WO2014169725A1 - 一种艾塞那肽微球制剂、其制备方法及其应用 - Google Patents
一种艾塞那肽微球制剂、其制备方法及其应用 Download PDFInfo
- Publication number
- WO2014169725A1 WO2014169725A1 PCT/CN2014/071524 CN2014071524W WO2014169725A1 WO 2014169725 A1 WO2014169725 A1 WO 2014169725A1 CN 2014071524 W CN2014071524 W CN 2014071524W WO 2014169725 A1 WO2014169725 A1 WO 2014169725A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- exenatide
- preparation
- microsphere
- rpm
- oil phase
- Prior art date
Links
- 239000004005 microsphere Substances 0.000 title claims abstract description 107
- 108010011459 Exenatide Proteins 0.000 title claims abstract description 98
- 229960001519 exenatide Drugs 0.000 title claims abstract description 97
- 238000002360 preparation method Methods 0.000 title claims abstract description 96
- HTQBXNHDCUEHJF-XWLPCZSASA-N Exenatide Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)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](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 HTQBXNHDCUEHJF-XWLPCZSASA-N 0.000 title claims abstract description 95
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 36
- 150000001413 amino acids Chemical class 0.000 claims abstract description 32
- 229920003232 aliphatic polyester Polymers 0.000 claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 20
- 239000002904 solvent Substances 0.000 claims abstract description 12
- 239000003995 emulsifying agent Substances 0.000 claims abstract description 10
- 210000003022 colostrum Anatomy 0.000 claims abstract description 8
- 235000021277 colostrum Nutrition 0.000 claims abstract description 8
- -1 exenatide compound Chemical class 0.000 claims abstract description 8
- 239000003223 protective agent Substances 0.000 claims abstract description 6
- 239000012071 phase Substances 0.000 claims description 41
- 235000001014 amino acid Nutrition 0.000 claims description 30
- 239000008346 aqueous phase Substances 0.000 claims description 28
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 25
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 21
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 15
- 229930182817 methionine Natural products 0.000 claims description 15
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 8
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 229920001577 copolymer Polymers 0.000 claims description 6
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims description 5
- 229920000331 Polyhydroxybutyrate Polymers 0.000 claims description 5
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims description 5
- 239000005015 poly(hydroxybutyrate) Substances 0.000 claims description 5
- 229920000747 poly(lactic acid) Polymers 0.000 claims description 5
- 239000004626 polylactic acid Substances 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000004471 Glycine Substances 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 230000002218 hypoglycaemic effect Effects 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 4
- 230000001954 sterilising effect Effects 0.000 claims description 4
- 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
- 229930195725 Mannitol Natural products 0.000 claims description 3
- 238000005119 centrifugation Methods 0.000 claims description 3
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 3
- 235000018417 cysteine Nutrition 0.000 claims description 3
- 238000004945 emulsification Methods 0.000 claims description 3
- 239000000594 mannitol Substances 0.000 claims description 3
- 235000010355 mannitol Nutrition 0.000 claims description 3
- 238000004659 sterilization and disinfection Methods 0.000 claims description 3
- 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 claims description 2
- 229920002307 Dextran Polymers 0.000 claims description 2
- 108010010803 Gelatin Proteins 0.000 claims description 2
- 102000008100 Human Serum Albumin Human genes 0.000 claims description 2
- 108091006905 Human Serum Albumin Proteins 0.000 claims description 2
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- 229920000954 Polyglycolide Polymers 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- 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 claims description 2
- 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 claims description 2
- 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 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 229920000159 gelatin Polymers 0.000 claims description 2
- 239000008273 gelatin Substances 0.000 claims description 2
- 235000019322 gelatine Nutrition 0.000 claims description 2
- 235000011852 gelatine desserts Nutrition 0.000 claims description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- ZPIRTVJRHUMMOI-UHFFFAOYSA-N octoxybenzene Chemical compound CCCCCCCCOC1=CC=CC=C1 ZPIRTVJRHUMMOI-UHFFFAOYSA-N 0.000 claims description 2
- 229920001432 poly(L-lactide) Polymers 0.000 claims description 2
- 229920000218 poly(hydroxyvalerate) Polymers 0.000 claims description 2
- 229920001610 polycaprolactone Polymers 0.000 claims description 2
- 239000004632 polycaprolactone Substances 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 239000004633 polyglycolic acid Substances 0.000 claims description 2
- 229920000136 polysorbate Polymers 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 1
- 229920005689 PLLA-PGA Polymers 0.000 claims 1
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
- 239000000883 anti-obesity agent Substances 0.000 claims 1
- 239000003472 antidiabetic agent Substances 0.000 claims 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 claims 1
- 238000004806 packaging method and process Methods 0.000 claims 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims 1
- 239000008280 blood Substances 0.000 abstract description 9
- 210000004369 blood Anatomy 0.000 abstract description 9
- 239000003814 drug Substances 0.000 abstract description 8
- 230000003247 decreasing effect Effects 0.000 abstract 1
- 230000008719 thickening Effects 0.000 abstract 1
- 229940068984 polyvinyl alcohol Drugs 0.000 description 23
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 23
- MWKFXSUHUHTGQN-UHFFFAOYSA-N decan-1-ol Chemical compound CCCCCCCCCCO MWKFXSUHUHTGQN-UHFFFAOYSA-N 0.000 description 22
- 239000002245 particle Substances 0.000 description 21
- 238000005538 encapsulation Methods 0.000 description 19
- 239000003960 organic solvent Substances 0.000 description 14
- 238000002347 injection Methods 0.000 description 13
- 239000007924 injection Substances 0.000 description 13
- 229940090044 injection Drugs 0.000 description 12
- 239000000843 powder Substances 0.000 description 12
- 238000009472 formulation Methods 0.000 description 11
- 239000002244 precipitate Substances 0.000 description 11
- 230000000694 effects Effects 0.000 description 7
- 229940047296 exenatide injection Drugs 0.000 description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 5
- MROCJMGDEKINLD-UHFFFAOYSA-N dichlorosilane Chemical compound Cl[SiH2]Cl MROCJMGDEKINLD-UHFFFAOYSA-N 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000008103 glucose Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000010254 subcutaneous injection Methods 0.000 description 5
- 239000007929 subcutaneous injection Substances 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000004108 freeze drying Methods 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 4
- 239000008215 water for injection Substances 0.000 description 4
- IXADHCVQNVXURI-UHFFFAOYSA-N 1,1-dichlorodecane Chemical compound CCCCCCCCCC(Cl)Cl IXADHCVQNVXURI-UHFFFAOYSA-N 0.000 description 3
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical class N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 230000004580 weight loss Effects 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 229920001213 Polysorbate 20 Polymers 0.000 description 2
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 229960001052 streptozocin Drugs 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- IMSVBNQVZVQSND-UHFFFAOYSA-N 1,5-bis(sulfanyl)pentan-3-one Chemical compound SCCC(=O)CCS IMSVBNQVZVQSND-UHFFFAOYSA-N 0.000 description 1
- ZRECPFOSZXDFDT-UHFFFAOYSA-N 1-decylpyrrolidin-2-one Chemical compound CCCCCCCCCCN1CCCC1=O ZRECPFOSZXDFDT-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- GUTLYIVDDKVIGB-OUBTZVSYSA-N Cobalt-60 Chemical compound [60Co] GUTLYIVDDKVIGB-OUBTZVSYSA-N 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 229930182558 Sterol Natural products 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 238000012661 block copolymerization Methods 0.000 description 1
- 229940084891 byetta Drugs 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000009775 high-speed stirring Methods 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- VUZPPFZMUPKLLV-UHFFFAOYSA-N methane;hydrate Chemical compound C.O VUZPPFZMUPKLLV-UHFFFAOYSA-N 0.000 description 1
- 239000012982 microporous membrane Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
-
- 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
- A61K38/26—Glucagons
-
- 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
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
- A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Definitions
- the invention belongs to the field of pharmaceutical preparations, and particularly relates to an exenatide microsphere preparation, a preparation method thereof and application thereof. Background technique
- Exenatide injection is the first inactivated insulin analog preparation to be marketed.
- the preparation has been clinically proven to have a good effect in improving blood sugar control and weight loss.
- the half-life of exenatide is only 2.4 hours, in order to control blood glucose smoothly, it is required to be administered twice daily by subcutaneous injection. Frequent injections make the patient's compliance poor, especially for patients who need insulin injection.
- the patent US 7,456,254 discloses an exenatide microsphere preparation, but the preparation process of the preparation is complicated, and it is a W/O/O (oil-in-oil-in-water) double emulsion method, and the preparation process takes a long time and is used. A large amount of organic solvent dissolves the main drug and the carrier, so the related impurities are also increased due to the complexity of the process, and the stability of the microsphere preparation is also affected, and the microsphere preparation is administered at a large dose (2 m g / week). There are also potential security risks. Some patents also disclose the preparation process of exenatide microsphere preparations, and the W/O/W (water-in-oil-in-water) double emulsion method is often used, and the process is complicated, and the above problems also exist.
- W/O/O oil-in-oil-in-water
- the present invention provides an exenatide microsphere preparation comprising: exenatide and an amino acid.
- the present invention also provides a method of preparing an Exenatide microsphere formulation of the present invention, comprising the steps of:
- the invention also provides the use of an Exenatide microsphere formulation of the invention for the manufacture of a hypoglycemic and/or weight loss medicament.
- the Exenatide microsphere preparation of the present invention is an oil-in-water (OAV) microsphere preparation, and the preparation method thereof is simple.
- OAV oil-in-water
- Fig. 1 is a line graph showing the effect of a microsphere preparation prepared in the present invention (sample 1 prepared in Example 1) on the body weight of streptozotocin (STZ) modeled mice.
- Fig. 2 is a line diagram showing the effect of a microsphere preparation (Sample 1 obtained in Example 1) on blood glucose of streptozotocin (STZ) model mice prepared by the present invention. detailed description
- the present invention provides a microsphere preparation comprising exenatide and an amino acid.
- the microsphere preparation of the present invention may be a liquid preparation containing water, for example, a microsphere injection, or may be a preparation in a dry form in which water is removed but reconstituted into a liquid preparation before use.
- the invention provides a microsphere formulation comprising exenatide, an amino acid, and water.
- the Exenatide microsphere formulation of the present invention further comprises an aliphatic polyester compound.
- the "aliphatic polyester compound” used in the present application generally includes poly-L-lactic acid, polyglycolic acid, poly-D-lactic acid-glycolic acid copolymer, poly-L-lactic acid-glycolic acid copolymer, poly-D.
- L-lactic acid-glycolic acid copolymer hereinafter referred to as "PLGA"
- polycaprolactone polyvalerolactone
- polyhydroxybutyrate polyhydroxyvalerate
- the aliphatic polyester compound is preferably PLGA, which is a polymer material obtained by block copolymerization of lactic acid (LA) and glycolic acid (GA) in different proportions, and has good biocompatibility and biodegradability.
- the final degradation products are carbon dioxide and water.
- the PLGA of the present invention is a polylactic acid: glycolic acid copolymer of 25:75 to 75:25 having a molecular weight of 5,000 to 20,000 Daltons.
- the invention provides an inclusion of exenatide,
- Microsphere preparation of PLGA and amino acids Microsphere preparation of PLGA and amino acids.
- the Exenatide microsphere preparation of the present invention preferably comprises Exendin: an aliphatic polyester compound (for example, PLGA) in a ratio of 1:1100 to 10:1, preferably 1:500 to 4:1, particularly preferably 1:245-1:6.
- Exendin an aliphatic polyester compound (for example, PLGA) in a ratio of 1:1100 to 10:1, preferably 1:500 to 4:1, particularly preferably 1:245-1:6.
- oil phase solvent generally means an organic solvent, including dichlorosilane, ethyl acetate, chloroform, acetone, dimethyl sulfoxide, dimethyl hydrazide, N-decyl pyrrolidone, Oxecyclohexane, tetrahydrofuran, mercaptoethyl ketone, acetonitrile, decyl alcohol, ethanol, isopropanol, butanol, and mixtures thereof, preferably a mixture of any two of the above solvents, more preferably dichlorosilane and decyl alcohol The mixture preferably has a mixing ratio of 1:1 to 1:0.1.
- amino acid of the present invention preferably includes tryptophan, methionine, glycine, histidine, cysteine, or a mixture thereof, more preferably methionine, glycine and tryptophan, and most preferably methionine.
- the "emulsifier” of the present invention is preferably a nonionic surfactant, including Tween, polyethylene glycol octylphenyl ether (Triton), benzze (Brij), polyvinylpyrrolidone, polyvinyl alcohol. (PVA), or a mixture thereof, more preferably polyvinyl alcohol.
- a nonionic surfactant including Tween, polyethylene glycol octylphenyl ether (Triton), benzze (Brij), polyvinylpyrrolidone, polyvinyl alcohol. (PVA), or a mixture thereof, more preferably polyvinyl alcohol.
- the Exenatide microsphere preparation of the present invention may further contain a microsphere protectant, preferably dextran, mannitol, carbonated, human serum albumin, gelatin, trehalose, sucrose, or a mixture thereof.
- the protectant can protect the protein polypeptide from degradation during the preparation of the microsphere preparation.
- the microsphere preparation of the present invention may comprise 0.05% to 10% w/w of exenatide and 44 to 98% of w/w of amino acid.
- the microsphere preparation of the present invention preferably comprises exenatide: the ratio of amino acid (e.g., methionine) is 1:1960-1:4.4, preferably 1:970-1:5, particularly preferably 1:475-1:8.
- amino acid e.g., methionine
- the microsphere preparation of the present invention preferably comprises from 0.1% to 8% w/w of exenatide, more preferably from 0.2% to 6% w/w.
- the microsphere formulation of the present invention preferably comprises 46-97% w/w of amino acid, more preferably 50-95% w/w.
- the microsphere preparation of the present invention may further comprise from 1% to 55% w/w of the aliphatic polyester compound, preferably from 2% to 50% w/w of the aliphatic polyester compound, more preferably from 4% to 49% w/ Wo
- the microsphere preparation of the present invention may further comprise 0.1-8% w/w of a microsphere protectant. It is preferably 0.5 to 5% w/w.
- the microspheres of the present invention have an average particle diameter of less than 85 ⁇ , preferably an average particle diameter of 10 to 60 ⁇ , more preferably an average particle diameter of 25 to 50 ⁇ , and particularly preferably have the above average particle diameter and a particle diameter range. It is a microsphere of 0.5-100 ⁇ m.
- the microsphere preparation is an injection preparation, more preferably a subcutaneous injection preparation.
- the preparation for injection described herein includes a liquid preparation for injection and a preparation for dry form for injection.
- the preparation for injection may be an injection or a lyophilized preparation for injection.
- the preparation for injection or the preparation for subcutaneous injection is particularly preferably in the form of an injection or a subcutaneous injection.
- the components of the present invention may be a component suitable for injection, and for example, the water of the present invention may be water for injection or the like.
- the present invention also provides a method of preparing an Exenatide microsphere formulation of the present invention, comprising the steps of:
- the method may also be followed by the step of centrifuging and drying after step (5).
- the method can also be carried out using prior art methods to obtain a dry form preparation.
- a dry form preparation can be obtained by a freeze-drying method.
- the method may further comprise the step of filtering, dispensing and/or sterilizing after step (5).
- filtering dispensing and/or sterilizing after step (5).
- the obtained microsphere preparation can be potted in an ampoule, filtered, and sterilized (for example, filter sterilization, cobalt-60 irradiation, full aseptic operation, etc.) by filtration using a 1.0 ⁇ microporous membrane.
- the amount of each material is: exenatide is 0.05%-2% w/w, preferably 0.1%-1% w/w; more preferably 0.2%-0.8% w/w;
- the aliphatic polyester compound is from 1% to 20% w/w, preferably from 3% to 15% w/w, more preferably from 4% to 13% w/w;
- the amino acid is 10-50% w/w, preferably 15%-48% w/w, more preferably 18%-45% w/w;
- the emulsifier is 30-88% w/w, preferably 40%-80% w/w, more preferably 44%-76% w/w.
- the step (1) can be carried out under stirring, for example, at a stirring speed of 500 to 2500 rpm, such as 1000 to 2000 rpm.
- the step (1) can be carried out under a low temperature condition, preferably at a temperature of 2 to 15 °C.
- the step (1) can be carried out under normal pressure.
- the step (2) can be carried out under stirring, for example, at a stirring speed of 500 to 2500 rpm, such as 1000 to 2000 rpm.
- the step (2) can be carried out under a low temperature condition, preferably at a temperature of 4 to 10 °C.
- the step (2) can be carried out under normal pressure.
- the step (3) can be carried out under high-speed stirring, for example, a stirring speed of 2500-12000 rpm, preferably 4000-10000 rpm.
- the step (3) can be carried out under low temperature conditions, preferably at a temperature of 4 to 10 °C.
- the step (3) can be carried out under normal pressure.
- the step (4) can be carried out under high-speed agitation conditions, for example, a stirring speed of 2500-12000 rpm, preferably 4000-10000 rpm.
- the step (4) can be carried out under normal pressure conditions.
- the step (4) can also be carried out under low temperature conditions, preferably at a temperature of 4 to 10 °C.
- the step (5) may evaporate the oil phase solvent at a low temperature by a method known in the art (for example, stirring under vacuum).
- the step (5) can be carried out under normal pressure or under reduced pressure.
- the microsphere protecting agent is added after the step (5).
- the exenatide, the aliphatic polyester compound, the amino acid, the emulsifier, and the amounts thereof are all of the same meaning and range as described above.
- Each component of the Exenatide microsphere preparation prepared by the method of the present invention (for example, Exenatide, The content of amino acids and the like is within the scope of the invention.
- the microsphere preparation prepared by the method of the present invention has an average particle diameter of less than 85 ⁇ , preferably an average particle diameter of 10 to 60 ⁇ , more preferably an average particle diameter of 25 to 50 ⁇ , and particularly preferably has the above average particle diameter and Microspheres having a particle size ranging from 0.5 to 100 ⁇ m.
- the invention also provides the use of an Exenatide microsphere formulation of the invention for the manufacture of a hypoglycemic and/or weight loss medicament.
- the invention is exemplified by the following examples, but it should not be construed that the scope of the invention is limited to the following examples. Any technique implemented based on the above description of the present invention is within the scope of the present invention.
- the compounds or reagents used in the following examples are commercially available or can be prepared by conventional methods known to those skilled in the art; the experimental apparatus used is commercially available.
- Example 1 (Sample 1)
- Example 2 (Sample 2)
- Example 3 (Sample 3)
- Example 7 (Sample 7)
- Example 9 (Sample 9)
- Example 10 (Sample 10)
- microsphere powder containing exenatide has a microsphere encapsulation efficiency of 86% and a particle diameter of 25-50 ⁇ m, and the content of each component in the finally prepared exenatide microsphere preparation is within the scope of the invention.
- Example 11 (Sample 11)
- the oil phase was slowly added to the aqueous phase; it was branched at 10 Torr and 10000 rpm; at 100 rpm, vacuumed, solidified for 3 h, the organic solvent was sufficiently evaporated, centrifuged, and the precipitate was collected and lyophilized to obtain
- the microsphere powder of exenatide, the encapsulation efficiency of the microspheres is 85%, and the particle size is 25-50 ⁇ m, and the content of each component in the finally prepared exenatide microsphere preparation is within the scope of the invention.
- Example 13 Under the light condition, the prepared sample 1, sample 2, sample 3, sample 4, and sample 11 were irradiated at 4000 LX under a light incubator at room temperature, and were sampled at 0 days, 5 days, and 10 days, respectively.
- the change of oxidized impurities in the preparation of the examples was as follows by HPLC:
- Encapsulation rate The 12 prescriptions were prepared, and the encapsulation efficiency was determined before the freeze-drying. The sample was processed by centrifugation (10000 rpm, 5 min) for HPLC detection.
- exenatide microsphere preparation samples were prepared in parallel, which were respectively A batch, B batch, C batch, D batch, E batch, F batch. Each took 4.5 mg, added 1.5 ml of release medium (pH 7.0 PBS containing 0.1% Tween 20, adding 0.02% sodium azide) in the sample tube, sealed, placed in a 37 °, 110 rpm constant temperature water bath shaker (Taiwan City, Jiangsuzhou experimental equipment Factory, model: THZ-C-1). Samples were taken at ld, 7d, 14d, and 21d, and the amount of exenatide contained in the remaining microsphere preparations was examined. The in vitro release results were as follows, and the cumulative release over 21 days was above 85%.
- the experiment was divided into a blank group (12 healthy ICR mice, normal feeding, without any treatment), model group (12 ICR mice modeled by STZ, only injected with water for injection), Exenatide injection Group (12 ICR mice modeled by STZ, exenatide injection product name: Byetta, commercially available, 2 times a day), sample 1 prepared into high, medium and low concentrations of drug suspension Liquid (suspension: Tween80 300mg, mannitol 16g, carboxymethyl cellulose 3g, 250mL with water), respectively, W1 group, W2 group, W3 group, according to 2.8 mg / kg (0.2 mg / kg / d) Administration, subcutaneous injection was administered once a day on the first day, and only once.
- the model group and the exenatide injection group were given water for injection (home-made), exenatide solution 0.1 mg/kg, twice daily, subcutaneously, on days 1-14.
- the W1 solution was administered at a concentration of 11.28 g/mL; the W2 solution was administered at a concentration of 43.32 g/mL; and the W3 solution was administered at a concentration of 83.16 g/mL.
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Diabetes (AREA)
- Epidemiology (AREA)
- Obesity (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hematology (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Child & Adolescent Psychology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明提供了一种艾塞那肽的微球制剂、其制备方法及其用于制备降血糖和/或减重药物中的应用。所述微球制剂包含艾塞那肽和氨基酸;优选地,所述制剂包含0.05%−10%w/w艾塞那肽、44%−98%w/w氨基酸和水,任选地包含脂肪族聚酯化合物和微球保护剂。所述微球制剂的制备方法包括:将脂肪族聚酯和艾塞那肽化合物先后溶解于油相溶剂以生成均一油相;将氨基酸和乳化剂溶于水以形成均一水相;将所述油相加入至所述水相中,形成初乳;将所述初乳勾化;将油相溶剂挥发。
Description
一种艾塞那肽微球制剂、 其制备方法及其应用 技术领域
本发明属于药物制剂领域, 具体涉及一种艾塞那肽微球制剂、 其制备方法及其应用。 背景技术
艾塞那肽注射剂是首个获准上市的肠促胰岛素类似物制剂。 该 制剂经临床证实在改善血糖控制及减轻体重方面具有良好效果。 但 是, 由于艾塞那肽的半衰期仅为 2.4小时, 为平稳控制血糖, 需每日 皮下注射给药两次, 频繁注射使得患者顺应性较差, 特别是还需注 射胰岛素的患者更难以接受。
为此, 专利 US 7,456,254公开了一种艾塞那肽微球制剂, 但其 制剂制备工艺很复杂, 为 W/O/O (油包油包水) 复乳法, 制备过程 耗时长, 且使用大量有机溶剂溶解主药和载体, 因此相关杂质也会 因工艺的复杂而增加, 微球制剂的稳定性也受到影响, 再加上所述 微球制剂给药剂量大(2mg/周) , 也存在潜在的安全隐患。 还有一 些专利也公开了艾塞那肽微球制剂的制备过程, 多采用 W/O/W (水 包油包水) 复乳法, 工艺很复杂, 也存在上述问题。
因此, 仍需要一种新的艾塞那肽微球制剂制备方法及由此制备 的艾塞那肽微球制剂, 以解决目前制剂中存在的一个或多个问题。 发明内容
本发明提供了一种艾塞那肽微球制剂, 所述制剂包含: 艾塞那 肽和氨基酸。
本发明还提供了一种制备本发明的艾塞那肽微球制剂的方法, 包括以下步骤:
( 1 )将脂肪族聚酯化合物和艾塞那肽溶先后溶解于油相溶剂以 生成均一油相;
( 2 )将氨基酸和乳化剂溶于水以形成均一水相;
( 3 )将所述油相加入至所述水相中, 形成初乳;
( 4 )将所述初乳匀化;
( 5 )将油相溶剂挥发。
本发明还提供了本发明的艾塞那肽微球制剂在用于制备降血糖 和 /或减重药物中的用途。
本发明的艾塞那肽微球制剂, 为一种水包油(OAV )微球制剂, 其制备方法简单。
本发明的艾塞那肽微球制剂的制备方法简单。 附图说明
图 1为本发明制备的一种微球制剂(实施例 1制得的样品 1 )对 链脲霉素 (STZ )造模小鼠体重影响折线图。
图 2为本发明制备的一种微球制剂(实施例 1制得的样品 1 )对 链脲霉素 (STZ )造模小鼠血糖影响折线图。 具体实施方式
本发明提供了一种包含艾塞那肽和氨基酸的微球制剂。 本发明 的微球制剂可以是包含水的液体制剂, 例如微球注射液, 或者也可 以是去除了水但可在临用前复溶为液体制剂的干燥形式的制剂, 例 剂。 在一个具体的方面, 本发明提供了一种包含艾塞那肽、 氨基酸 和水的微球制剂。
本发明的艾塞那肽微球制剂还包含脂肪族聚酯化合物。
本申请中所使用的 "脂肪族聚酯化合物" 通常包括聚 -L-乳酸、 聚羟基乙酸、 聚 -D-乳酸 -羟基乙酸共聚物、 聚 -L-乳酸-羟基乙酸共聚 物、 聚 -D,L-乳酸-羟基乙酸共聚物 (下文中简称 "PLGA" ) 、 聚己 内酯、 聚戊内酯、 聚羟基丁酸酯和聚羟基戊酸酯, 但不限于此。 其 中, 脂肪族聚酯化合物优选为 PLGA, 其是由乳酸(LA )和羟基乙 酸 ( GA ) 以不同比例嵌段共聚而成的一种高分子材料, 具有良好的 生物相容性和可生物降解性, 最终降解产物为二氧化碳和水。 优选 地,本发明所述的 PLGA是聚乳酸:羟基乙酸为 25:75至 75:25的共 聚物, 其分子量为 5000-20000道尔顿。
在一个优选的实施方案中, 本发明提供了一种包含艾塞那肽、
PLGA和氨基酸的微球制剂。
本发明的艾塞那肽微球制剂优选包含艾塞那肽: 脂肪族聚酯化 合物 (例如 PLGA ) 的比例为 1:1100-10:1 , 优选为 1:500-4:1 , 特别 优选为 1:245-1:6。
本申请中所使用的 "油相溶剂" 一般是指有机溶剂, 包括二氯 曱烷、 乙酸乙酯、 氯仿、 丙酮、 二曱基亚砜、 二曱基曱酰胺、 N-曱 基吡咯烷酮、 二氧杂环己烷、 四氢呋喃、 曱基乙基酮、 乙腈、 曱醇、 乙醇、 异丙醇、 丁醇, 及其混合物, 优选上述任意两种溶剂的混合 物,更优选二氯曱烷和曱醇的混合物,其混合比例优选为 1:1至 1:0.1。
本发明所述的 "氨基酸" 优选包括色氨酸、 蛋氨酸、 甘氨酸、 组氨酸、 半胱氨酸, 或其混合物, 更优选为蛋氨酸、 甘氨酸和色氨 酸, 最优选为蛋氨酸。
本发明所述的 "乳化剂" 优选为一种非离子型表面活性剂, 包 括吐温、 聚乙二醇辛基苯基醚(Triton ) 、 苄泽(Brij ) 、 聚乙烯吡 咯烷酮、 聚乙烯醇 (PVA ) , 或其混合物, 更优选为聚乙烯醇。
本发明的艾塞那肽微球制剂还可以含有微球保护剂, 优选为右 旋糖酐、 甘露醇、 碳酸辞、 人血清白蛋白、 明胶、 海藻糖、 蔗糖, 或其混合物。 所述保护剂可以保护蛋白多肽类物质在制备微球制剂 的过程中不降解。
具体而言, 本发明的微球制剂可以包含 0.05%-10% w/w的艾塞 那肽和 44-98% w/w的氨基酸。
本发明的微球制剂优选包含艾塞那肽: 氨基酸 (例如蛋氨酸) 的比例为 1:1960-1:4.4, 优选为 1:970-1:5, 特别优选为 1:475-1:8。
本发明的微球制剂优选包含 0.1%-8% w/w的艾塞那肽, 更优选 0.2% -6% w/w。
本发明的微球制剂优选包含 46-97% w/w 的氨基酸, 更优选 50-95% w/w。
本发明的微球制剂还可包含 1%-55% w/w脂肪族聚酯化合物, 优选包含 2%-50% w/w的脂肪族聚酯化合物,更优选为 4%-49% w/Wo 本发明的微球制剂还可以进一步包含 0.1-8% w/w的微球保护剂,
优选 0.5-5% w/w。
以上所述各个组分使用范围可根据制剂需要组合使用。
本发明的微球制剂中的微球平均粒径低于 85 μιη ,优选平均粒径 为 10-60 μιη, 更优选平均粒径为 25-50 μιη, 尤为优选具有上述平均 粒径且粒径范围为 0.5-100 μιη的微球。
优选地, 所述微球制剂为注射用制剂, 更优选地为皮下注射用 制剂。 本文中所述的注射用制剂包括注射用液体制剂和注射用干燥 形式制剂, 具体而言, 所述注射用制剂可以是注射液或注射用冻干 制剂。 所述注射用制剂或皮下注射用制剂尤为优选为注射液或皮下 注射液的形式。 由此, 本发明的各组分可以是适合用于注射剂的组 分, 例如, 本发明所述的水可为注射用水等等。 本发明还提供了一种制备本发明的艾塞那肽微球制剂的方法, 包括以下步骤:
( 1 )将脂肪族聚酯化合物和艾塞那肽先后溶解于油相溶剂以生 成均一油相;
( 2 ) 将氨基酸和乳化剂溶于水以形成均一水相;
( 3 ) 将所述油相加入至所述水相中, 形成初乳;
( 4 ) 将所述初乳匀化;
( 5 ) 将油相溶剂挥发。
在本发明方法的另一个实施方案中,所述方法还可以在步骤(5 ) 后进行离心、 干燥的步骤。 具体而言, 所述方法还可以使用现有技 术方法, 获得干燥形式制剂的步骤。 例如, 可通过冷冻干燥的方法 获得干燥形式制剂。
在所述方法的另一个实施方案中, 所述方法还可以包括在步骤 ( 5 )后进行过滤、 分装和 /或灭菌的步骤。 本领域技术人员容易确定 如何进行过滤、分装或灭菌。例如,可使用 1.0 μιη的微孔滤膜过滤, 将所得微球制剂灌封于安瓿瓶中, 充氮气, 灭菌 (例如, 过滤除菌、 钴 -60照射、 全无菌操作等)。
在一个具体实施方案中, 在所述方法中, 各物料用量分别为: 艾塞那肽为 0.05%-2% w/w, 优选为 0.1 %-1% w/w; 更优选为
0.2%-0.8% w/w;
脂肪族聚酯化合物为 1%-20% w/w, 优选为 3%-15% w/w, 更 优选为 4%-13% w/w;
氨基酸为 10-50% w/w,优选为 15%-48% w/w,更优选为 18%-45% w/w; 和
乳化剂为 30-88% w/w,优选为 40%-80% w/w,更优选为 44%-76% w/w„
所述步骤 ( 1 ) 可以在搅拌条件下进行, 例如, 搅拌速度为 500-2500 rpm, 如 1000-2000 rpm。 所述步骤 (1 ) 可以在低温条件 下进行, 优选在 2-15°C的温度条件下进行。 所述步骤(1 )可以在常 压下进行。
所述步骤 (2 ) 可以在搅拌条件下进行, 例如, 搅拌速度为 500-2500 rpm, 如 1000-2000 rpm。 所述步骤 (2 ) 可以在低温条件 下进行, 优选在 4-10°C的温度条件下进行。 所述步骤(2 )可以在常 压下进行。
所述步骤 (3 ) 可以在高速搅拌条件下进行, 例如, 搅拌速度为 2500-12000 rpm, 优选为 4000-10000 rpm。 所述步骤 (3 ) 可以在低 温条件下进行, 优选在 4-10°C的温度条件下进行。 所述步骤(3 )可 以在常压下进行。
所述步骤 (4 ) 可以在高速搅拌条件下进行, 例如, 搅拌速度为 2500-12000 rpm, 优选 4000-10000 rpm。 所述步骤(4 )可以在常压 条件下进行。所述步骤(4 )也可以在低温条件下进行,优选在 4-10°C 的温度条件下进行。
所述步骤 (5 ) 可以在低温下以本领域已知的方法 (例如, 在抽 真空条件下进行搅拌) 蒸发油相溶剂。 所述步骤 (5 )可以在常压下 或减压下进行。
在本发明的微球制剂制备方法中, 优选地, 在步骤 (5 )后加入 所述微球保护剂。
在本发明的方法中, 所述艾塞那肽、 脂肪族聚酯化合物、 氨基 酸、 乳化剂以及它们的用量均具有与上文所述相同的含义和范围。 由本发明方法制得的艾塞那肽微球制剂中各成分(例如,艾塞那肽、
氨基酸等) 的含量均在本发明范围内。 由本发明的方法制得的微球 制剂的微球平均粒径低于 85 μιη, 优选平均粒径为 10-60 μιη, 更优 选平均粒径为 25-50 μιη, 尤为优选具有上述平均粒径且粒径范围为 0.5-100 μιη的微球。 本发明还提供了本发明的艾塞那肽微球制剂在用于制备降血糖 和 /或减重药物中的用途。 以下通过实施例形式举例说明本发明, 但不应将此理解为本发 明主题的范围仅限于以下的实例。 凡基于本发明上述内容所实现的 技术均属于本发明的范围。 以下实施例中使用的化合物或试剂可通 过商业途径购得, 或者通过本领域技术人员已知的常规方法制备得 到; 所使用的实验仪器可通过商业途径购得。 实施例 1 (样品 1 )
将 20 mg艾塞那肽(采用固相合成法制备,方法出 《Fmoc Solid Phase Peptide Synthesis》 )和 400 mg PLGA (购自羸创德固赛特种 化学有限公司)溶解于 1 ml二氯曱烷和 0.8ml曱醇中, 在 600转下 形成均一油相; 然后将 0.8 g的聚乙烯醇(PVA ) (购自湖北潜江制 药)在 600转下溶于 80 ml注射用水中, 加入 2g蛋氨酸(购自石家 庄翼荣药业有限公司),充分溶解后,形成均一水相;在 10Ό且 6000 rpm下, 将油相緩慢加入到水相中; 在 10Ό且 5000 rpm下勾化; 在 lOO rpm下, 抽真空, 固化 3 h, 充分挥发有机溶剂, 离心, 收集沉 淀, 冷冻干燥, 得含有艾塞那肽的微球粉末, 微球包封率 93% , 粒 径 25-50 μιη, 最终制得的艾塞那肽微球制剂中各成分含量均在本发 明范围内。 实施例 2 (样品 2 )
将 20 m 艾塞那肽和 400 mg PLGA (购自羸创德固赛特种化学 有限公司)溶解于 1 ml二氯曱烷和 0.8 ml乙酸乙酯中, 在 800转下 形成均一油相; 然后将 0.8 g的聚乙烯醇(PVA ) (购自湖北潜江制
药)在 800转下溶于 80 ml水中, 加入 2g半胱氨酸(购自湖北省八 峰药化股份有限公司), 充分溶解后, 形成均一水相; 在 且 5000 rpm下,将油相緩慢加入到水相;在 且 4000 rpm下勾化;在 100 rpm下, 抽真空, 固化 3 h, 充分挥发有机溶剂, 离心, 收集沉淀, 冷冻干燥, 得含有艾塞那肽的微球粉末, 微球包封率 91% , 粒径 25-50μιη ,最终制得的艾塞那肽微球制剂中各成分含量均在本发明范 围内。 实施例 3 (样品 3 )
将 20 m 艾塞那肽和 400 mg PLGA (购自羸创德固赛特种化学 有限公司)溶解于 1 ml二氯曱烷和 0.8 ml曱醇中, 在 1000转下形 成均一油相;然后将 0.8 g的聚乙烯醇(PVA ) (购自湖北潜江制药) 在 1000转下溶于 80 ml水中,加入 2g色氨酸(湖北省八峰药化股份 有限公司) , 充分溶解后, 形成均一水相; 在 12Ό且 4000 rpm下, 将油相緩慢加入到水相; 在 12 Ό且 10000 rpm下勾化; 在 100 rpm 下, 抽真空, 固化 3 h, 充分挥发有机溶剂, 离心, 收集沉淀, 冷冻 干燥,得含有艾塞那肽的微球粉末,微球包封率 91% ,粒径 25-50 μιη, 最终制得的艾塞那肽微球制剂中各成分含量均在本发明范围内。 实施例 4 (样品 4 )
将 20 m 艾塞那肽和 400 mg PLGA (购自羸创德固赛特种化学 有限公司)溶解于 1 ml二氯曱烷和 0.8 ml曱醇中, 在 500转下形成 均一油相; 然后将 0.8 g的聚乙烯醇 (PVA ) (购自湖北潜江制药) 在 500转下溶于 80 ml水中, 充分溶解后, 形成均一水相; 在 13Ό 且 4000 rpm下,将油相緩慢加入到水相;在 13Ό且 10000 rpm下匀 化; 在 100 rpm下, 抽真空, 固化 3 h, 充分挥发有机溶剂, 离心, 收集沉淀,冷冻干燥,得含有艾塞那肽的微球粉末,微球包封率 81% , 粒径 25-50 μιη。 实施例 5 (样品 5 )
将 10 mg艾塞那肽和 400 mg PLA (购自上海研拓生物科技有限
公司)溶解于 1 ml二氯曱烷和 0.6 ml曱醇中, 在 600转下形成均一 油相; 然后将 1.6g的聚乙烯醇(PVA ) (购自湖北潜江制药)在 600 转下溶于 80 ml水中, 加入 1.6g蛋氨酸(湖北省八峰药化股份有限 公司), 充分溶解后, 形成均一水相; 在 10Ό且 6000 rpm下, 将油 相緩慢加入到水相; 在 10Ό且 7000 rpm下勾化; 在 lOO rpm下,抽 真空, 固化 3 h, 充分挥发有机溶剂, 离心, 收集沉淀, 冷冻干燥, 得含有艾塞那肽的微球粉末, 微球包封率 90% , 粒径 25-50 μιη, 最 终制得的艾塞那肽微球制剂中各成分含量均在本发明范围内。 实施例 6 (样品 6 )
将 10 mg艾塞那肽和 400 mg PLA (购自上海研拓生物科技有限 公司)溶解于 1 ml二氯曱烷和 0.6 ml曱醇中, 在 600转下形成均一 油相; 然后将 1.6 的 tween80 (购自德国 MERCK公司)在 600转 下溶于 80 ml水中, 加入 1.6g蛋氨酸(湖北省八峰药化股份有限公 司) , 充分溶解后, 形成均一水相; 在 9Ό且 8000 rpm下, 将油相 緩慢加入到水相; 在 9Ό且 llOOO rpm下勾化; 在 lOO rpm下, 抽真 空, 固化 3 h, 充分挥发有机溶剂, 离心, 收集沉淀, 冷冻干燥, 得 含有艾塞那肽的微球粉末, 微球包封率 87% , 粒径 25-50 μιη, 最终 制得的艾塞那肽微球制剂中各成分含量均在本发明范围内。 实施例 7 (样品 7 )
将 10 mg艾塞那肽和 400 mg PLA (购自上海研拓生物科技有限 公司)溶解于 1 ml二氯曱烷和 0.6 ml甲醇充分解后, 在 550转下形 成均一油相; 然后将 1.6 g的聚乙烯吡咯烷酮 (PVP ) (购自潍坊中 航生物科技有限公司)在 550转下溶于 80 ml水中, 加入 1.6g蛋氨 酸(湖北省八峰药化股份有限公司), 充分溶解后, 形成均一水相; 在 5Ό且 6000 rpm下, 将油相緩慢加入到水相; 在 5"C且 8000 rpm 下匀化; 在 lOO rpm下, 抽真空, 固化 3 h, 充分挥发有机溶剂, 离 心, 收集沉淀, 冷冻干燥, 得含有艾塞那肽的微球粉末, 微球包封 率 90% , 粒径 25-50 μιη, 最终制得的艾塞那肽微球制剂中各成分含 量均在本发明范围内。
实施例 8 (样品 8 )
将 10 mg艾塞那肽和 100 m 聚羟基丁酸酯(购自 Aldrich公司) 溶解于 1 ml二氯曱烷和 0.3ml曱醇中, 在 600转下形成均一油相; 然后将 0.4g的聚乙烯醇 (PVA ) (购自湖北潜江制药)在 600转下 溶于 80 ml水中,加入 1.6g蛋氨酸(湖北省八峰药化股份有限公司), 充分溶解后, 形成均一水相; 在 6Ό且 9000 rpm下, 将油相緩慢加 入到水相; 在 6Ό且 7000 rpm下匀化; 在 lOO rpm下, 抽真空, 固 化 3 h, 充分挥发有机溶剂, 离心, 收集沉淀, 冷冻干燥, 得含有艾 塞那肽的微球粉末, 微球包封率 86% , 粒径 25-50 μιη, 最终制得的 艾塞那肽微球制剂中各成分含量均在本发明范围内。 实施例 9 (样品 9 )
将 10 mg艾塞那肽和 100 mg聚羟基丁酸酯(购自 Aldrich公司) 溶解于 1 ml二氯曱烷和 0.3 ml曱醇中, 在 600转下形成均一油相; 然后将 0.4g的聚乙烯醇 (PVA ) (购自湖北潜江制药)在 600转下 溶于 80 ml水中,加入 1.6g蛋氨酸(湖北省八峰药化股份有限公司), 充分溶解后, 形成均一水相; 在 10Ό且 8000 rpm下, 将油相緩慢加 入到水相; 在 10Ό且 10000 rpm下勾化; 在 lOO rpm下, 抽真空, 固化 3 h, 充分挥发有机溶剂, 离心, 收集沉淀, 冷冻干燥, 得含有 艾塞那肽的微球粉末, 微球包封率 88% , 粒径 25-50 μιη, 最终制得 的艾塞那肽微球制剂中各成分含量均在本发明范围内。 实施例 10 (样品 10 )
将 10 mg艾塞那肽和 100 mg聚羟基丁酸酯(购自 Aldrich公司) 溶解于 1 ml二氯曱烷和 0.3 ml曱醇充分解后, 在 1600转下形成均 一油相; 然后将 0.4g的聚乙烯醇 (PVA ) (购自湖北潜江制药)在 1600转下溶于 80 ml水中, 加入 1.6g蛋氨酸(湖北省八峰药化股份 有限公司) , 充分溶解后, 形成均一水相; 在 且 6000 rpm下, 将油相緩慢加入到水相;在 8Ό且 8000 rpm下匀化;在 100 rpm下, 抽真空, 固化 3 h,充分挥发有机溶剂, 离心,收集沉淀,冷冻干燥,
得含有艾塞那肽的微球粉末, 微球包封率 86% , 粒径 25-50 μιη, 最 终制得的艾塞那肽微球制剂中各成分含量均在本发明范围内。 实施例 11 (样品 11 )
将 20 mg艾塞那肽和 300 m 聚戊内酯 (购自 Aldrich公司)溶 解于 1 ml二氯曱烷和 0.8 ml曱醇中, 在 1300转下形成均一油相; 然后将 0.8 g的聚乙烯醇(PVA ) (购自湖北潜江制药)在 1300转 下溶于 80 ml水中,充分溶解后,形成均一水相;在 10Ό且 4000 rpm 下,将油相緩慢加入到水相;在 10Ό且 10000 rpm下勾化;在 100 rpm 下, 抽真空, 固化 3 h, 充分挥发有机溶剂, 离心, 收集沉淀, 冷冻 干燥,得含有艾塞那肽的微球粉末,微球包封率 80% ,粒径 25-50 μιη。 实施例 12 (样品 12 )
将 20 m 艾塞那肽和 300 m 聚戊内酯 (购自 Aldrich公司)溶 解于 1 ml二氯曱烷和 0.8 ml曱醇中, 在 1300转下形成均一油相; 然后将 0.8 g的聚乙烯醇(PVA ) (购自湖北潜江制药)在 1300转 下溶于 80 ml水中, 加入 0.4 g蛋氨酸(湖北省八峰药化股份有限公 司), 充分溶解后, 形成均一水相; 在 10Ό且 4000 rpm下, 将油相 緩慢加入到水相; 在 10Ό且 10000 rpm下勾化; 在 100 rpm下, 抽 真空, 固化 3 h, 充分挥发有机溶剂, 离心, 收集沉淀, 冷冻干燥, 得含有艾塞那肽的微球粉末, 微球包封率 85% , 粒径 25-50 μιη, 最 终制得的艾塞那肽微球制剂中各成分含量均在本发明范围内。 实施例 13:光照条件下,即将所制备的样品 1、样品 2、样品 3、 样品 4、样品 11于光照培养箱下 4000LX, 常温条件下照射, 分别于 0天、 5天、 10天进行取样, 经 HPLC进行检测, 实施例制剂中的 氧化杂质的变化如下表:
表 1. 光照条件下微球样品氧化杂质含量
5天
1.42% 1.39% 1.51% 15% 13%
10天
结果表明, 氨基酸的加入能有效的防止艾塞那肽的氧化, 即样 品 1、 样品 2、 样品 3和不加氨基酸的样品 4和样品 11相比, 氧化 杂质低, 有显著性差异。 实施例 14
包封率: 所制备的 12个处方, 分别在未冻干前, 进行包封率测 定, 采用离心方法 (10000 转, 5min )进行样品处理, 进行 HPLC 检测;
包封率 =系统中包封的药量 /系统中包封与未包封的总药量= (系 统中包封与未包封的总药量-液体介质中未包封的药量) /系统中包封 与未包封的总药量 X 100%
结果表明, 见表 2, 样品 1-12中, 除样品 4、 11 (不含氨基酸) 外, 含有氨基酸的微球包封率均在 85%以上, 且乳化剂的种类以及 脂肪族聚酯化合物的种类的不同, 对包封率无显著性影响。 实施例 15
突释: 分别取上述样品 1-12中各微球样品 4.5 mg, 加入 1.5 ml 释放介质(pH7.0 PBS含 0.1%吐温 20, 加入 0.02%的叠氮化钠)于 样品管中, 密封, 置于 37度、 110转的恒温水浴摇床(江苏太仓市 实验设备厂, 型号: THZ-C-1 ) 中。 于 0.5h取出样品, 检查剩余微 球中含有艾塞那肽的量, 用于评价微球制剂的突释情况。
结果表明, 见表 2, 样品 1-12中, 除样品 4、 11 (不含氨基酸) 外, 含有氨基酸的微球样品 0.5小时的突释均在 20%以下, 说明氨 基酸的加入, 明显提高了微球的包封率, 降低了突释, 且乳化剂的 种类以及脂肪族聚酯化合物的种类的不同, 对突释无显著性影响。
表 2. 微球样品 0.5小时突释结果(n=3, 平均值)
包封率% 突释%
93 9
样品 1
91 10
样品 2
91 9
样品 3
81 33
样品 4
90 12
样品 5
87 14
样品 6
90 12
样品 7
86 9
样品 8
88 11
样品 9
86 15
样品 10
80 35
样品 11
85 13
样品 12
实施例 16: 体外释放
以本发明样品 1的处方组成, 平行制得 6批的艾塞那肽微球制 剂样品, 分别为 A批、 B批、 C批、 D批、 E批、 F批.各取 4.5 mg, 加入 1.5 ml释放介质( pH7.0 PBS含 0.1%吐温 20, 加入 0.02%的叠 氮化钠)于样品管中, 密封, 置于 37度、 110转的恒温水浴摇床(江 苏太仓市实验设备厂, 型号: THZ-C-1 ) 中。 于 ld、 7d、 14d、 21d 取出样品, 检查剩余微球制剂中含有艾塞那肽的量, 体外释放结果 如下, 21天的累积释放均在 85%以上。
艾塞那肽微球制剂体外释放结果(n=6 )
Id 7d 14d 21d
18.8% 34.2% 65.6% 87.5%
A批
13.1% 32.1% 64.1% 89.8%
B批
12.3% 37.6% 61.4% 85.2%
C批
10.9% 31.3% 63.2% 88.3%
D批
14.9% 35.6% 60.2% 90.8%
E批
16.4% 39.7% 59.8% 87.2%
F批
实施例 17: 动物实验
本实验分为空白组(健康 ICR小鼠 12只, 正常饲养, 不经任何 处理) 、 模型组 (经 STZ造模的 ICR小鼠 12只, 只注射了注射用 水) 、 艾塞那肽注射液组 (经 STZ造模的 12只 ICR小鼠, 艾塞那 肽注射液商品名: Byetta, 市售, 每天注射 2次) 、 将样品 1制备成 高、 中、 低三组浓度的药物混悬液(助悬剂: Tween80 300mg, 甘露 醇 16g,羧曱基纤维素 3g,用水加满 250mL即可),分别为 W1组、 W2组、 W3组, 按 2.8 mg/kg (0.2 mg/kg/d)给药, 于第 1天皮下注射 给药 1次, 仅给药一次。 模型组和艾塞那肽注射液组于第 1-14天给 予注射用水(自制) 、 艾塞那肽溶液 0.1 mg/kg, 每日两次, 皮下注 射。
其中, W1溶液给药浓度为 11.28 g/mL; W2溶液给药浓度 43.32 g/ mL; W3溶液给药浓度为浓度 83.16 g/ mL。
试验期间监测第 0、 2、 4、 6、 8、 10、 12、 14 天血糖、 体重的 变化如图 1和图 2所示:
小鼠状态: 实验期间各组小鼠体重随着天数增加成上升趋势, 但体重均低于空白组, 与空白组比较, 有统计学意义, 状态良好, 见图 1。
血糖变化: 空白组血糖正常; 与模型组相比, Wl、 W2、 W3组
均能降低血糖, 三组降糖作用均达到空白组和对照组 (即, 艾塞那 肽注射液组) 的理想效果, 见图 2。 本发明所得到的艾塞那肽微球制剂, 经体外释放结果表明, 21 天累积释放 85 %以上,并且与本发明制得的对照样品(样品 4和 11 ) 相比, 无明显突释现象, 载药量和包封率高; 经动物实验表明, 能 有效地、平稳地控制血糖,达到市售的艾塞那肽注射液的理想效果。 显然, 根据本发明的上述内容, 按照本领域的普通技术知识和 惯用手段, 在不脱离本发明上述基本技术思想前提下, 还可以进行 其它多种形式的修改、 替换或变更。 本领域人员能够理解, 本申请 所描述的本发明技术方案的各个特征均可根据需要进行适当的组合,
Claims
1. 一种艾塞那肽微球制剂, 其特征在于, 所述制剂包含艾塞那 肽和氨基酸; 优选地, 所述制剂包含艾塞那肽氨基酸和水;
优选地,其中所述艾塞那肽为 0.05%-10% w/w,优选为 0.1%-8% w/w, 更优选为 0.2%-6% w/w;
优选地, 其中所述氨基酸为 44%-98% w/w, 优选为 46%-97% w/w, 更优选为 50%-95% w/w;
更优选地,
所述艾塞那肽为 0.05%-10% w/w,所述氨基酸为 44%-98% w/w; 特别优选地,
所述艾塞那肽为 0.1%-8% w/w, 所述氨基酸为 46%-97% w/w; 最优选地,
所述艾塞那肽为 0.2%-6% w/w, 所述氨基酸为 50%-95% w/w。
2. 权利要求 1的艾塞那肽微球制剂, 其特征在于, 所述制剂还 包含脂肪族聚酯化合物,优选地,所述脂肪族聚酯化合物为 1%-55% w/w, 优选为 2%-50% w/w, 更优选为 4%-49% w/w。
3. 权利要求 1的艾塞那肽微球制剂, 其特征在于, 所述制剂还 包含微球保护剂, 优选为右旋糖酐、 甘露醇、 碳酸辞、 人血清白蛋 白、 明胶、 海藻糖、 蔗糖, 或其混合物; 优选地, 所述微球保护剂 为 0.1-8% w/w, 更优选 0.5-5% w/w。
4. 权利要求 2的艾塞那肽微球制剂, 其中所述脂肪族聚酯化合 物选自以下所列的一种或多种: 聚 -L-乳酸、 聚羟基乙酸、 聚 -D-乳酸 -羟基乙酸共聚物、 聚 -L-乳酸 -羟基乙酸共聚物、 聚 -D,L-乳酸-羟基乙 酸共聚物、 聚己内酯、 聚戊内酯、 聚羟基丁酸酯和聚羟基戊酸酯; 其中, 脂肪族聚酯化合物优选为 PLGA, 其是聚乳酸: 羟基乙酸为 25:75至 75:25的共聚物, 其分子量为 5000-20000道尔顿;
优选地, 艾塞那肽: 脂肪族聚酯化合物的比例为 1:1100-10:1 , 优选为 1:500-4:1 , 特别优选为 1:245-1:6。
5. 权利要求 1的艾塞那肽微球制剂,其中所述氨基酸为色氨酸、 蛋氨酸、甘氨酸、 组氨酸、 半胱氨酸, 或其混合物, 优选为蛋氨酸、
甘氨酸和色氨酸, 更优选为蛋氨酸;
优选地, 艾塞那肽: 氨基酸的比例为 1:1960-1:4.4 , 优选为 1:970-1:5, 特别优选为 1:475-1:8。
6. 一种制备权利要求 1-4中任一项的艾塞那肽微球制剂的方法, 包括以下步骤:
( 1 )将脂肪族聚酯和艾塞那肽化合物先后溶解于油相溶剂以生 成均一油相;
( 2 ) 将氨基酸和乳化剂溶于水以形成均一水相;
( 3 ) 将所述油相加入至所述水相中, 形成初乳;
( 4 ) 将所述初乳匀化;
( 5 ) 将油相溶剂挥发;
优选地, 在所述方法中, 各物料用量分别为:
艾塞那肽为 0.05%-2% w/w, 优选为 0.1%-1% w/w; 更优选为 0.2%-0.8% w/w;
脂肪族聚酯化合物为 1%-20% w/w, 优选为 3%-15% w/w, 更 优选为 4%-13% w/w;
氨基酸为 10-50% w/w,优选为 15%-48% w/w,更优选为 18%-45% w/w; 和
乳化剂为 30-88% w/w,优选为 40%-80% w/w,更优选为 44%-76% w/w。
7. 权利要求 6的艾塞那肽微球制剂的制备方法, 其中包括在步 骤( 5 )后加入微球保护剂,优选其用量为 0.1-8% w/w,更优选 0.5-5% w/w; 优选地, 还包括离心、 干燥的步骤; 更优选地, 还包括过滤、 分装和 /或灭菌的步骤。
8. 权利要求 6的艾塞那肽微球制剂的制备方法, 其中油相溶剂 包括二氯曱烷、 乙酸乙酯、 氯仿、 丙酮、 二曱基亚砜、 二曱基曱酰 胺、 N-曱基吡咯烷酮、 二氧杂环己烷、 四氢呋喃、 曱基乙基酮、 乙 腈、 曱醇、 乙醇、 异丙醇、 丁醇, 及其混合物, 优选上述任意两种 溶剂的混合物, 更优选二氯曱烷和曱醇的混合物, 其混合比例优选 为 1:1至 1:0.1。
9. 权利要求 6的艾塞那肽微球制剂的制备方法, 其中所述乳化
剂为选自以下所列的一种或多种: 吐温、 聚乙二醇辛基苯基醚、 苄 泽、 聚乙烯吡咯烷酮、 聚乙烯醇, 或其混合物, 更优选为聚乙烯醇。
10. 权利要求 6的艾塞那肽微球制剂的制备方法,其中步骤( 1 ) 所述的制备温度为 2-15°C; 步骤(2) - (5) 的温度为 4-10°C;
优选地, 步骤(1) - (2) 的搅拌速度为 500-2500 rpm, 优选为
1000-2000 rpm; 步骤( 3 ) - ( 4 )的搅拌速度为 2500-12000 rpm; 优 选为 4000-10000 rpm;
优选地, 步骤( 1 ) - ( 4 )在常压下进行, 步骤( 5 )在常压或减 压下进行。
11. 权利要求 1 的艾塞那肽微球制剂在用于制备降血糖和 /或减 重药物中的用途。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201310133644.3A CN104107165B (zh) | 2013-04-17 | 2013-04-17 | 一种艾塞那肽微球制剂、其制备方法及其应用 |
CN201310133644.3 | 2013-04-17 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2014169725A1 true WO2014169725A1 (zh) | 2014-10-23 |
Family
ID=51704287
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2014/071524 WO2014169725A1 (zh) | 2013-04-17 | 2014-01-27 | 一种艾塞那肽微球制剂、其制备方法及其应用 |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN104107165B (zh) |
WO (1) | WO2014169725A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2020028907A1 (en) * | 2018-08-03 | 2020-02-06 | Brown University | Compositions and methods for improving the bioavailability of glp1 and analogues thereof |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106667958B (zh) * | 2015-11-04 | 2019-07-02 | 四川科伦药物研究院有限公司 | 一种多肽缓释微球制剂及其制备方法 |
CN115920126A (zh) * | 2022-11-30 | 2023-04-07 | 广州远想医学生物技术有限公司 | 负载植物外泌体的聚羟基脂肪酸酯微球及其制备方法 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101646424A (zh) * | 2007-03-27 | 2010-02-10 | 菲特伦株式会社 | 用于控释艾赛那肽的组合物和微球及其制备方法 |
CN101658496A (zh) * | 2009-09-11 | 2010-03-03 | 中国人民解放军第二军医大学 | 艾塞那肽缓释微球制剂及其制备方法和应用 |
CN102198103A (zh) * | 2011-05-30 | 2011-09-28 | 深圳翰宇药业股份有限公司 | 一种稳定的艾塞那肽缓释微球制剂及制备方法 |
CN103417957A (zh) * | 2013-06-26 | 2013-12-04 | 深圳翰宇药业股份有限公司 | 一种艾塞那肽缓释微球及其制备方法和制剂 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101559041B (zh) * | 2009-05-19 | 2014-01-15 | 中国科学院过程工程研究所 | 粒径均一的多肽药物缓释微球或微囊制剂及制备方法 |
CN102488619B (zh) * | 2011-12-05 | 2014-08-06 | 上海交通大学 | 连续生产艾塞那肽微球的装置及控制微球释放速度的方法 |
-
2013
- 2013-04-17 CN CN201310133644.3A patent/CN104107165B/zh not_active Expired - Fee Related
-
2014
- 2014-01-27 WO PCT/CN2014/071524 patent/WO2014169725A1/zh active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101646424A (zh) * | 2007-03-27 | 2010-02-10 | 菲特伦株式会社 | 用于控释艾赛那肽的组合物和微球及其制备方法 |
CN101658496A (zh) * | 2009-09-11 | 2010-03-03 | 中国人民解放军第二军医大学 | 艾塞那肽缓释微球制剂及其制备方法和应用 |
CN102198103A (zh) * | 2011-05-30 | 2011-09-28 | 深圳翰宇药业股份有限公司 | 一种稳定的艾塞那肽缓释微球制剂及制备方法 |
CN103417957A (zh) * | 2013-06-26 | 2013-12-04 | 深圳翰宇药业股份有限公司 | 一种艾塞那肽缓释微球及其制备方法和制剂 |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2020028907A1 (en) * | 2018-08-03 | 2020-02-06 | Brown University | Compositions and methods for improving the bioavailability of glp1 and analogues thereof |
Also Published As
Publication number | Publication date |
---|---|
CN104107165B (zh) | 2018-11-30 |
CN104107165A (zh) | 2014-10-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
RU2422134C1 (ru) | Композиция биоразлагающихся микросфер, пригодная для контролируемого высвобождения контролирующего уровень глюкозы пептида, и ее состав | |
KR101701544B1 (ko) | 폴리옥사졸린 및 생리활성제를 포함하는 약물 전달 시스템 | |
JP5933025B2 (ja) | 投薬を制御放出又は徐放するためのミクロスフィア | |
RU2409348C2 (ru) | Лекарственные составы с контролируемым высвобождением, основанные на блок-сополимерах | |
WO2013189282A1 (zh) | 多肽药物缓释微球制剂及其制备方法 | |
JPH06172208A (ja) | 医薬物質を持続的に制御して放出できる組成物およびその製造方法 | |
JP2012513984A (ja) | 水難溶性薬物を含有する高分子ミセル組成物の製造方法 | |
EP4104820A2 (en) | Pharmaceutical composition comprising sustained-release microspheres including glp-1 analogue or pharmaceutically acceptable salt thereof | |
WO2003004024A1 (fr) | Microspheres injectables a liberation prolongee de composes d'huperzine a | |
JP7366544B2 (ja) | 非経口投与用の生分解性ポリマーミクロスフェア組成物 | |
WO2010119455A2 (en) | An injectable sustained release pharmaceutical composition | |
KR20220112737A (ko) | 리바스티그민을 포함하는 장기지속형 제제 및 이의 제조방법 | |
CN113018277B (zh) | 注射用缓释制剂及其制备方法 | |
ES2324009A1 (es) | Composicion farmaceutica de liberacion sostenida de somatostatina o un analogo suyo. | |
JP5425890B2 (ja) | 難溶性薬物を含む均一なサイズの高分子ナノ粒子製造方法 | |
WO2014169725A1 (zh) | 一种艾塞那肽微球制剂、其制备方法及其应用 | |
US11911508B2 (en) | Microparticles containing dutasteride, and preparation method therefor | |
WO2019214715A1 (zh) | 一种美洛昔康组合物、制剂及其制备方法与应用 | |
EP1778290A1 (fr) | Utilisation du dipalmitostearate de glycerol pour ameliorer la biodisponibilite de principes actifs proteiques en formulations injectables sous-cutanees ou intramusculaires | |
JP6530480B2 (ja) | 微小インスリン、微小インスリン類似体及びそれらの製造方法 | |
JP7194208B2 (ja) | インスリン及びインスリン類似体の高純度吸入粒子、並びにそれらの高効率の製造方法 | |
US20240189234A1 (en) | Silicon particles for drug delivery | |
RU2716706C1 (ru) | Способ получения полимерсодержащей композиции силибина | |
WO2014007239A1 (ja) | アムホテリシンb含有組成物 | |
KR20230157365A (ko) | 루라시돈을 포함하는 마이크로스피어 제제 및 이의 제조 및 사용 방법 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 14785156 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 14785156 Country of ref document: EP Kind code of ref document: A1 |