CN102113996A - Oral formulations containing protein or peptide, and preparation method and application thereof - Google Patents
Oral formulations containing protein or peptide, and preparation method and application thereof Download PDFInfo
- Publication number
- CN102113996A CN102113996A CN2011100441458A CN201110044145A CN102113996A CN 102113996 A CN102113996 A CN 102113996A CN 2011100441458 A CN2011100441458 A CN 2011100441458A CN 201110044145 A CN201110044145 A CN 201110044145A CN 102113996 A CN102113996 A CN 102113996A
- Authority
- CN
- China
- Prior art keywords
- weight portion
- emulsion
- fatty acid
- weight
- protein
- 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
- 238000002360 preparation method Methods 0.000 title claims abstract description 49
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 41
- 108090000623 proteins and genes Proteins 0.000 title claims abstract description 41
- 102000004169 proteins and genes Human genes 0.000 title claims abstract description 40
- 239000000203 mixture Substances 0.000 title abstract description 29
- 238000009472 formulation Methods 0.000 title abstract description 21
- 239000000839 emulsion Substances 0.000 claims abstract description 82
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 31
- 239000003995 emulsifying agent Substances 0.000 claims abstract description 24
- 150000002711 medium chain fatty acid esters Chemical class 0.000 claims abstract description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000003814 drug Substances 0.000 claims description 31
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound 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 claims description 30
- 229920001184 polypeptide Polymers 0.000 claims description 29
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 24
- 102000004877 Insulin Human genes 0.000 claims description 20
- 108090001061 Insulin Proteins 0.000 claims description 20
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 18
- 210000004369 blood Anatomy 0.000 claims description 18
- 239000008280 blood Substances 0.000 claims description 18
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 17
- 239000000194 fatty acid Substances 0.000 claims description 17
- 229930195729 fatty acid Natural products 0.000 claims description 17
- 150000004665 fatty acids Chemical class 0.000 claims description 17
- 229940079593 drug Drugs 0.000 claims description 16
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims description 16
- 229940125396 insulin Drugs 0.000 claims description 15
- 239000012071 phase Substances 0.000 claims description 15
- 239000003921 oil Substances 0.000 claims description 14
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 13
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 claims description 12
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](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)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 claims description 12
- 102400000322 Glucagon-like peptide 1 Human genes 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 229930003427 Vitamin E Natural products 0.000 claims description 12
- 238000004108 freeze drying Methods 0.000 claims description 12
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 12
- 150000003904 phospholipids Chemical class 0.000 claims description 12
- 229940083466 soybean lecithin Drugs 0.000 claims description 12
- 239000011709 vitamin E Substances 0.000 claims description 12
- 235000019165 vitamin E Nutrition 0.000 claims description 12
- 229940046009 vitamin E Drugs 0.000 claims description 12
- 108090000445 Parathyroid hormone Proteins 0.000 claims description 11
- DCXXMTOCNZCJGO-UHFFFAOYSA-N Glycerol trioctadecanoate Natural products CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 claims description 10
- 102000003982 Parathyroid hormone Human genes 0.000 claims description 10
- 150000004667 medium chain fatty acids Chemical class 0.000 claims description 10
- -1 medium-chain fatty acid propylene glycol ester Chemical class 0.000 claims description 10
- 239000000199 parathyroid hormone Substances 0.000 claims description 10
- 229960001319 parathyroid hormone Drugs 0.000 claims description 10
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 10
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 claims description 8
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 8
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 8
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 claims description 7
- 108060001064 Calcitonin Proteins 0.000 claims description 7
- 102000055006 Calcitonin Human genes 0.000 claims description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 7
- 239000000872 buffer Substances 0.000 claims description 7
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 claims description 7
- 229960004015 calcitonin Drugs 0.000 claims description 7
- 206010012601 diabetes mellitus Diseases 0.000 claims description 7
- 229950007687 macrogol ester Drugs 0.000 claims description 7
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 7
- 229920000053 polysorbate 80 Polymers 0.000 claims description 7
- 229920001661 Chitosan Polymers 0.000 claims description 6
- 239000002202 Polyethylene glycol Substances 0.000 claims description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 6
- 239000004530 micro-emulsion Substances 0.000 claims description 6
- 229920001993 poloxamer 188 Polymers 0.000 claims description 6
- 229940044519 poloxamer 188 Drugs 0.000 claims description 6
- 229920001223 polyethylene glycol Polymers 0.000 claims description 6
- 102000018997 Growth Hormone Human genes 0.000 claims description 5
- 108010051696 Growth Hormone Proteins 0.000 claims description 5
- 208000001132 Osteoporosis Diseases 0.000 claims description 5
- YAJCHEVQCOHZDC-QMMNLEPNSA-N actrapid Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3N=CNC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@H](C)CC)[C@H](C)CC)[C@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C(N)=O)C1=CNC=N1 YAJCHEVQCOHZDC-QMMNLEPNSA-N 0.000 claims description 5
- 125000005456 glyceride group Chemical group 0.000 claims description 5
- 239000000122 growth hormone Substances 0.000 claims description 5
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 5
- 239000001384 succinic acid Substances 0.000 claims description 5
- 239000004471 Glycine Substances 0.000 claims description 4
- 101000976075 Homo sapiens Insulin Proteins 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
- 239000004698 Polyethylene Substances 0.000 claims description 4
- 239000003963 antioxidant agent Substances 0.000 claims description 4
- 230000003078 antioxidant effect Effects 0.000 claims description 4
- 235000006708 antioxidants Nutrition 0.000 claims description 4
- 239000008346 aqueous phase Substances 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 239000001913 cellulose Substances 0.000 claims description 4
- 229920002678 cellulose Polymers 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- PBGKTOXHQIOBKM-FHFVDXKLSA-N insulin (human) Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 PBGKTOXHQIOBKM-FHFVDXKLSA-N 0.000 claims description 4
- 239000007951 isotonicity adjuster Substances 0.000 claims description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 4
- 229920000573 polyethylene Polymers 0.000 claims description 4
- 229940051841 polyoxyethylene ether Drugs 0.000 claims description 4
- 229920000056 polyoxyethylene ether Polymers 0.000 claims description 4
- 239000000377 silicon dioxide Substances 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 claims description 3
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 102000002322 Egg Proteins Human genes 0.000 claims description 3
- 108010000912 Egg Proteins Proteins 0.000 claims description 3
- 241000287828 Gallus gallus Species 0.000 claims description 3
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 claims description 3
- 239000008367 deionised water Substances 0.000 claims description 3
- 229910021641 deionized water Inorganic materials 0.000 claims description 3
- 239000000787 lecithin Substances 0.000 claims description 3
- 235000010445 lecithin Nutrition 0.000 claims description 3
- 229940067606 lecithin Drugs 0.000 claims description 3
- 235000019359 magnesium stearate Nutrition 0.000 claims description 3
- 210000004681 ovum Anatomy 0.000 claims description 3
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- 235000012239 silicon dioxide Nutrition 0.000 claims description 3
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 claims description 2
- 230000021736 acetylation Effects 0.000 claims description 2
- 238000006640 acetylation reaction Methods 0.000 claims description 2
- 239000004359 castor oil Substances 0.000 claims description 2
- 235000019438 castor oil Nutrition 0.000 claims description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 2
- 229940074046 glyceryl laurate Drugs 0.000 claims description 2
- 239000002609 medium Substances 0.000 claims description 2
- YUPOCHDBBHTUBJ-UHFFFAOYSA-N nonadecan-10-one Chemical compound CCCCCCCCCC(=O)CCCCCCCCC YUPOCHDBBHTUBJ-UHFFFAOYSA-N 0.000 claims description 2
- 230000006320 pegylation Effects 0.000 claims description 2
- 229920001992 poloxamer 407 Polymers 0.000 claims description 2
- 229940044476 poloxamer 407 Drugs 0.000 claims description 2
- OGBMKVWORPGQRR-UMXFMPSGSA-N teriparatide Chemical compound C([C@H](NC(=O)[C@H](CCSC)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)C(C)C)[C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CNC=N1 OGBMKVWORPGQRR-UMXFMPSGSA-N 0.000 claims description 2
- VLPFTAMPNXLGLX-UHFFFAOYSA-N trioctanoin Chemical compound CCCCCCCC(=O)OCC(OC(=O)CCCCCCC)COC(=O)CCCCCCC VLPFTAMPNXLGLX-UHFFFAOYSA-N 0.000 claims description 2
- 239000002245 particle Substances 0.000 abstract description 9
- 230000001804 emulsifying effect Effects 0.000 abstract description 5
- 238000009826 distribution Methods 0.000 abstract description 2
- 235000018102 proteins Nutrition 0.000 description 28
- 241000700159 Rattus Species 0.000 description 26
- 238000012360 testing method Methods 0.000 description 15
- 238000002347 injection Methods 0.000 description 13
- 239000007924 injection Substances 0.000 description 13
- 239000000243 solution Substances 0.000 description 12
- 238000000034 method Methods 0.000 description 7
- 210000002303 tibia Anatomy 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 210000002784 stomach Anatomy 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000000693 micelle Substances 0.000 description 5
- 210000001672 ovary Anatomy 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 230000002146 bilateral effect Effects 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 235000011167 hydrochloric acid Nutrition 0.000 description 4
- 230000008521 reorganization Effects 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- 239000004094 surface-active agent Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000003623 enhancer Substances 0.000 description 3
- 229940125532 enzyme inhibitor Drugs 0.000 description 3
- 239000002532 enzyme inhibitor Substances 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 239000007929 subcutaneous injection Substances 0.000 description 3
- 238000010254 subcutaneous injection Methods 0.000 description 3
- 238000010998 test method Methods 0.000 description 3
- 239000003643 water by type Substances 0.000 description 3
- JVKUCNQGESRUCL-UHFFFAOYSA-N 2-Hydroxyethyl 12-hydroxyoctadecanoate Chemical compound CCCCCCC(O)CCCCCCCCCCC(=O)OCCO JVKUCNQGESRUCL-UHFFFAOYSA-N 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 208000035126 Facies Diseases 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229920001304 Solutol HS 15 Polymers 0.000 description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 230000037182 bone density Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 210000003022 colostrum Anatomy 0.000 description 2
- 235000021277 colostrum Nutrition 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 238000001647 drug administration Methods 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 210000003405 ileum Anatomy 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 2
- 239000003094 microcapsule Substances 0.000 description 2
- 239000004005 microsphere Substances 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 2
- 235000019799 monosodium phosphate Nutrition 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000000575 pesticide Substances 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- 229940001482 sodium sulfite Drugs 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 239000000811 xylitol Substances 0.000 description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 2
- 229960002675 xylitol Drugs 0.000 description 2
- 235000010447 xylitol Nutrition 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- IYMAXBFPHPZYIK-BQBZGAKWSA-N Arg-Gly-Asp Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O IYMAXBFPHPZYIK-BQBZGAKWSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 241000972773 Aulopiformes Species 0.000 description 1
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 101150071808 PTHLH gene Proteins 0.000 description 1
- 102100036893 Parathyroid hormone Human genes 0.000 description 1
- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 1
- 101710176384 Peptide 1 Proteins 0.000 description 1
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 description 1
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 description 1
- 244000184734 Pyrus japonica Species 0.000 description 1
- 241001620634 Roger Species 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- VLSOAXRVHARBEQ-UHFFFAOYSA-N [4-fluoro-2-(hydroxymethyl)phenyl]methanol Chemical compound OCC1=CC=C(F)C=C1CO VLSOAXRVHARBEQ-UHFFFAOYSA-N 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 239000008293 association colloid Substances 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 238000010523 cascade reaction Methods 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 238000001246 colloidal dispersion Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 235000021245 dietary protein Nutrition 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 210000001842 enterocyte Anatomy 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000013221 female mouse model Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 1
- 235000003969 glutathione Nutrition 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 238000000703 high-speed centrifugation Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000002433 hydrophilic molecules Chemical class 0.000 description 1
- 125000001165 hydrophobic group Chemical group 0.000 description 1
- 239000000859 incretin Substances 0.000 description 1
- MGXWVYUBJRZYPE-YUGYIWNOSA-N incretin Chemical class C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=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](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)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)[C@H](C)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=C(O)C=C1 MGXWVYUBJRZYPE-YUGYIWNOSA-N 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 230000003870 intestinal permeability Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000002398 materia medica Substances 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 235000011837 pasties Nutrition 0.000 description 1
- 229960002275 pentobarbital sodium Drugs 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- RWPGFSMJFRPDDP-UHFFFAOYSA-L potassium metabisulfite Chemical compound [K+].[K+].[O-]S(=O)S([O-])(=O)=O RWPGFSMJFRPDDP-UHFFFAOYSA-L 0.000 description 1
- 229940043349 potassium metabisulfite Drugs 0.000 description 1
- 235000010263 potassium metabisulphite Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- 235000019515 salmon Nutrition 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000001338 self-assembly Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
Images
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
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
-
- 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
- A61K38/23—Calcitonins
-
- 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
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/27—Growth hormone [GH], i.e. somatotropin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K38/28—Insulins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/29—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Endocrinology (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Zoology (AREA)
- Diabetes (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Rheumatology (AREA)
- Obesity (AREA)
- Emergency Medicine (AREA)
- Hematology (AREA)
- Dispersion Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention belongs to the field of pharmacology and pharmaceutics and relates to an oral formulation containing proteins or peptides and a preparation method and application thereof, and particularly relates to an emulsion formulation which contains proteins or peptides, a water phase, an oil phase and an emulsifier. The invention is characterized in that the oil phase contains medium-chain fatty acid esters, and the emulsifier comprises an emulsifier with the HLB value more than 12. The emulsion formulation not only retains a high bioavailability but also has an excellent emulsifying property. When the emulsion formulation is diluted with water, the emulsion formulation can uniformly disperse in water to form emulsion droplets, and the particle size distribution of the emulsion droplets is relatively uniform so that the emulsion is not turbid.
Description
Technical field
The invention belongs to materia medica and galenic pharmacy field, relate to a kind of oral formulations, Preparation Method And The Use that contains protein or polypeptide.
Background technology
Insulin (insulin), parathyroid hormone (parathyroid hormone), calcitonin (calcitonin), growth hormone (growth hormone), incretin sample peptide-1 protein or polypeptide drugs such as (GLP-1) are the important drugs in the clinical treatment.But the common feature of this class medicine is the oral administration nearly unavailable, needs frequent drug administration by injection.
Protein and peptide class medicine has limited their application owing to lack oral administration route in clinical, in the gastrointestinal tract multiple effects limit such as the degraded of protease and enterocyte barrier action the oral administration biaavailability of this class medicine.In decades, research worker adopts strategies such as covalent modification, enzyme inhibitor, absorption enhancer, microcapsules and microsphere parcel, W/O (Water-In-Oil) Emulsion, in the hope of solving the low problem of protein and peptide class drug oral bioavailability.Carino?G.P.et?al(2000)J.Control.Release.65：261-269；KathrynWehitehead，et?al(2004)J.Control.Release.98：37-45；YanPan，et?al(2002)Int.J.Pharm?249：139-147；Nerurkar?M.M.etal(1996)Pharm.Res.13：528-534；Marschutz?M.K.et?al(2000)Biomaterials?21：1499-1507；Christopher?J.H.et?al(1997)Adv.Drug.Deliver.Rev.25：71-89；Jeff?Wang，et?al(2003)J.Control.Release.88：369-380；Roger?R.C.New，et?al(1997)Adv.Drug.Deliver.Rev.25：59-69；Anja?Graf，et?al(2008)Int.J.Pharm.350：351-360；R.Neslihan?Gursoy?et?al(2004)Biomed.Pharmacother.58：173-182；CN01115327.X，US4849405，US5824638。
Above-mentioned strategy exists significantly not enough, can reduce pharmaceutically active as covalent modification, and may change pharmacology, the toxicity of drug molecule, brings high preparation cost and serious potential safety hazard; The enzyme inhibitor can effectively be avoided the hydrolysis of protease, but enzyme inhibitor has also influenced the digestion of food proteins simultaneously, takes enlargement or the hypertrophy of digesting and assimilating disorder even pancreas with causing for a long time; Absorption enhancer might cell membrane cause irreversible destruction when increasing intestinal permeability, take for a long time to cause membrane poisoning; Often need the participation of organic solvent in the microcapsules and microsphere preparation engineering, and need steps such as high speed centrifugation, increased the complexity of technology.
There are some researches show in addition, medium-chain fatty acid can be used as substrate initiation cascade reaction and finally opens iuntercellular and closely connects, thereby increase the permeability (Masahiro Hayashi, etal (1997) ADV.DRUG.DELIVER.REV.28:191-204.) of intestinal.People such as Panayiostis with medium chain length fatty acid triglyceride as absorption enhancer, studied assimilation effect (Panayiostis P.Constantinides, etal (1994) the PHARM RES 11:1385-90 of w/o type microemulsion formulation to the hydrophilic small molecules medicine; Panayiostis P.Constantinides, et al (1996) PHARM RES 13:210-215.), but its used drug molecule quantity not sufficient 700 dalton, and the direct oral artifact availability of such medicine can reach 2%, has essential distinction with protein and peptide class medicine.Through further research, P.Constantinides is by high HLB value (hydrophile-lipophile balance value) surfactant of use in conjunction and low HLB value surfactant, obtained to comprise the self emulsifying W/O preparation of different hydrophilic molecules such as RGD, calcitonin, insulin, but its oral administration biaavailability effect there is not disclosed report.People such as Mao-BoCheng have prepared the oral w/o type microemulsion formulation (Mao-Bo Cheng, etal (2008) J.Control.Release.129:41-48) that contains Lumbrukinase.
Above-mentioned document is a carrier with the microemulsion, has realized the parcel to protein or polypeptide drugs, is exactly that these preparation emulsifying effectivenesses are poor but there is the problem of a maximum, and the size great disparity is very big, and layering has appearred in (dilution back) emulsion after the emulsifying; Perhaps limpid zone is narrow and small, can not homodisperse after the dilution, thus can limit its oral administration biaavailability effect.Even may cause the emulsion droplet breakdown of emulsion, the protein and peptide quasi-molecule that is wrapped in the internal layer aqueous phase can be fast released out, by the proteasome degradation in the gastrointestinal tract, or with material such as medium chain fatty acid ester because the problem of incompatibility, wadding collection, precipitation take place in the protein and peptide quasi-molecule, cause pharmaceutically active to lose and be difficult to and are absorbed by body.
Summary of the invention
The inventor is by a large amount of tests and performing creative labour, be surprised to find, by selecting high HLB value surfactant and medium chain fatty acid ester (when adding phospholipid especially again) for use, the compatibility of the Emulsion that contains protein or polypeptide that obtains and stability are fine, Emulsion keeps excellent emulsifiability when keeping high bioavailability.And Emulsion is when being diluted by water, can homodisperse, and the emulsion droplet particle size distribution of generation is more even, can not cause emulsion unclear.Following invention is provided thus:
One aspect of the present invention relates to a kind of Emulsion, comprise protein or polypeptide, water, oil phase, emulsifying agent, it is characterized in that described oil phase contains medium chain fatty acid ester (for example medium chain length fatty acid triglyceride), and described emulsifying agent comprises that the HLB value is greater than 12 emulsifying agent; Particularly, described oil phase is medium chain fatty acid ester (a for example medium chain length fatty acid triglyceride), and described emulsifying agent is the HLB value greater than 12 emulsifying agent.
Described protein or polypeptide are the effective ingredient (active ingredient) or the active component of Emulsion.Described protein or polypeptide can separate acquisition from living organism, also can obtain by the genetic engineering means (for example gene recombinaton) or the mode of chemosynthesis.
According to each described Emulsion of the present invention, wherein, described protein or polypeptide are calcitonin, insulin, GLP-1, parathyroid hormone, parathyroid hormone 1-84, parathyroid hormone 1-34 or growth hormone.In some embodiments, described calcitonin comprises salmon, Anguillar japonica and people's calcitonin; Described insulin comprises the insulin of pig, cattle, people and reorganization; Described GLP-1 comprises reorganization and synthetic GLP-1; Described parathyroid hormone comprises human pthrp hormone 1-84, reorganization and/or synthetic parathyroid hormone 1-34; Described long hormone comprises the growth hormone of pig, cattle, human body and reorganization.
According to each described Emulsion of the present invention; wherein, described medium chain fatty acid ester is medium chain length fatty acid triglyceride, acetylation medium chain length fatty acid triglyceride, medium-chain fatty acid propylene glycol ester, medium-chain fatty acid butanediol ester or the medium-chain fatty acid macrogol ester of medium chain length fatty acid triglyceride, Pegylation.Described medium chain length fatty acid triglyceride can be in medium-chain fatty acid monoglyceride, medium-chain fatty acid diglyceride and the MCT Oil one or more.Medium-chain fatty acid in the described medium chain length fatty acid triglyceride can be combined in any one or a plurality of hydroxy position in the glycerol molecule, when forming medium-chain fatty acid diglyceride or MCT Oil, bonded medium-chain fatty acid molecule can be identical or different on the hydroxyl in the glycerol molecule.In the present invention, medium-chain fatty acid is meant the fatty acid of carbon number 6-12, and it can be saturated, also can be undersaturated, can be straight chain, also can be side chain.Particularly, described medium-chain fatty acid is sad and/or capric acid.
In one embodiment of the invention, described medium chain fatty acid ester is monoglyceride, diglyceride and/or the triglyceride of the fatty acid of carbon number 6-12; More specifically, for being selected from sad caprin, Polyethylene Glycol caprylic/capric glyceride, caprylin, the caprin one or more.
According to each described Emulsion of the present invention, wherein, described HLB value greater than 12 emulsifying agent for being selected from poloxamer 188, poloxamer 407, polysorbas20, Tween 80, polyethyleneglycol-12-hydroxy stearin, polyoxyethylene ether (35) Oleum Ricini, polyoxyethylene ether (40) castor oil hydrogenated, tocofecol succinic acid macrogol ester, Polyethylene Glycol-32-glyceryl laurate ester, the Polyethylene Glycol-32-tristerin one or more.
According to each described Emulsion of the present invention, wherein, described protein or polypeptide are the 0.01-1 weight portion, and described medium chain fatty acid ester (for example medium chain length fatty acid triglyceride) is the 50-1000 weight portion, and described HLB value is the 20-2000 weight portion greater than 12 emulsifying agent; Particularly, described protein or polypeptide are the 0.01-0.5 weight portion, and described medium chain fatty acid ester (for example medium chain length fatty acid triglyceride) is the 100-500 weight portion, and described HLB value is the 50-1000 weight portion greater than 12 emulsifying agent; More specifically, described protein or polypeptide are the 0.01-0.3 weight portion, and described medium chain fatty acid ester (for example medium chain length fatty acid triglyceride) is the 100-300 weight portion, and described HLB value is the 50-500 weight portion greater than 12 emulsifying agent.
According to each described Emulsion of the present invention, preferably, described Emulsion also contains phospholipid, and the mol ratio of phospholipid and protein or polypeptide is 10: 1 to 1000: 1.The mol ratio of described phospholipid and protein or polypeptide is preferably 20: 1 to 500: 1, more preferably 60: 1 to 200: 1.Described phospholipid is preferably soybean lecithin and/or Ovum Gallus domesticus Flavus lecithin.
According to each described Emulsion of the present invention, it also comprises acceptable accessories, for example disperse medium, isotonic agent, antioxidant, freeze drying protectant or pH regulator agent.
According to each described Emulsion of the present invention, wherein, described disperse medium is selected from one or more in chitosan, silicon dioxide, Magnesiumaluminumsilicate, sodium carboxymethyl cellulose, cross-linked cellulose sodium, cross-linking sodium carboxymethyl cellulose, magnesium sulfate, magnesium stearate, PEG400 and the glycerol.
According to each described Emulsion of the present invention, wherein, described isotonic agent is selected from one or more in xylitol, sodium chloride, fructose, sorbitol and the glucose.
According to each described Emulsion of the present invention, wherein, described antioxidant is selected from one or more in L-cysteine hydrochloride, sodium sulfite, sodium sulfite, propyl gallate, glutathion, sodium pyrosulfite, potassium metabisulfite and the vitamin E.
According to each described Emulsion of the present invention, wherein, described freeze drying protectant is selected from one or more in sucrose, lactose, trehalose, glucose, glycine, arginine and the xylitol.
According to each described Emulsion of the present invention, wherein, described pH value regulator is selected from one or more in hydrochloric acid, sulphuric acid, lactic acid, malic acid, acetic acid, citric acid, phosphoric acid, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydrogen phosphate and the sodium dihydrogen phosphate.
According to each described Emulsion of the present invention, it is a microemulsion.Microemulsion is meant by water, oil, emulsifying agent to be formed, isotropism, transparent, thermodynamically stable dispersion, and particle diameter is less than 500nm usually.
According to each described Emulsion of the present invention, it passes through oral administration.
According to each described Emulsion of the present invention, its each component and content are as follows:
Recombinant human insulin 0.008-0.012 weight portion
Hydrochloric acid is an amount of
Chitosan 0.04-0.06 weight portion
Normal saline 0.4-0.6 weight portion
MCT Oil (Crodamol for example
GTCC) 0.8-1.2 weight portion
Polyethyleneglycol-12-hydroxy stearin (for example
Solutol HS15, BASF) 0.8-1.2 weight portion
Tween 80 1.2-1.8 weight portion
Vitamin E 0.08-0.12 weight portion;
The invention still further relates to the purposes of this Emulsion in the medicine of preparation treatment or prevent diabetes or blood sugar lowering.The invention still further relates to the method for a kind of treatment or prevent diabetes or blood sugar lowering, comprise the step of this Emulsion that gives effective dose.In one embodiment of the invention, the component of described Emulsion and content are as follows:
Recombinant human insulin's 0.01 weight portion
Hydrochloric acid is an amount of
Chitosan 0.05 weight portion
Normal saline 0.5 weight portion
MCT Oil (Crodamol for example
GTCC) 1 weight portion
Polyethyleneglycol-12-hydroxy stearin (for example
Solutol HS15, BASF) 1 weight portion
Tween 80 1.5 weight portions
Vitamin E 0.1 weight portion.
According to each described Emulsion of the present invention, its each component and content are as follows:
The invention still further relates to the purposes of this Emulsion in the medicine of preparation treatment or prevent diabetes or blood sugar lowering.The invention still further relates to the method for a kind of treatment or prevent diabetes or blood sugar lowering, comprise the step of this Emulsion that gives effective dose.In one embodiment of the invention, the component of described Emulsion and content are as follows:
According to each described Emulsion of the present invention, its each component and content are as follows:
The invention still further relates to the purposes of this Emulsion in the medicine of preparation treatment or prevention of osteoporosis.The invention still further relates to the method for a kind of treatment or prevention of osteoporosis, comprise the step of this Emulsion that gives effective dose.In one embodiment of the invention, the component of described Emulsion and content are as follows:
According to each described Emulsion of the present invention, its each component and content are as follows:
The invention still further relates to the purposes of this Emulsion in the medicine of preparation treatment or prevent diabetes or blood sugar lowering.The invention still further relates to the method for a kind of treatment or prevent diabetes or blood sugar lowering, comprise the step of this Emulsion that gives effective dose.In one embodiment of the invention, the component of described Emulsion and content are as follows:
According to each described Emulsion of the present invention, it is freeze-dried emulsion (lyophilized formulations).To those skilled in the art; can make the lyophilized formulations of above-mentioned Emulsion, for example in above-mentioned Emulsion, add an amount of freeze drying protectant, then by lyophilization (temperature-40 ℃ for example; working vacuum degree 30pa) moisture is removed in the back, thereby obtains exsiccant protein or polypeptide freeze-dried emulsion.Emulsion does not contain water after the lyophilizing, can make whole dosage forms such as tablet, capsule.
The present invention the preparation method of Emulsion, for example can adopt following step:
1) following steps A or B:
A. under 4-25 ℃ of condition, protein or peptide molecule are soluble in the aqueous phase;
B. the phosphatide complexes for preparing protein or polypeptide;
2) under 20-70 ℃ of condition, medium chain fatty acid ester, HLB value are mixed mutually greater than 12 emulsifying agent, and under the 200-800rmp stirring condition, continue to stir, be the transparent clear shape until whole system;
3) under 4-37 ℃ of condition, the step 1) product is joined step 2) in the product, and under the 200-800rmp condition, continue to stir, until the even preparation that forms transparent clear, the final Emulsion that obtains to contain protein or polypeptide drugs.
About steps A, alternatively, the composition that is soluble in the aqueous phase also comprises pH regulator agent and/or isotonic agent.
About step B,, can prepare described phosphatide complexes for to those skilled in the art.For example adopt in the following method: respectively phospholipid and albumen are dissolved in organic facies and water, after the mixing, lyophilization (40 to-150 ℃, in addition lower; Pressure is lower than-200 handkerchiefs for being lower than-100 handkerchiefs, perhaps is lower than-300 handkerchiefs; Freeze-drying time is more than 12 hours, and for example 12-24 hour perhaps is more than 24 hours, for example 24-48 hour), obtain the albumen phosphatide complexes.In preferred embodiments, the mol ratio of phospholipid and protein or polypeptide is 10: 1 to 1000: 1.The mol ratio of described phospholipid and protein or polypeptide more preferably 20: 1 to 500: 1, more preferably 60: 1 to 200: 1.Described phospholipid is preferably soybean lecithin and/or Ovum Gallus domesticus Flavus lecithin.Organic facies is dichloromethane, acetone or dimethyl sulfoxide, preferred dimethyl sulfoxide.
About step 2), alternatively, the mixed mutually deionized water that also comprises; Alternatively, also comprise disperse medium and/or antioxidant.
In one embodiment of the invention, described preparation method also comprises step 4): the Emulsion that makes in the step 3) is carried out lyophilizing, obtain freeze-dried emulsion.Step B) and the step of freeze drying that relates in the step 4) freeze drying protectant that can use the present invention to describe.
In the present invention, term " micelle (micelles) " is meant that in solution what formed by some solute molecules or ion association is that kernel, hydrophilic group are the molecular assembly aggregation of shell with the hydrophobic group.Micelle is a kind of colloidal dispersion system, belongs to a class association colloid.When the amphipathy macromolecule material disperseed to reach critical micelle concentration (CMC) in solution, the molecular association self assembly formed micelle.
The beneficial effect of the invention
Be that non-ionic surface active agent more than 12 is an emulsifying agent by selecting HLB value (hydrophile-lipophile balance value) for use in the present invention, medium chain fatty acid ester is an oil phase, the aqueous solution that contains the protein and peptide medicine is a water, prepare good dispersion, particle diameter is even, the Emulsion of emulsifiability excellent protein polypeptide.Distinguishing feature of the present invention, it is the problem that has solved protein and peptide class Emulsion emulsifiability, can significantly increase the oral administration biaavailability of protein or polypeptide drugs, has application prospect, and preparation technology is simple, be suitable for suitability for industrialized production, the dosage form of this product can be Emulsion, micellar solution, self emulsifying drug delivery system, pasty masses or pressed powder.
Description of drawings
Fig. 1: phasor during the rat serum saccharifying after the ileum administration.
Fig. 2: PTH1-34 blood drug level.
Fig. 3: the PTH1-34 test of pesticide effectiveness.For each group among four groups of proximal tibia BMD, proximal tibia BMC, tibia BMD, the tibia BMD, four column figures are from left to right represented oral group, injection group, matched group, sham operated rats respectively.
The specific embodiment
Below in conjunction with embodiment embodiment of the present invention are described in detail, but it will be understood to those of skill in the art that the following example only is used to illustrate the present invention, and should not be considered as limiting scope of the present invention.Unreceipted actual conditions person among the embodiment carries out according to the condition of normal condition or manufacturer's suggestion.The unreceipted person of production firm of agents useful for same or instrument, being can be by the conventional products of commercial acquisition.
Embodiment 1: the preparation of Macrulin (sample 1)
It is composed as follows:
The preparation method of said preparation is as follows:
1) under the room temperature, the Iletin II (Lilly) of above-mentioned weight is dissolved in 0.2 gram PBS buffer, adds an amount of sodium hydroxide, the gained solution stirring is to clarification, A solution;
2) under the room temperature, the soybean lecithin of above-mentioned weight is dissolved in the dimethyl sulfoxide of 60ml, after stirring to clarify, add the A solution in the step 1), under the 300r/min condition, stir 5min, be placed into 30min in the liquid nitrogen subsequently, products therefrom obtains Iletin II (Lilly) soybean lecithin complex after lyophilization;
3) under 70 ℃, glycine, the pool Luo Samu 188 of above-mentioned weight is dissolved in residue PBS buffer,, mixes and be stirred to transparent clear with the Polyethylene Glycol caprylic/capric glyceride of above-mentioned weight;
4) under the room temperature, Iletin II (Lilly) soybean lecithin complex joins in the product in the step 3), under the 200r/min rotating speed mixture is stirred 15min;
5) under the room temperature, after the silicon dioxide of above-mentioned weight, cross-linked cellulose sodium, stearic acid mixed, under the 200r/min rotating speed, dropwise add the product of step 4), improve rotating speed subsequently to 300r/min, and keep 30min; Products therefrom finally obtains insulin oral preparation after lyophilization (temperature-40 ℃, working vacuum degree 30pa), be sample 1.
Sample 1 can be made whole dosage forms such as tablet, capsule.
Although it will be understood by those skilled in the art that the unit of weight of each component among the embodiment 1 is gram, also can be understood as weight portion, the part by weight among the embodiment 1 above promptly satisfying between each component just can.
Embodiment 2: the preparation of insulin oral preparation (sample 2)
It is composed as follows:
The preparation method of said preparation is as follows:
1) under the room temperature, Recombulin, chitosan are dissolved in normal saline, add appropriate hydrochloric acid, stir to clarify, get A solution;
2) under 40 ℃,, mix and be stirred to transparent clear MCT Oil, polyethyleneglycol-12-hydroxy stearin, Tween 80 and the vitamin E of above-mentioned weight;
3) under the room temperature,, dropwise join step 2 with A solution) product in, under the 200r/min rotating speed, mixture is stirred to transparent clear, finally obtain insulin oral preparation, be sample 2.
Although it will be understood by those skilled in the art that the unit of weight of each component among the embodiment 2 is gram, also can be understood as weight portion, the part by weight among the embodiment 2 above promptly satisfying between each component just can.
Embodiment 3: the preparation of recombinant human parathyroid hormone 1-34 oral formulations (sample 3)
It is composed as follows:
The preparation method of said preparation is as follows:
1) under the room temperature, the PTH1-34 of above-mentioned weight is dissolved in the PBS buffer, stirs to clarify, A solution;
2) under 60 ℃,, mix and be stirred to transparent clear sad caprin, polyethyleneglycol-12-hydroxy stearin, tocofecol succinic acid macrogol ester, polysorbas20, the vitamin E of above-mentioned weight;
3) under the room temperature,, dropwise join step 2 with A solution) product in, under the 100r/min rotating speed, mixture is stirred 15min, finally obtain the PTH1-34 oral formulations, be sample 3.
Although it will be understood by those skilled in the art that the unit of weight of each component among the embodiment 3 is gram, also can be understood as weight portion, the part by weight among the embodiment 3 above promptly satisfying between each component just can.
The preparation of embodiment 4:GLP-1 oral formulations (sample 4)
It is composed as follows
The preparation method of said preparation is as follows:
1) under the room temperature, the GLP-1 of above-mentioned weight is dissolved in 5 gram deionized waters, the soybean lecithin of above-mentioned weight is dissolved in the dichloromethane of 30ml, after the biphase mixing, place liquid nitrogen 30min, lyophilization, products therefrom is a GLP-1 soybean phospholipid complex;
2) under 70 ℃,, mix and be stirred to transparent clear sad caprin, pool Luo Samu 188, the 5 gram deionized waters of above-mentioned weight;
3) under the room temperature, under the 500r/min rotating speed, GLP-1 soybean lecithin complex is added step 2) product in, continue to stir 5min, colostrum B;
4) under the room temperature, glycerol, Polyethylene Glycol, vitamin E with above-mentioned weight, mix with remaining 50 gram water, under the 500r/min rotating speed, dropwise add colostrum B, after continuing to stir 5min, handle (450bar circulates 5 times) through high pressure homogenizer (Italian Niro Soavi), the micellar solution of the final transparent clear that obtains, be the GLP-1 oral formulations, be sample 4.
Although it will be understood by those skilled in the art that the unit of weight of each component among the embodiment 4 is gram, also can be understood as weight portion, the part by weight among the embodiment 4 above promptly satisfying between each component just can.
Embodiment 5: the stability study of sample 2,3,4
Whether the stability of oral formulations sample 2,3,4 flocculent substance occurs or generation " oil-water " interface is judged by the perusal preparation.
The stability of insulin in the sample 1,2 adopts high performance liquid chromatography to study, and used chromatograph is Agilent 1200.
The chromatography eluant condition:
Mobile phase is linear gradient elution, and wherein mobile phase A is an acetonitrile, and Mobile phase B is 0.05mol/L sodium dihydrogen phosphate (pH3.0): the 0-10min mobile phase A rises to 50% from 20%, and Mobile phase B fades to 50% from 80%; The 11-15min mobile phase A fades to 80% from 50%, and Mobile phase B fades to 20% from 50%; The 21-25min mobile phase A fades to 20% from 80%, and Mobile phase B fades to 80% from 20%.Flow velocity 1.0mL/min, the detection wavelength is 214nm, 40 ℃ of column temperatures.
In 6 months probation, sample 2 preparations, sample 3 preparations, sample 4 preparations that are positioned over 4 ℃ do not produce macroscopic flocculent substance, do not produce " oil-water " interface yet.
Contrast high-efficient liquid phase chromatogram in addition, we find retention time, the peak area of sample 1,2 at its active ingredient insulin of different time (0,3m, 6m), and significant change does not all take place, and this just shows, under 4 ℃ of conditions, the gained sample can keep 6 months stability at least.
Embodiment 6: the changes of contents test of the ingredient of sample 1-4
The gained preparation is as for 4 ℃ of refrigerators, and 0 day, the 3rd month, the 6th month mensuration medicament contg after placement.Adopt the HPLC method to carry out the active constituents of medicine Determination on content, the result is as shown in table 1.
Table 1: the variation of sample 1-4 content of active component
Embodiment 7: Emulsion diluent particle diameter and outward appearance research
The sample 2,3 of embodiment 2, embodiment 3 preparations is placed 4 ℃ of refrigerators, and measures Emulsion particle diameter and the limpid situation of outward appearance in 0 day, the 3rd month, the 6th month.With the particle diameter that MalvernZetasizer 3000HSA Particle Size Analyzer detects, before the mensuration, sample 2,3 usefulness Millipore ultra-pure waters dilute 5,30,100 times respectively, and naked eyes whether measure each diluent outward appearance limpid.The result is shown in following table 2.
Table 2: the result of Emulsion diluent particle diameter and outward appearance
Embodiment 8: the insulin oral preparation drug efficacy study
Test group 1: body weight is the male SD rat of 180-220 gram scope, and 6, administration is the sample 1 of embodiment 1 preparation.
Test group 2: body weight is the male SD rat of 180-220 gram scope, and 6, administration is the sample 2 of embodiment 2 preparations.
Test method:
Be to begin test behind the male SD rat fasting 12h of 180-220 gram scope with body weight; Be that the pentobarbital sodium of 50mg is anaesthetized animal with dosage before the experiment.After treating Animal Anesthesia, by facing upward a mode it is bundled, and cuts an osculum at abdominal part, with administrator to the ileum administration.After the administration, sew up the incision, and 0.5,1,2,3, the 4h moment point, get blood by the tail vein, use Luo Shi blood sugar detection instrument to measure blood glucose and calculate every group in the average blood sugar values of 6 rats.Wherein administration is a sample 1 in the test group 1, and by insulin, dosage is 0.3mg/kg; Administration is a sample 2 in the test group 2, and by insulin, dosage is 1mg/kg.After the administration, rat blood sugar changes as shown in Figure 1.Fig. 1 show sample 1 and sample 2 all can reduce the blood glucose of rat effectively.
The filling stomach absorption test of embodiment 9:PTH1-34 oral formulations
Test group: body weight is the male SD rat of 180-220 gram scope, and 12, administration is the sample 3 of embodiment 3 preparations, the stomach administration.
Matched group: body weight is the male SD rat of 180-220 gram scope, and 10, administration is a PTH1-34PBS solution, subcutaneous injection.
Test method:
All rats begin test behind fasting 12h.Test group adopts the stomach administering mode, and matched group is selected the PTH1-34 injection for use.Stomach administration: adopt administrator,, the rat stomach is poured into the PTH1-34 oral formulations by 50 μ g/kg dosage in PTH1-34; Drug administration by injection: in PTH1-34, by 10 μ g/kg dosage, subcutaneous injection PTH1-34 injection.
After the administration 15,30,45,60,75,90,105mi n moment point, get blood by the tail vein, isolate serum and be equipped with and survey.PTH1-34 concentration PTH1-34 high sensitivity EIA test kit (U.S. Alpco Diagnostic in the serum, article No. 31-IPTHUU-E01) detects, this test kit only with external source PTH1-34 specific reaction, and do not react with the PTH of rat own, thereby institute can detected PTH1-34, is the PTH1-34 that enters after the administration in the rat blood.Irritating the stomach treated animal is 12, and the injection treated animal is 10.After the administration, PTH1-34 blood drug level changes as shown in Figure 2.Fig. 2 shows that behind the gastric infusion, PTH1-34 can enter rapidly in the rat body, and by blood drug level, the gastric infusion group is 6.73% with respect to the bioavailability of injection group.
The test of pesticide effectiveness of embodiment 10:PTH1-34 oral formulations
By setting up the female mouse model of castration, study of the influence of oral PTH1-34 preparation to animal bone density, bone mineral content.
Oral group: choose 6 of the female rats at 2 monthly ages, excise female Mus bilateral ovaries, administration is the sample 3 of embodiment 3 preparations, the administration of oral administration gavage mode.
The injection group: choose 6 of the female rats at 2 monthly ages, excise female Mus bilateral ovaries, administration is the sample 3 of embodiment 3 preparations, PTH1-34PBS injection, subcutaneous injection.
Matched group: choose 6 of the female rats at 2 monthly ages, excise female Mus bilateral ovaries, administration is the sample 3 of embodiment 3 preparations, not administration.
Sham operated rats: choose 5 of the female rats at 2 monthly ages, keep ovary, near the fat of the equal size spay, not administration.
Test method:
Choose the female rats at 2 monthly ages, be divided into castration group (neuter at random, by excision rat bilateral ovaries, comprise oral group, injection group, matched group) and sham operated rats, raised for 6 weeks, oral subsequently group and 8 weeks of injection group successive administration, administration is 6 days weekly, once a day, administration is preceding to rat fasting 10 hours.Wherein oral group dosage 100 μ g/kg (n=6), injection group dosage 10 μ g/kg (n=6), matched group (n=6), not administration of sham operated rats (n=5).Bone density (BMD), the bone mineral content (BMC) (the dual-energy x-ray absorption process detects, dual X-ray absorptimetry) of left side tibia, * P＜0.01, * * P＜0.05 are measured in the back then.The result as shown in Figure 3.
As shown in Figure 3, compare, through treatment, tibia of osteoporosis model rat and the proximal tibia BMD (g/cm of unit with matched group
2), BMC (g of unit) all has remarkable increase, this just shows, PTH1-34 injection and PTH1-34 oral formulations all can promote skeleton to generate, and osteoporosis is had significant curative effect.
Although the specific embodiment of the present invention has obtained detailed description, it will be understood to those of skill in the art that.According to disclosed all instructions, can carry out various modifications and replacement to those details, these change all within protection scope of the present invention.Four corner of the present invention is provided by claims and any equivalent thereof.
Claims (15)
1. an Emulsion comprises protein or polypeptide, water, oil phase, emulsifying agent, it is characterized in that, described oil phase contains medium chain fatty acid ester, and described emulsifying agent comprises that the HLB value is greater than 12 emulsifying agent.
2. Emulsion according to claim 1, wherein, described protein or polypeptide are calcitonin, insulin, GLP-1, parathyroid hormone, parathyroid hormone 1-84, parathyroid hormone 1-34 or growth hormone.
3. Emulsion according to claim 1, wherein, described medium chain fatty acid ester is medium chain length fatty acid triglyceride, acetylation medium chain length fatty acid triglyceride, medium-chain fatty acid propylene glycol ester, medium-chain fatty acid butanediol ester, the medium-chain fatty acid macrogol ester of medium chain length fatty acid triglyceride, Pegylation; Particularly, be monoglyceride, diglyceride and/or the triglyceride of the fatty acid of carbon number 6-12; More specifically, for being selected from sad caprin, Polyethylene Glycol caprylic/capric glyceride, caprylin, the caprin one or more.
4. Emulsion according to claim 1, wherein, described HLB value greater than 12 emulsifying agent for being selected from poloxamer 188, poloxamer 407, polysorbas20, Tween 80, polyethyleneglycol-12-hydroxy stearin, polyoxyethylene ether (35) Oleum Ricini, polyoxyethylene ether (40) castor oil hydrogenated, tocofecol succinic acid macrogol ester, Polyethylene Glycol-32-glyceryl laurate ester, the Polyethylene Glycol-32-tristerin one or more.
5. Emulsion according to claim 1, wherein, described protein or polypeptide are the 0.01-1 weight portion, and described medium chain fatty acid ester is the 50-1000 weight portion, and described HLB value is the 20-2000 weight portion greater than 12 emulsifying agent; Particularly, described protein or polypeptide are the 0.01-0.5 weight portion, and described medium chain fatty acid ester is the 100-500 weight portion, and described HLB value is the 50-1000 weight portion greater than 12 emulsifying agent; More specifically, described protein or polypeptide are the 0.01-0.3 weight portion, and described medium chain fatty acid ester is the 100-300 weight portion, and described HLB value is the 50-500 weight portion greater than 12 emulsifying agent.
6. Emulsion according to claim 1, wherein, described emulsifying agent also contains phospholipid.
7. Emulsion according to claim 6, wherein, the mol ratio of phospholipid and protein or polypeptide is 10: 1 to 1000: 1, is preferably 20: 1 to 500: 1, more preferably 60: 1 to 200: 1.
8. Emulsion according to claim 6, wherein, described phospholipid is soybean lecithin and/or Ovum Gallus domesticus Flavus lecithin.
9. according to each described Emulsion in the claim 1 to 8, it also comprises acceptable accessories, for example disperse medium, isotonic agent, antioxidant, freeze drying protectant or pH regulator agent.
10. Emulsion according to claim 2, its each component and content are shown in arbitrary group in the group of following (1)-(6):
(1)
Recombinant human insulin 0.008-0.012 weight portion
Hydrochloric acid is an amount of
Chitosan 0.04-0.06 weight portion
Normal saline 0.4-0.6 weight portion
MCT Oil 0.8-1.2 weight portion
Polyethyleneglycol-12-hydroxy stearin 0.8-1.2 weight portion
Tween 80 1.2-1.8 weight portion
Vitamin E 0.08-0.12 weight portion;
(2)
Recombinant human insulin's 0.01 weight portion
Hydrochloric acid is an amount of
Chitosan 0.05 weight portion
Normal saline 0.5 weight portion
MCT Oil 1 weight portion
Polyethyleneglycol-12-hydroxy stearin 1 weight portion
Tween 80 1.5 weight portions
Vitamin E 0.1 weight portion;
(3)
Iletin II (Lilly) 0.004-0.006 weight portion
Sodium hydroxide is an amount of
PBS buffer 0.8-1.2 weight portion
Polyethylene Glycol caprylic/capric glyceride 1.8-2.2 weight portion
Poloxamer 188 0.15-0.25 weight portions
Soybean lecithin 0.4-0.6 weight portion
Silicon dioxide 0.8-1.2 weight portion
Cross-linked cellulose sodium 0.1-0.14 weight portion
Magnesium stearate 0.013-0.017 weight portion
Glycine 0.25-0.35 weight portion;
(4)
Iletin II (Lilly) 0.005 weight portion
Sodium hydroxide is an amount of
PBS buffer 1 weight portion
Polyethylene Glycol caprylic/capric glyceride 2 weight portions
Poloxamer 188 0.2 weight portions
Soybean lecithin 0.5 weight portion
The silica 1 weight portion
Cross-linked cellulose sodium 0.12 weight portion
Magnesium stearate 0.015 weight portion
Glycine 0.3 weight portion;
(5)
GLP-1 0.08-0.12 weight portion
Deionized water 55-65 weight portion
Sad caprin 12-18 weight portion
Poloxamer 188 1.3-1.7 weight portions
Soybean lecithin 6-8 weight portion
Glycerol 8-12 weight portion
PEG400 6-8 weight portion
Vitamin E 0.25-0.35 weight portion;
(6)
GLP-1 0.1 weight portion
Deionized water 60 weight portions
Sad caprin 15 weight portions
Poloxamer 188 1.5 weight portions
Soybean lecithin 7 weight portions
Glycerol 10 weight portions
PEG400 7 weight portions
Vitamin E 0.3 weight portion.
11. Emulsion according to claim 2, its each component and content are as follows:
PTH 1-34 0.0008-0.0012 weight
Part
PBS buffer 0.4-0.6 weight portion
Sad caprin 0.6-0.8 weight portion
Polyethyleneglycol-12-hydroxy stearin 1.8-2.2 weight portion
Tocofecol succinic acid macrogol ester 0.4-0.6 weight portion
Polysorbas20 0.4-0.6 weight portion
Vitamin E 0.08-0.12 weight portion;
Particularly, the component of described Emulsion and content are as follows:
PTH1-34 0.001 weight portion
PBS buffer 0.5 weight portion
Sad caprin 0.7 weight portion
Polyethyleneglycol-12-hydroxy stearin 2 weight portions
Tocofecol succinic acid macrogol ester 0.5 weight portion
Polysorbas20 0.5 weight portion
Vitamin E 0.1 weight portion.
12. according to each described Emulsion in the claim 1 to 11, it is microemulsion or freeze-dried emulsion.
13. the preparation method of each described Emulsion of claim 1-12 item comprises the steps:
1) following steps A or B:
A. under 4-25 ℃ of condition, protein or peptide molecule are soluble in the aqueous phase;
B. the phosphatide complexes for preparing protein or polypeptide;
2) under 20-70 ℃ of condition, medium chain fatty acid ester, HLB value are mixed mutually greater than 12 emulsifying agent, and under the 200-800rmp stirring condition, continue to stir, be the transparent clear shape until whole system;
3) under 4-37 ℃ of condition, the step 1) product is joined step 2) in the product, and under the 200-800rmp condition, continue to stir, until the even preparation that forms transparent clear, the final Emulsion that obtains to contain protein or polypeptide drugs.
14. the purposes of the described Emulsion of claim 10 in the medicine of preparation treatment or prevent diabetes or blood sugar lowering.
15. the purposes of the described Emulsion of claim 11 in the medicine of preparation treatment or prevention of osteoporosis.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100441458A CN102113996B (en) | 2011-02-24 | 2011-02-24 | Oral formulations containing protein or peptide, and preparation method and application thereof |
| PCT/CN2011/000815 WO2012113117A1 (en) | 2011-02-24 | 2011-05-10 | Oral preparation comprising protein or polypeptide, preparation method thereof, and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100441458A CN102113996B (en) | 2011-02-24 | 2011-02-24 | Oral formulations containing protein or peptide, and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102113996A true CN102113996A (en) | 2011-07-06 |
| CN102113996B CN102113996B (en) | 2013-06-12 |
Family
ID=44212997
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011100441458A Active CN102113996B (en) | 2011-02-24 | 2011-02-24 | Oral formulations containing protein or peptide, and preparation method and application thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN102113996B (en) |
| WO (1) | WO2012113117A1 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102125520A (en) * | 2011-02-24 | 2011-07-20 | 美迪思生物科技(北京)有限公司 | Emulsion containing hydrophilic biological macromolecule, preparation method and application thereof |
| CN102552174A (en) * | 2011-11-18 | 2012-07-11 | 中山大学 | Preparation method of polypeptide/proteinic drug nanoparticle with high drug loading and high encapsulation efficiency |
| CN103655487A (en) * | 2013-11-15 | 2014-03-26 | 西安力邦制药有限公司 | Injection alprostadil freeze-dried emulsion |
| CN103861090A (en) * | 2012-12-18 | 2014-06-18 | 美迪思生物科技(北京)有限公司 | Protein or peptide containing hydrophobic solution, preparation method and application thereof |
| CN110639425A (en) * | 2019-10-22 | 2020-01-03 | 湖北文理学院 | Preparation method of composite emulsifier |
| CN113952301A (en) * | 2021-11-17 | 2022-01-21 | 胡振华 | Application of medium-chain fatty acid as absorption enhancer to preparation of pharmaceutical composition emulsion |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100453115C (en) * | 2003-05-26 | 2009-01-21 | 上海医药工业研究院 | Self-emulsifying agglomerant of oral polypeptide medicine |
| CN101422431B (en) * | 2007-12-28 | 2011-03-23 | 上海医药工业研究院 | Insulation administration preparation through nose |
-
2011
- 2011-02-24 CN CN2011100441458A patent/CN102113996B/en active Active
- 2011-05-10 WO PCT/CN2011/000815 patent/WO2012113117A1/en active Application Filing
Non-Patent Citations (4)
| Title |
|---|
| 《Pharmaceutical Research》 19951231 Panayiotis P.Constantinides 《Lipid Microemulsions for Improving Drug Dissolution and Oral Absorption:Physical and Biopharmaceutical Aspects》 第1568页表7，第1561页第1段至1566页第3段 1-9,12 第12卷, 第11期 2 * |
| 《中国生化药物杂志》 20061231 刘绛光等 《微乳在口服多肽类药物中的应用》 56-58页 1-15 第27卷, 第1期 2 * |
| 《中国药师》 20081231 吕娟丽等 《微乳促进药物口服吸收的机理及应用概述》 575-577页 1-15 第11卷, 第5期 2 * |
| 《中国药科大学学报》 20061231 孟博宇等 《胰岛素微乳大鼠肠道给药降糖作用的研究》 第305页表1，第305页第2段4-7行，摘要 1-9,12 第37卷, 第4期 2 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102125520A (en) * | 2011-02-24 | 2011-07-20 | 美迪思生物科技(北京)有限公司 | Emulsion containing hydrophilic biological macromolecule, preparation method and application thereof |
| CN102552174A (en) * | 2011-11-18 | 2012-07-11 | 中山大学 | Preparation method of polypeptide/proteinic drug nanoparticle with high drug loading and high encapsulation efficiency |
| CN103861090A (en) * | 2012-12-18 | 2014-06-18 | 美迪思生物科技(北京)有限公司 | Protein or peptide containing hydrophobic solution, preparation method and application thereof |
| CN103655487A (en) * | 2013-11-15 | 2014-03-26 | 西安力邦制药有限公司 | Injection alprostadil freeze-dried emulsion |
| CN103655487B (en) * | 2013-11-15 | 2015-05-06 | 西安力邦制药有限公司 | Injection alprostadil freeze-dried emulsion |
| CN110639425A (en) * | 2019-10-22 | 2020-01-03 | 湖北文理学院 | Preparation method of composite emulsifier |
| CN113952301A (en) * | 2021-11-17 | 2022-01-21 | 胡振华 | Application of medium-chain fatty acid as absorption enhancer to preparation of pharmaceutical composition emulsion |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2012113117A1 (en) | 2012-08-30 |
| CN102113996B (en) | 2013-06-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR100508695B1 (en) | Formulation for oral delivery of insulin and preparation method thereof | |
| US7674767B2 (en) | Nanoparticle compositions of water-soluble drugs for oral administration and preparation methods thereof | |
| CN102113996B (en) | Oral formulations containing protein or peptide, and preparation method and application thereof | |
| DK1742616T3 (en) | The microsphere-discharge-system for the prolonged delivery and methods of making and using the same | |
| US20110091420A1 (en) | Injectable Sustained-Release Pharmaceutical Formulation and the Preparation Method Thereof | |
| KR20020066778A (en) | Formulation to enhance bioavailability of bioactive materials and preparation method thereof | |
| CN103702662B (en) | Control release peptide formulations | |
| KR20070001876A (en) | Surfactant-based gel as an injectable, sustained drug delivery vehicle | |
| BRPI0715469A2 (en) | Pharmaceutical compositions for sustained release of peptides | |
| US20230372436A1 (en) | Somatostatin receptor agonist formulations | |
| CN110664755B (en) | Protein polypeptide self-microemulsion and preparation method and application thereof | |
| CN102125520A (en) | Emulsion containing hydrophilic biological macromolecule, preparation method and application thereof | |
| CN105878190A (en) | Preparation method of slow-released microgranules, prepared slow-released microgranules and application thereof | |
| AU2017443632B2 (en) | Pharmaceutical compositions having a selected release duration | |
| CN101199479A (en) | Officinal submicro emulsion and process for preparing same | |
| CN101416963A (en) | Nimodipine freeze-drying sub micellar emulsion for injection and preparation method thereof | |
| CN104667258A (en) | Octreotide acetate tablet and preparation method thereof | |
| CN101380462A (en) | Obtaining method of novel insulin oil-phase solution and preparation technique thereof | |
| CN1555886A (en) | Brilliant bingruilin acetate solid lipid nano particle oral preparation and its preparation method | |
| CN103385851B (en) | For anticancer injectable pharmaceutical composition | |
| EP2861209B1 (en) | Somatostatin receptor agonist formulations |
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 |