composition according to claim 1, wherein said stabilizing agent are selected from L-glutathion, L-arginine, L-histidine, arginine, sodium thiosulfate, sodium sulfite or sodium sulfite.
10. pharmaceutical composition according to claim 9, wherein said stabilizing agent is selected from the L-glutathion.
11. according to claim 9 or 10 described pharmaceutical compositions, wherein said stabilizing agent dosage is 0.01% to 5.0%.
12. pharmaceutical composition according to claim 11, wherein said stabilizing agent dosage are 0.02% to 0.5%.
13. pharmaceutical composition according to claim 1, wherein said isoosmotic adjusting agent is selected from sodium chloride, mannitol, sorbitol, glycerol or xylitol.
14. pharmaceutical composition according to claim 1, wherein the scope of pH is 3.0 to 10.0.
15. pharmaceutical composition according to claim 1 wherein comprises pharmacy and can accept buffer.
Buffer is selected from phosphate or/and acetic acid and salt buffer thereof 16. pharmaceutical composition according to claim 15, wherein said pharmacy can be accepted.
17. pharmaceutical composition according to claim 16, wherein said buffer are selected from acetic acid, sodium acetate, ammonium acetate, potassium acetate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium hydrogen phosphate or/and sodium dihydrogen phosphate.
18. preparation is as the method for any described pharmaceutical composition of claim 1-17, it comprises described thymus peptide 1 derivative dissolving and mixed stabilizer and isoosmotic adjusting agent.
19. method according to claim 18, wherein said dissolving are to finish under cryogenic conditions.
20. method according to claim 19, wherein said temperature is between 0 ℃ and 30 ℃.
21. method according to claim 20, wherein said temperature is between 0 ℃ and 20 ℃.
22. according to the method for claim 21, wherein said temperature is between 0 ℃ and 15 ℃.
23. according to any described method of claim 19-22, wherein pH is between 3.0 to 10.0.
24. method according to claim 23, wherein pH is between 4.5 to 8.5.
25. method according to claim 24, wherein pH is between 5.0 to 7.5.
26. method according to claim 25, wherein pH is 6.8.
27. method according to claim 25, wherein pH is 7.2.
28. method according to claim 25, wherein pH is 6.5.
29. according to any described method of claim 19-28, wherein aseptic filtration packing inflated with nitrogen encapsulation after the pharmaceutical compositions.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110112139 CN102233130B (en) | 2010-04-28 | 2011-04-25 | Stable pharmaceutical preparation containing thymosin 1 derivatives |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010158369.7 | 2010-04-28 | ||
| CN201010158369 | 2010-04-28 | ||
| CN 201110112139 CN102233130B (en) | 2010-04-28 | 2011-04-25 | Stable pharmaceutical preparation containing thymosin 1 derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102233130A true CN102233130A (en) | 2011-11-09 |
| CN102233130B CN102233130B (en) | 2013-05-01 |
Family
ID=44884552
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201110112139 Expired - Fee Related CN102233130B (en) | 2010-04-28 | 2011-04-25 | Stable pharmaceutical preparation containing thymosin 1 derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102233130B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103566354A (en) * | 2012-07-25 | 2014-02-12 | 江苏豪森药业股份有限公司 | Pharmaceutical composition containing derivatives of GLP-1 analogue or medicinal salts thereof |
| CN103861089A (en) * | 2012-12-17 | 2014-06-18 | 江苏豪森药业股份有限公司 | Derivative of GLP-1 analogues or pharmaceutical salt injection of derivative as well as preparation method and applications of derivative of GLP-1 analogues or pharmaceutical salt injection of derivative |
| CN104511013A (en) * | 2013-09-26 | 2015-04-15 | 长春海悦药业有限公司 | Pharmaceutical composition containing thymulin and preparation thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1739794A (en) * | 2005-05-11 | 2006-03-01 | 北京双鹭药业股份有限公司 | Thymosin alpha-1 aqua prepn and its prepn process and application |
| CN101934068A (en) * | 2010-09-26 | 2011-01-05 | 武汉华龙生物制药有限公司 | Preparation method of thymopetidum injection |
-
2011
- 2011-04-25 CN CN 201110112139 patent/CN102233130B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1739794A (en) * | 2005-05-11 | 2006-03-01 | 北京双鹭药业股份有限公司 | Thymosin alpha-1 aqua prepn and its prepn process and application |
| CN101934068A (en) * | 2010-09-26 | 2011-01-05 | 武汉华龙生物制药有限公司 | Preparation method of thymopetidum injection |
Non-Patent Citations (2)
| Title |
|---|
| 《药学服务与研究》 20050930 张晓芳等 聚乙二醇胸腺肽alpha1和胸腺肽alpha1 对肝损伤大鼠保护作用的比较 271-274 1-29 第5卷, 第3期 * |
| 张晓芳等: "聚乙二醇胸腺肽α1和胸腺肽α1 对肝损伤大鼠保护作用的比较", 《药学服务与研究》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103566354A (en) * | 2012-07-25 | 2014-02-12 | 江苏豪森药业股份有限公司 | Pharmaceutical composition containing derivatives of GLP-1 analogue or medicinal salts thereof |
| CN103566354B (en) * | 2012-07-25 | 2017-12-05 | 江苏豪森药业集团有限公司 | The pharmaceutical composition of derivative or its officinal salt containing the analogs of GLP 1 |
| CN103861089A (en) * | 2012-12-17 | 2014-06-18 | 江苏豪森药业股份有限公司 | Derivative of GLP-1 analogues or pharmaceutical salt injection of derivative as well as preparation method and applications of derivative of GLP-1 analogues or pharmaceutical salt injection of derivative |
| CN103861089B (en) * | 2012-12-17 | 2019-06-28 | 江苏豪森药业集团有限公司 | The derivative of GLP-1 analog or its officinal salt injection and its preparation method and application |
| CN104511013A (en) * | 2013-09-26 | 2015-04-15 | 长春海悦药业有限公司 | Pharmaceutical composition containing thymulin and preparation thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102233130B (en) | 2013-05-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108135980B (en) | Method for preparing stable glucagon therapeutic agent in non-proton polar solvent | |
| EP2525796B1 (en) | Aqueous solution comprising 3-quinuclidinones for the treatment of hyperproliferative, autoimmune and heart disease | |
| CA3035070C (en) | Bendamustine solution formulations | |
| FI78837B (en) | FOERFARANDE FOER FRAMSTAELLNING AV EN FOER INJEKTIONSADMINISTRATION LAEMPLIG, STABIL OCH SALTSYRAHALTIG VATTENLOESNING AV CIS-PLATINA. | |
| WO2015038431A1 (en) | Stable compositions of peptide epoxy ketones | |
| CN105434373A (en) | Oxiracetam freeze-drying preparation for injection and preparation method thereof | |
| KR20170008252A (en) | Formulations of cyclophosphamide liquid concentrate | |
| KR102656841B1 (en) | Injectable pharmaceutical formulation of lefamulin | |
| CN102233130B (en) | Stable pharmaceutical preparation containing thymosin 1 derivatives | |
| CN105919931B (en) | A kind of fasudil hydrochloride injection of stabilization and preparation method thereof | |
| CN102813632A (en) | Stable thymalfasin preparation and preparation method thereof | |
| AU2004314154B2 (en) | Pharmaceutical composition of vinflunine which is intended for parenteral administration preparation method thereof and use of same | |
| CN101317846B (en) | Tetrodotoxin formulation for drug rehabilitation , pain ease | |
| EP3040067A1 (en) | Chlorogenic acid powder-injection and preparation method thereof | |
| CN107126418A (en) | Injection Diclofenac sodium pharmaceutical composition and preparation method thereof | |
| CN115518037A (en) | Safe and stable-quality levosimendan injection composition and preparation method thereof | |
| CN115804771A (en) | Lipid drug delivery system with long-acting sustained release effect and preparation method thereof | |
| CN110693861A (en) | Terbutaline sulfate solution preparation for aerosol inhalation and preparation method thereof | |
| JP2001163776A (en) | Stabilized liquid agent | |
| CN103239416B (en) | Injection composition with isosorbide mononitrate and preparation method for injection composition | |
| WO2009103209A1 (en) | Stable s-(-)- nadifloxacin-l-arginine composition, its preparation method and use | |
| EP3679925A1 (en) | Pharmaceutical composition of docetaxel conjugate and preparation method | |
| CN106937944A (en) | A kind of injection metronidazole freeze-dried powder and preparation method thereof | |
| KR20120030530A (en) | Ipamorelin diacetate injection and infusion solutions | |
| WO2023237093A1 (en) | Pemetrexed disodium liquid composition, preparation method therefor and use thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Owner name: JIANGSU HANSOH MEDICAL GROUP CO.,LTD. Free format text: FORMER OWNER: JIANGSU HANSOH MEDICAL RESEARCH INSTITUTE CO., LTD. Effective date: 20140616 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20140616 Address after: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Patentee after: JIANGSU HANSOH PHARMACEUTICAL Co.,Ltd. Patentee after: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. Address before: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Patentee before: JIANGSU HANSOH PHARMACEUTICAL Co.,Ltd. Patentee before: JIANGSU HANSOH MEDICINE INSTITUTE Co.,Ltd. |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| C56 | Change in the name or address of the patentee | ||
| CP01 | Change in the name or title of a patent holder |
Address after: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Patentee after: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. Address before: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Patentee before: Jiangsu best Pharmaceutical Co.,Ltd. Patentee before: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. Address after: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Patentee after: Jiangsu best Pharmaceutical Co.,Ltd. Patentee after: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. Address before: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Patentee before: JIANGSU HANSOH PHARMACEUTICAL Co.,Ltd. Patentee before: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20160318 Address after: 222047 Lianyungang economic and Technological Development Zone, Jiangsu Patentee after: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. Address before: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Patentee before: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. |
|
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20130501 |