CN116407614A - Stable preparation of novel tri-agonist innovative biological medicine - Google Patents
Stable preparation of novel tri-agonist innovative biological medicine Download PDFInfo
- Publication number
- CN116407614A CN116407614A CN202111644995.1A CN202111644995A CN116407614A CN 116407614 A CN116407614 A CN 116407614A CN 202111644995 A CN202111644995 A CN 202111644995A CN 116407614 A CN116407614 A CN 116407614A
- Authority
- CN
- China
- Prior art keywords
- buffer
- concentration
- pharmaceutical formulation
- buffer solution
- antioxidant
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims description 41
- 239000003814 drug Substances 0.000 title description 31
- 239000000556 agonist Substances 0.000 title description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 39
- 238000000034 method Methods 0.000 claims abstract description 13
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 45
- 239000000872 buffer Substances 0.000 claims description 43
- 239000000203 mixture Substances 0.000 claims description 34
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 33
- 239000000243 solution Substances 0.000 claims description 31
- 239000003963 antioxidant agent Substances 0.000 claims description 29
- 239000007853 buffer solution Substances 0.000 claims description 29
- 230000003204 osmotic effect Effects 0.000 claims description 29
- 239000003755 preservative agent Substances 0.000 claims description 28
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 27
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 26
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 claims description 26
- 230000002335 preservative effect Effects 0.000 claims description 25
- 239000004480 active ingredient Substances 0.000 claims description 23
- 230000003078 antioxidant effect Effects 0.000 claims description 23
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 22
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 20
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 19
- 229930182817 methionine Natural products 0.000 claims description 19
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 15
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 15
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 15
- 235000006109 methionine Nutrition 0.000 claims description 15
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 claims description 13
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 claims description 12
- 239000011780 sodium chloride Substances 0.000 claims description 11
- 229960003589 arginine hydrochloride Drugs 0.000 claims description 10
- 235000011187 glycerol Nutrition 0.000 claims description 10
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 10
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 8
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 8
- 229930195725 Mannitol Natural products 0.000 claims description 8
- 229930006000 Sucrose Natural products 0.000 claims description 8
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 8
- 239000000594 mannitol Substances 0.000 claims description 8
- 235000010355 mannitol Nutrition 0.000 claims description 8
- 239000000600 sorbitol Substances 0.000 claims description 8
- 235000010356 sorbitol Nutrition 0.000 claims description 8
- 239000005720 sucrose Substances 0.000 claims description 8
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 7
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 7
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 6
- 239000013543 active substance Substances 0.000 claims description 6
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 claims description 6
- IWDCLRJOBJJRNH-UHFFFAOYSA-N p-cresol Chemical compound CC1=CC=C(O)C=C1 IWDCLRJOBJJRNH-UHFFFAOYSA-N 0.000 claims description 6
- 239000008055 phosphate buffer solution Substances 0.000 claims description 6
- QFOHBWFCKVYLES-UHFFFAOYSA-N Butylparaben Chemical compound CCCCOC(=O)C1=CC=C(O)C=C1 QFOHBWFCKVYLES-UHFFFAOYSA-N 0.000 claims description 5
- 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 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 claims description 5
- 239000008101 lactose Substances 0.000 claims description 5
- 239000012064 sodium phosphate buffer Substances 0.000 claims description 5
- 235000010265 sodium sulphite Nutrition 0.000 claims description 5
- IVLXQGJVBGMLRR-UHFFFAOYSA-N 2-aminoacetic acid;hydron;chloride Chemical compound Cl.NCC(O)=O IVLXQGJVBGMLRR-UHFFFAOYSA-N 0.000 claims description 4
- 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 claims description 4
- 239000001509 sodium citrate Substances 0.000 claims description 4
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 4
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 claims description 3
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 claims description 3
- 229960001269 glycine hydrochloride Drugs 0.000 claims description 3
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 claims description 3
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 claims description 3
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 3
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 claims description 3
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 claims description 3
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 claims description 3
- 239000007974 sodium acetate buffer Substances 0.000 claims description 3
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 2
- 239000000811 xylitol Substances 0.000 claims description 2
- 235000010447 xylitol Nutrition 0.000 claims description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 2
- 229960002675 xylitol Drugs 0.000 claims description 2
- 229940043351 ethyl-p-hydroxybenzoate Drugs 0.000 claims 1
- 239000013559 triple agonist Substances 0.000 abstract description 12
- 238000003860 storage Methods 0.000 abstract description 8
- 229960000074 biopharmaceutical Drugs 0.000 abstract description 2
- 210000004369 blood Anatomy 0.000 description 24
- 239000008280 blood Substances 0.000 description 24
- 235000006708 antioxidants Nutrition 0.000 description 20
- 238000009472 formulation Methods 0.000 description 20
- 239000008103 glucose Substances 0.000 description 18
- 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 17
- 230000000694 effects Effects 0.000 description 17
- 239000000178 monomer Substances 0.000 description 17
- 229940079593 drug Drugs 0.000 description 15
- 239000000126 substance Substances 0.000 description 15
- 238000002474 experimental method Methods 0.000 description 14
- 239000008363 phosphate buffer Substances 0.000 description 13
- 150000001875 compounds Chemical class 0.000 description 12
- 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 description 12
- 239000003381 stabilizer Substances 0.000 description 12
- 102000051325 Glucagon Human genes 0.000 description 11
- 108060003199 Glucagon Proteins 0.000 description 11
- 238000001514 detection method Methods 0.000 description 11
- 229960004666 glucagon Drugs 0.000 description 11
- 108090000765 processed proteins & peptides Proteins 0.000 description 11
- 241000699670 Mus sp. Species 0.000 description 10
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(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](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)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(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000005286 illumination Methods 0.000 description 9
- 230000001133 acceleration Effects 0.000 description 8
- 238000011835 investigation Methods 0.000 description 8
- 230000015556 catabolic process Effects 0.000 description 7
- 238000006731 degradation reaction Methods 0.000 description 7
- 102000004877 Insulin Human genes 0.000 description 6
- 108090001061 Insulin Proteins 0.000 description 6
- 230000037396 body weight Effects 0.000 description 6
- 206010012601 diabetes mellitus Diseases 0.000 description 6
- 239000013583 drug formulation Substances 0.000 description 6
- 229940125396 insulin Drugs 0.000 description 6
- 235000018102 proteins Nutrition 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 230000028327 secretion Effects 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 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 description 5
- 230000008859 change Effects 0.000 description 5
- 230000001276 controlling effect Effects 0.000 description 5
- 230000037406 food intake Effects 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 230000000291 postprandial effect Effects 0.000 description 5
- 238000004007 reversed phase HPLC Methods 0.000 description 5
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 4
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 4
- CBMPTFJVXNIWHP-UHFFFAOYSA-L disodium;hydrogen phosphate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].OP([O-])([O-])=O.OC(=O)CC(O)(C(O)=O)CC(O)=O CBMPTFJVXNIWHP-UHFFFAOYSA-L 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 235000012631 food intake Nutrition 0.000 description 4
- 230000002496 gastric effect Effects 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 230000007774 longterm Effects 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000010172 mouse model Methods 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 238000003998 size exclusion chromatography high performance liquid chromatography Methods 0.000 description 4
- 230000004936 stimulating effect Effects 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 229960001052 streptozocin Drugs 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- 239000012490 blank solution Substances 0.000 description 3
- 150000001720 carbohydrates Chemical class 0.000 description 3
- 239000003153 chemical reaction reagent Substances 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
- 238000004090 dissolution Methods 0.000 description 3
- 229940000406 drug candidate Drugs 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 150000004665 fatty acids Chemical class 0.000 description 3
- 229940088597 hormone Drugs 0.000 description 3
- 239000005556 hormone Substances 0.000 description 3
- 230000002218 hypoglycaemic effect Effects 0.000 description 3
- 230000003914 insulin secretion Effects 0.000 description 3
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 3
- 235000019799 monosodium phosphate Nutrition 0.000 description 3
- 238000010606 normalization Methods 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 108010011459 Exenatide Proteins 0.000 description 2
- HTQBXNHDCUEHJF-XWLPCZSASA-N Exenatide Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 HTQBXNHDCUEHJF-XWLPCZSASA-N 0.000 description 2
- 108010063919 Glucagon Receptors Proteins 0.000 description 2
- 108010086246 Glucagon-Like Peptide-1 Receptor Proteins 0.000 description 2
- 101800000224 Glucagon-like peptide 1 Proteins 0.000 description 2
- 102100032882 Glucagon-like peptide 1 receptor Human genes 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 208000013016 Hypoglycemia Diseases 0.000 description 2
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 2
- 208000008589 Obesity Diseases 0.000 description 2
- 102100040918 Pro-glucagon Human genes 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- 230000007059 acute toxicity Effects 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 230000036528 appetite Effects 0.000 description 2
- 235000019789 appetite Nutrition 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 2
- 235000018417 cysteine Nutrition 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 229960001519 exenatide Drugs 0.000 description 2
- 238000012494 forced degradation Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 229960002449 glycine Drugs 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 235000014304 histidine Nutrition 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229960002216 methylparaben Drugs 0.000 description 2
- 239000004005 microsphere Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 235000020824 obesity Nutrition 0.000 description 2
- -1 osmolality regulator Substances 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 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(=O)NCC(O)=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 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 235000013772 propylene glycol Nutrition 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 238000011287 therapeutic dose Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 210000001835 viscera Anatomy 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- 108010039627 Aprotinin Proteins 0.000 description 1
- 238000011746 C57BL/6J (JAX™ mouse strain) Methods 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- 102100040890 Glucagon receptor Human genes 0.000 description 1
- 229940089838 Glucagon-like peptide 1 receptor agonist Drugs 0.000 description 1
- 102000018071 Immunoglobulin Fc Fragments Human genes 0.000 description 1
- 108010091135 Immunoglobulin Fc Fragments Proteins 0.000 description 1
- 229930064664 L-arginine Natural products 0.000 description 1
- 235000014852 L-arginine Nutrition 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
- 108090001060 Lipase Proteins 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 108010047320 Pepsinogen A Proteins 0.000 description 1
- 102000015731 Peptide Hormones Human genes 0.000 description 1
- 108010038988 Peptide Hormones Proteins 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 208000032140 Sleepiness Diseases 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- XNKLLVCARDGLGL-JGVFFNPUSA-N Stavudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C[C@@H](CO)O1 XNKLLVCARDGLGL-JGVFFNPUSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 229940093740 amino acid and derivative Drugs 0.000 description 1
- 239000000883 anti-obesity agent Substances 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 229960004405 aprotinin Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit 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
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000013043 chemical agent Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000006240 deamidation Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 210000003158 enteroendocrine cell Anatomy 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 230000008713 feedback mechanism Effects 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 230000030136 gastric emptying Effects 0.000 description 1
- 108010036598 gastric inhibitory polypeptide receptor Proteins 0.000 description 1
- 230000030135 gastric motility Effects 0.000 description 1
- 230000004110 gluconeogenesis Effects 0.000 description 1
- 208000007345 glycogen storage disease Diseases 0.000 description 1
- 235000009200 high fat diet Nutrition 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 1
- 239000012155 injection solvent Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 230000004130 lipolysis Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 238000002715 modification method Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 1
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 1
- 230000010494 opalescence Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000000065 osmolyte Effects 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000813 peptide hormone Substances 0.000 description 1
- 108010011903 peptide receptors Proteins 0.000 description 1
- 102000014187 peptide receptors Human genes 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000006920 protein precipitation Effects 0.000 description 1
- 230000001603 reducing effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 235000004400 serine Nutrition 0.000 description 1
- 238000001542 size-exclusion chromatography Methods 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229960001203 stavudine Drugs 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- AURFVNDXGLQSNN-UHFFFAOYSA-K trisodium 2-hydroxypropane-1,2,3-tricarboxylic acid phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O.OC(=O)CC(O)(C(O)=O)CC(O)=O AURFVNDXGLQSNN-UHFFFAOYSA-K 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 239000012905 visible particle Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
-
- 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
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The present invention relates to a stable pharmaceutical composition for preparing a triple agonist innovative biopharmaceutical VS-S103A and a method for preparing the same, a stable product thus obtained and stability during transportation and storage of the stable pharmaceutical composition of VS-S103A obtained by the method is ensured.
Description
Technical Field
The invention belongs to the field of preparation of triple agonist innovative biological medicines, and particularly relates to a triple agonist pharmaceutical preparation prepared in a buffer system of sodium phosphate, in particular to a formula composition of a VS-S103A preparation and a preparation method thereof.
Background
VS-S103A is a triple agonist directed against glucagon-like peptide-1 (GLP-1) receptor, glucagon (GCG) receptor, and Gastric Inhibitory Peptide (GIP) receptor.
GLP-1 is a polypeptide hormone secreted by intestinal L cells. The insulin acts on islet beta cells in a glucose-dependent manner, so that the biosynthesis and secretion of insulin are promoted, and the rise of insulin brings about an obvious blood glucose reducing effect; simultaneously, the proliferation and differentiation of beta cells are stimulated, the apoptosis of the beta cells is inhibited, the number of islet beta cells is increased, the secretion of glucagon is inhibited, the appetite and ingestion are inhibited, and the emptying of gastric contents is delayed by 2. Based on the functions, glucagon-like peptide-1 (GLP-1) and analogues thereof are non-insulin hypoglycemic and antiobesity drugs widely used at present, and the products on the market are very abundant.
Glucagon (GCG) is a hormone secreted by islet alpha cells. Acting to increase blood glucose as opposed to insulin. Glucagon has strong functions of promoting glycogenosis and gluconeogenesis, so that the blood sugar is obviously increased; meanwhile, the lipase can be activated, the lipolysis can be promoted, the oxidation of fatty acid can be enhanced, and the generation of ketone bodies can be increased by 3. GCG thus has a remarkable lipid-lowering and weight-lowering effect, though it is contrary to the goal of lowering blood sugar.
Whereas aprotinin, or glucose-dependent insulin release peptide (GIP), is a class of hormones produced by K cells of the mucosa of the small intestine, which inhibit gastric acid secretion; inhibiting pepsinogen secretion; stimulating insulin release; inhibit gastric motility and emptying; stimulating secretion of intestinal juice; stimulating glucagon secretion 4.
VS-S103A acts as a triple agonist to GLP-1 receptor, GCG receptor and GIP receptor, and is capable of simultaneously functioning as three classes of hormone 5,6.GLP-1 can reduce blood sugar and suppress appetite; GCG is able to break down fat, reduce body weight, but raise blood glucose; GIP stimulates insulin secretion primarily, but also has the activity of stimulating GCG secretion, bringing insulin into dynamic equilibrium with GCG concentration. The three are matched with each other to form a feedback mechanism according to the blood sugar concentration, so that the blood sugar can be controlled, the fat can be decomposed, the weight can be reduced, and the risk of hypoglycemia is minimized. Triple agonists have significant advantages over GLP-1 analogues alone for the treatment of diabetes, obesity, non-alcoholic fatty liver disease (NASH). The compound patent of VS-S103A as an innovative molecule has been granted (patent number: CN 111040022B).
The main development direction of the GLP-1 analogue medicaments on the market is to prolong the half life in vivo, reduce the administration frequency and improve the compliance of patients. Long acting GLP-1 receptor agonists, such as lozenithal, can be administered once a week using polyethylene glycol modification; du Latang peptides, linked to the antibody Fc fragment, can also be administered once a week; the exenatide microsphere can be used once a week by applying a microsphere preparation process on the basis of exenatide; the semaglutin can also be used once a week by using an improved fatty acid chain modification method. The VS-S103A also uses fatty acid chain modification technology and introduces unnatural amino acid, so that once-a-week medication can be realized, and long-term and stable storage of the medicine can be realized by matching with the preparation process disclosed by the invention.
Biological products often face a great challenge in product storage stability, as do VS-S103A triple agonists. Firstly, for biological products, the environmental temperature for storage and use is often one of the most critical influencing factors for the service life of the products, and the biological activity of the products is reduced due to higher temperature, which is often caused by physical and chemical changes such as oxidation, deamidation, aggregation, isomerization and the like of active ingredients, and the changes often lead to the reduction of the therapeutic effect of the products, and even cause the problem of safety for users. Therefore, the improvement of the stability of the product preparation is a primary aim of preparation development, and the index of the biological product accepted in the industry is that the purity of the active ingredient reaches over 90% in the storage period.
At present, due to the problem of drug absorption, most of administration routes of biological product preparations are injection administration, so that evaluation indexes of biological product quality are required, besides purity requirements of active ingredients, other requirements for drug formulation properties are required, generally, the properties of drugs are not changed significantly in storage period, particularly clear liquid medicine is not required, generation of visible foreign matters and aggregation and precipitation of proteins are not required, the problems are generated, firstly, precipitation of packaging materials is caused, generation of foreign matters is caused, and sometimes visible particles are generated, and can be detected by means of microscopy technology, photoresistance technology and the like, on the other hand, protein molecules are aggregated to different degrees, protein molecules are provided with different charges, and different areas on the whole structure show different hydrophilias or hydrophobicity, and under different physical conditions, such as vibration, light, heat, high-low temperature difference and the like, balance force among the protein molecules can be destroyed, so that the proteins are aggregated, and then particles are formed and precipitation is generated. This therefore requires good thermodynamic stability and package compatibility of the pharmaceutical formulation.
Accordingly, there is a need to provide a solution that can improve the stability and effectiveness of pharmaceutical formulations.
Disclosure of Invention
In order to solve the problems in the prior art, the application obtains a stable pharmaceutical preparation system containing the VS-S103A triple agonist through a large number of prescription screening, forced degradation and stability experiments.
The technical scheme of the invention is as follows:
it is a first object of the present invention to provide a pharmaceutical formulation comprising VS-S103A, said VS-S103A being a triple agonist, said pharmaceutical formulation comprising VS-S103A and a pharmaceutically acceptable buffer, said VS-S103A being dissolved in the pharmaceutically acceptable buffer, said pharmaceutical formulation comprising VS-S103A having a pH in the range of 6.5 to 9.5, preferably a pH in the range of 7.0 to 8.8, further preferably a pH in the range of 7.4 to 8.4.
Further, the VS-S103A is the only active ingredient of the pharmaceutical formulation.
Further, the buffer solution is one or different combination buffers selected from sodium phosphate buffer solution, tris-HCL buffer solution, sodium citrate buffer solution, arginine hydrochloride buffer solution, glycine hydrochloride buffer solution, phosphoric acid-sodium citrate buffer solution and sodium acetate buffer solution.
Further, the concentration of the buffer is in the range of 5mM/L to 200mM/L, preferably 5mM to 100mM, and most preferably 10mM to 50mM/L.
Further, the concentration of the VS-S103A in the buffer solution ranges from 0.1mg/ml to 10mg/ml.
Further, the pharmaceutical preparation further comprises a pharmaceutically acceptable preservative selected from phenol, m-cresol, o-cresol, p-cresol, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate and butyl parahydroxybenzoate, wherein the concentration of the preservative in the pharmaceutical preparation ranges from 1mg/ml to 10mg/ml.
Further, the pharmaceutical preparation further comprises a pharmaceutically acceptable osmotic pressure regulator, wherein the osmotic pressure regulator is one of stabilizing agents, the osmotic pressure regulator is selected from glycerol, propylene glycol, trehalose, sucrose, mannitol, xylitol, lactose, sodium chloride, sorbitol and the like or a combination of different osmotic pressure regulators, and the concentration of the osmotic pressure regulator in the pharmaceutical preparation ranges from 0.5mg/ml to 200mg/ml.
Further, the pharmaceutical preparation also comprises a pharmaceutically acceptable antioxidant, wherein the antioxidant is one of stabilizers, the antioxidant is selected from one or a combination of different antioxidants such as methionine, sodium thiosulfate, sodium sulfite and the like, and the concentration range of the antioxidant in the pharmaceutical preparation is 0.5 mg/ml-50 mg/ml.
The buffer solution, the osmotic pressure regulator, the antioxidant and the preservative belong to the category of stabilizers, can maintain the stability of the pharmaceutical preparation aiming at the characteristics of physics, chemistry and microorganisms, has a promoting effect on the stability of the pharmaceutical preparation, and has the efficacy of the stabilizers.
Further, the pharmaceutical preparation contains 0.1mg/ml to 30mg/ml of VS-S103A as an active ingredient; contains disodium hydrogen phosphate buffer solution with pH of 7.0-8.8 and concentration of 5 mM-200 mM or Tris-HCL buffer solution with concentration of 5 mM-200 mM as buffer solution; contains 10 mg/ml-50 mg/ml propylene glycol or 10 mg/ml-100 mg/ml mannitol and 10 mg/ml-200 mg/ml trehalose as osmotic pressure regulator; methionine of 0.5mg/ml to 50mg/ml as an antioxidant; contains 1mg/ml to 10mg/ml of phenol or m-cresol as a preservative.
Further, the pharmaceutical preparation contains 0.1mg/ml to 20mg/ml of VS-S103A as an active ingredient; comprises disodium hydrogen phosphate buffer solution with the pH range of 7.4-8.4 and the concentration of 10 mM-50 mM as buffer solution; contains propylene glycol with the concentration of 8mg/ml to 20mg/ml or trehalose with the concentration of 10mg/ml to 150mg/ml as an osmotic pressure regulator; methionine of 0.5mg/ml to 30mg/ml as an antioxidant; phenol or m-cresol with the concentration of 2mg/ml to 8mg/ml is used as a preservative; preferably, the specific prescription of the pharmaceutical preparation containing VS-S103A is any one of the following:
further, the pharmaceutical preparation contains 0.1mg/ml to 20mg/ml of VS-S103A as an active ingredient; contains Tris-HCL buffer solution with pH of 7.4-8.4 and concentration of 5-50 mM as buffer solution; one or more compositions containing 8mg/ml to 20mg/ml of glycerin or 10mg/ml to 150mg/ml of trehalose or 0.5mg/ml to 30mg/ml of methionine or sodium thiosulfate are used as antioxidants; phenol or m-cresol with the concentration of 2mg/ml to 8mg/ml is used as a preservative; preferably, the specific prescription of the pharmaceutical preparation containing VS-S103A is any one of the following:
further, the pharmaceutical preparation contains 0.1mg/ml to 20mg/ml of VS-S103A as an active ingredient; comprises disodium hydrogen phosphate buffer solution and/or arginine hydrochloride buffer solution with the pH range of 7.4-8.4 and the concentration of 10-50 mM as buffer solution; contains 8 mg/ml-20 mg/ml sorbitol or 1 mg/ml-10 mg/ml sodium chloride as osmotic pressure regulator; methionine of 0.5mg/ml to 30mg/ml as an antioxidant; phenol or m-cresol with the concentration of 2mg/ml to 8mg/ml is used as a preservative; preferably, the specific prescription of the pharmaceutical preparation containing VS-S103A is any one of the following:
it is a second object of the present invention to provide a method for preparing the aforementioned pharmaceutical formulation comprising VS-S103A, said method comprising dissolving said VS-S103A, preservative, osmolality regulator, antioxidant in a pharmaceutically acceptable buffer in prescribed amounts.
Further, the active substances, preservative, osmotic pressure regulator and antioxidant are premixed for 10 to 20 minutes and then diluted into a concentrated solution by a buffer solution, wherein the concentrated solution is 60 to 80 percent of the target capacity.
Further, the pH of the buffer used in the preparation is controlled to 8.0 to 9.0.
The "three agonists of VS-S103A" as used herein refers to pharmaceutically active compounds that are administered to a patient for treatment, specifically, triple agonists against glucagon-like peptide-1 receptor, glucagon receptor, and gastric inhibitory peptide receptor as described in CN111040022B patent.
As used herein, "drug" refers to a pharmaceutical formulation of a pharmaceutical agent suitable for administration of a pharmaceutically active compound to a patient.
The term "route of administration" as used herein refers to subcutaneous administration.
As used herein, "pharmaceutical formulation" refers to a product comprising an active compound or salt thereof, and pharmaceutical excipients such as (buffers, osmolytes, preservatives, antioxidants, surfactants) which can be used to treat, prevent or reduce the severity of a disease or condition by administering the pharmaceutical formulation to a human.
As used herein, a "storage-stable pharmaceutical formulation" refers to a pharmaceutical combination that is stable at least during the period required by regulatory authorities associated with therapeutic proteins. Preferably, the storage-stable pharmaceutical formulation is stable for at least 1 year at 2-8 ℃ and at least 3 months at 25 ℃, the stability comprising physical and chemical stability.
As used herein, "stable solution" refers to a preparation of a compound that is useful as an intermediate in the preparation of a storage-stable pharmaceutical formulation as described above.
As used herein, "pharmaceutically acceptable" refers to those compositions which are suitable for normal pharmaceutical use, i.e., do not produce adverse events in a patient, etc.
The term "pH" as used herein refers to the pH of a pharmaceutical formulation to ensure the activity and stability of the active substance, and the pH of the pharmaceutical formulation is preferably in the range of 6.5 to 9.5, more preferably 7.0 to 8.8, and most preferably 7.4 to 8.4.
As used herein, "buffer" refers to a compound in a pharmaceutical formulation that reduces the tendency of the pH of the composition to change over time, which would otherwise occur as a result of a chemical reaction. The buffer reagent is selected from chemical reagents such as: disodium hydrogen phosphate buffer, sodium dihydrogen phosphate buffer, tris-hydrochloride buffer, sodium citrate buffer, glycine-hydrochloric acid buffer, arginine hydrochloride buffer, sodium phosphate-sodium citrate buffer, sodium acetate buffer, and their mixture. The buffer is preferably disodium hydrogen phosphate buffer, sodium dihydrogen phosphate buffer, tris-hydrochloride buffer, sodium citrate buffer, glycine hydrochloride buffer, arginine hydrochloride buffer, or sodium phosphate-sodium citrate buffer, more preferably disodium hydrogen phosphate buffer, sodium dihydrogen phosphate buffer, tris-hydrochloride buffer, or sodium phosphate-sodium citrate buffer, and most preferably disodium hydrogen phosphate buffer. The concentration of the buffer is usually 5mM/L to 200mM/L, preferably 5mM/L to 100mM/L, and most preferably 10mM/L to 50mM/L.
As used herein, "preservative" refers to a compound that is added to a pharmaceutical formulation to prevent or retard the activity (growth and metabolism) of microbial compounds. Pharmaceutically acceptable preservatives are phenol, m-cresol, o-cresol, p-cresol, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate. The preservative of the inventive medicament is preferably phenol or m-cresol, which can be used singly or in combination. The amount of the preservative to be added is generally controlled to be 0.1mg/ml to 15mg/ml, preferably 1mg/ml to 10mg/ml, and most preferably 4mg/ml to 6mg/ml.
The term "osmotic pressure regulator" as used herein refers to a compound used in a pharmaceutical preparation to change the osmotic pressure of the pharmaceutical preparation so that the osmotic pressure meets or approximates the osmotic pressure of human blood plasma, and also has the effect of maintaining the stability of the preparation, and is also used as a stabilizer. Osmotic pressure regulator comprises sodium chloride, glycerol, propylene glycol, sucrose, trehalose, mannitol, sorbitol, etc. The osmotic pressure regulator can control the osmotic pressure and play the role of different stabilizers through a plurality of prescription screening tests, and can play different roles of protecting active ingredients to different degrees by combining a plurality of osmotic pressure regulators, and can improve the solubility of active substances and other auxiliary materials to a certain degree for compounds containing hydroxyl. The osmolality adjustment according to the invention is preferably sodium chloride, glycerol, propylene glycol, sucrose, trehalose, mannitol, more preferably sodium chloride, glycerol, propylene glycol, sucrose, trehalose, most preferably one of propylene glycol, trehalose and sodium chloride and mixtures thereof. The amount of osmolality regulator to meet the osmolality requirement is preferably 5mg/ml to 100mg/ml, more preferably 10mg/ml to 50mg/ml, most preferably 13mg/ml to 20mg/ml, of the alcohol formulation. The concentration of the saccharide formulation is preferably 5mg/ml to 200mg/ml, more preferably 20mg/ml to 150mg/ml, most preferably 80mg/ml to 120mg/ml. The concentration of sodium chloride is preferably 1mg/ml to 10mg/ml, most preferably 3mg/ml to 5mg/ml.
As used herein, "stabilizer" refers to a chemical agent added to a peptide-containing pharmaceutical formulation to stabilize the peptide, thereby increasing the shelf life and the time of use of the pharmaceutical formulation. Stabilizers for pharmaceutical formulations are various amino acids and derivatives thereof, such as: l-arginine, arginine hydrochloride, methionine, glycine, cysteine, serine, aspartic acid, succinic acid, histidine, tryptophan, lysine, phenylalanine, and the like, and derivatives thereof; antioxidants for inhibiting oxidation of active substances include sodium thiosulfate, vitamin C and its derivatives, sodium sulfite, etc.; sugar and alcohol agents for maintaining the biological activity of the active substance include sucrose, trehalose, lactose, mannitol, glycerol, propylene glycol, sorbitol, etc. The stabilizing agent in the pharmaceutical formulation of the present invention is preferably one or a mixture of L-arginine, methionine, glycine, cysteine, histidine, sodium thiosulfate, sodium sulfite, sucrose, trehalose, lactose, mannitol, glycerol, propylene glycol, sorbitol, more preferably one or a mixture of methionine, sucrose, sodium sulfite, propylene glycol, most preferably a mixture of methionine and propylene glycol. The concentration of the stabilizer is preferably 0.5mg/ml to 200mg/ml, more preferably 1mg/ml to 100mg/ml, most preferably 2mg/ml to 80mg/ml. Wherein the concentration of the alcohol formulation is preferably 10mg/ml to 50mg/ml, most preferably 13mg/ml to 20mg/ml. The concentration of the saccharide formulation is preferably 10mg/ml to 100mg/ml, most preferably 30mg/ml to 80mg/ml. The concentration of the amino acid and its derivatives is preferably 0.5mg/ml to 20mg/ml, most preferably 2mg/ml to 8mg/ml. The concentration of the antioxidant formula is preferably 0.5mg/ml to 20mg/ml, and most preferably 2mg/ml to 8mg/ml.
As used herein, "isoelectric point" refers to the pH at which the total electrostatic charge of a macromolecule (e.g., peptide) is zero. There may be several dotted groups in the peptide, and at the isoelectric point the sum of all these charges is zero. The total electrostatic charge of the peptide is negative at a pH above the isoelectric point and positive at a pH below the isoelectric point. Typically, at the isoelectric point, the solubility of the protein decreases significantly.
Compared with the prior art, the technical scheme has the following beneficial effects:
the invention relates to a stable pharmaceutical formulation for preparing a triple agonist innovative biopharmaceutical VS-S103A and a method for preparing the same, a stable product thus obtained and a stability during transportation and storage of the stable pharmaceutical formulation of VS-S103A obtained by the method.
Drawings
Fig. 1: drug efficacy comparison of candidate drug formulations in STZ diabetes model mice
FIG. 1A, day 7 of dosing, fasted 6h blood glucose;
FIG. 1B, day 14 of dosing, fasted 6h blood glucose;
FIG. 1C, fasting for 6h blood glucose two days after day 28 dosing;
figure 1D postprandial blood glucose one day after day of dosing on day 21;
FIG. 1E postprandial blood glucose after two days of dosing on day 22;
in the figure, serma refers to semaglutin, used at a high dose of 10 nmol/kg; PAM-03 refers to both digital and nod tri-agonists, using low doses of 3 nmol/kg; CAM-03 is selected from the group consisting of the prescription P1 in Table 11; CAM-04 is selected from the group consisting of the prescription P3 in Table 11; CAM-07 is selected from the group consisting of the prescription P4 in Table 11.
Fig. 2:
FIG. 2A effect of test on food intake in mice;
FIG. 2B effect of test on mouse body weight;
FIG. 2C effect of test on the rate of weight gain in mice, wherein positive refers to semaglutin.
FIG. 3 image of the anatomical viscera of mice
Fig. 3A male 04 drug group;
fig. 3B male semaglutin group;
fig. 3C female 04 drug group;
fig. 3D female semaglutin group.
Detailed Description
The present inventors have obtained a number of stable pharmaceutical combinations comprising VS-S103A for subcutaneous administration through a number of prescription screening, process studies and influencing factors and stability experiments.
Example 1 investigation of the Effect of different pH on the solubility of VS-S103A drug
Appropriate amount of VS-S103A raw material powder is respectively dissolved in water for injection, citric acid buffer solution and sodium phosphate buffer solution with different pH values, and the dissolution conditions are shown in Table 1:
TABLE 1 dissolution of VS-S103A drug substance powders in solutions of different pH
The above experiments show that: the solubility of the VS-S103A bulk drug powder is not high under the condition of neutral and slightly acidic in water, the powder is hardly dissolved, the acidic pH is less than 2.5, the powder can be dissolved under neutral and alkaline conditions, and the dissolution speed is faster along with the strengthening of the alkaline conditions. This is very relevant to the isoelectric point of VS-S103A and has a very pronounced effect on solubility.
Example 2 examination of the Effect of different pH of different buffers on the quality of VS-S103A formulations
Solutions of VS-S103A at different pH values were prepared according to Table 2, and degradation of active ingredients in each of the solutions of VS-S103A was examined by measuring the main peak purity results of the monomer content (SEC-HPLC) and the related substances (RP-HPLC) through an influence factor light experiment and an acceleration experiment.
The SEC-UPLC (size exclusion chromatography) detection is mainly used for examining the percentages of the monomers of biomolecules such as polypeptide, fusion protein, monoclonal antibody and the like, and is one of important indexes for evaluating the quality of biological product pharmaceutical preparations (injection). The method adopted in the experiment is as follows:
RP-HPLC (reverse phase chromatography) detection is mainly used for examining the purity of polypeptide molecules and is one of important indexes for evaluating the quality of pharmaceutical preparations. The method adopted in the experiment is as follows:
controlling the illuminance intensity of cold white light to be 5000+/-500 Lux through an influence factor illumination experiment, controlling the temperature of the cold white light to be 3-8 ℃ during strong light irradiation, and taking 1 week and 2 weeks for investigation; the investigation conditions of the acceleration experiment are 37 ℃ and the investigation time is 2 weeks and 1 month. The preparation comprises the following components:
TABLE 2 formulation of VS-S103A solutions at different pH
Formulation number | Buffer X | pH Y |
1 | 50mM sodium citrate-sodium phosphate buffer | pH2.0 |
2 | 50mM disodium hydrogen phosphate buffer | pH7.0 |
3 | 50mM disodium hydrogen phosphate buffer | pH7.5 |
4 | 50mM disodium hydrogen phosphate buffer | pH8.0 |
5 | 50mM disodium hydrogen phosphate buffer | pH8.5 |
6 | 50mM disodium hydrogen phosphate buffer | pH9.0 |
7 | 50mM Tris-HCl buffer | pH7.2 |
8 | 50mM Tris-HCl buffer | pH7.8 |
9 | 50mM Tris-HCl buffer | pH8.5 |
10 | 10mM disodium hydrogen phosphate+20 mM arginine hydrochloride buffer | pH7.2 |
11 | 10mM disodium hydrogen phosphate+20 mM arginine hydrochloride buffer | pH8.5 |
Weighing disodium hydrogen phosphate or Tris to prepare a proper amount of blank solution with the component proportion in the formula, controlling the pH value of all blank solutions to be 1-10 target values in the table, ensuring that VS-S103A can be well dissolved in each blank solution, slowly stirring the solution until the VS-S103A is dissolved, and then adjusting the pH value to the required target value. And then filtering the preparation solution through a 0.22 mu m filter to obtain a target preparation, wherein all samples are colorless and clear solutions, no visible foreign matters exist, no crystals are separated out in the preparation process from the beginning to the end, and the properties of the samples are unchanged within 2 hours.
The samples were placed under the conditions to be investigated according to the experimental protocol for forced degradation (intense light) and acceleration experiments.
The results within 2 weeks of the intense light illumination experiment are shown below:
TABLE 3 detection results of the monomer content and the purity of the main peaks of the related substances under the illumination condition
* And (3) injection: the characteristics of all the inspected point samples have opalescence change, and the prescription instability can be obviously seen without liquid phase detection, so that the inspection by a liquid phase method is not needed, and the accelerated test result is not needed.
The results within 1 month of the acceleration experiment are shown below:
TABLE 4 detection results of the monomer content and the purity of the main peaks of the related substances under accelerated conditions
The above results can be seen: the quality of the VS-S103A formulation is significantly affected by pH. When the pH is slightly acidic, the active ingredients are degraded very rapidly, the properties of the sample change after 1 week of illumination, compared with the preparation, the sample has the generation of micro-opalescence, when the pH is more than 7.0, the stability of the preparation is obviously improved, and the degradation of the active ingredients shows a slow degradation trend along with the further increase of the pH; the Tris-HCL buffer or disodium hydrogen phosphate compound arginine hydrochloride buffer can well inhibit the degradation of active ingredients in the range of ph 7.0-8.5 in the prescription of a small amount of sodium chloride, phenol and methionine. All formulations were clear solutions during the study period with no visible foreign body production, but formulations with pH > 8.5 produced a pale yellow color change.
Example 3 investigation of the Effect of osmotic pressure regulator (stabilizer) ratio on the quality of VS-S103A formulations
Dissolving proper osmotic pressure regulator, preservative, etc. in disodium hydrogen phosphate buffer with pH value of 8.0-8.8 to obtain blank preparation, adding proper VS-S103A material medicine powder into the blank preparation, slowly stirring at 20-30 deg.c, after the medicine powder is completely dissolved, regulating pH value of the solution to 7.75 + -1 with dilute hydrochloric acid/sodium hydroxide, and filtering the solution with 0.22 micron filter to obtain final preparation solution. The composition of the preparation is as follows:
TABLE 5 osmotic pressure regulator X concentration table
The prepared preparation is respectively placed in a cold white light environment with the temperature of 5000 Lux+/-500 Lux (containing ultraviolet light) and the temperature is controlled to be 3-8 ℃ and the acceleration (37 ℃) environment, and the main peak purity (area normalization method) of the monomer content (SEC-HPLC) and related substances (RP-HPLC) is detected, so that the following results are obtained:
TABLE 6 detection results of the monomer content and the purity of the main peaks of the related substances under the illumination condition
* And (3) injection: the drop in monomer content was very significant, and none of the prescriptions reached the expected value (> 95%), so the subsequent tests were not examined.
TABLE 7 detection results of the monomer content and the purity of the main peaks of the related substances under accelerated conditions
The above results can be seen: after most of the alcohol and saccharide osmolality regulators or the combination thereof are combined with a small amount of m-cresol and methionine, the stability of VS-S103A can be well maintained, but the preparation is very sensitive to illumination conditions, so that the preparation product needs to be careful to avoid light. In the prescription combination, five prescriptions of glycerin, propylene glycol, sorbitol, trehalose and sodium chloride are superior, the purity of a main peak can be guaranteed to be higher than 80% under the condition of accelerating for 1 month at 37 ℃, the purity of the main peak can be kept to be higher than 94% under the condition of strong light for 2 weeks, but the stability of lactose to the prescriptions is poor. All prescriptions were colorless, clear solutions during the study period, with no visible foreign body.
Example 4 examination of the Effect of different antioxidants, preservative containing formulations of VS-S103A
Weighing a proper amount of auxiliary materials according to the following prescription composition to prepare blank preparation mother liquor, wherein the stabilizer comprises an antioxidant or a preservative, dissolving a proper amount of VS-S103A raw material powder in different blank preparations, slowly stirring until the medicine powder is completely dissolved, controlling the temperature to be 20-30 ℃, regulating the pH value of the solution to a target value of 7.5 by using dilute hydrochloric acid/sodium hydroxide, and filtering the preparation solution by a filter of 0.22 mu m to obtain a target preparation solution, wherein the preparation is colorless and clear solution without visible foreign matters.
The formula comprises the following components:
table 8 prescription composition-2
The prepared preparation is respectively placed in a cold white light environment with the temperature of 5000 Lux+/-500 Lux (containing ultraviolet light) and the temperature is controlled to be 3-8 ℃ and the acceleration (37 ℃) environment, and the main peak purity (area normalization method) of the monomer content (SEC-HPLC) and related substances (RP-HPLC) is detected, so that the following results are obtained:
TABLE 9 detection results of the monomer content and the purity of the main peaks of the related substances under the illumination condition
TABLE 10 detection results of the monomer content and the purity of the main peaks of the related substances under accelerated conditions
The above results can be seen: the formula containing the preservative has very remarkable monomer degradation under the illumination condition, and the antioxidant can inhibit the degradation speed of the active ingredient, wherein methionine has better effect compared with sodium thiosulfate. Both preservatives and methionine can better maintain the stability of VS-S103A under acceleration conditions, can inhibit the generation of impurities, and all the prescriptions are colorless and clear solutions during investigation without visible foreign matters.
Example 5 composition and formulation of the Compound recipe
Through a large number of single-factor investigation experiments, several auxiliary materials with better compatibility are screened out for combination preparation, and the prescription is shown in table 11. Weighing a buffer agent according to a proper amount to prepare a buffer solution, sequentially weighing an osmotic pressure regulator, an antioxidant, a preservative and an active ingredient VS-S103A according to the prescription in the table, dissolving the osmotic pressure regulator, the antioxidant, the preservative and the active ingredient VS-S103A into the buffer solution, premixing the VS-S103A and the organic reagent before dissolving for 10-20 min, and not waiting for complete dissolving until the active ingredient VS-S103A is dissolved into the buffer solution to ensure that the concentration of the active ingredient VS-S103A is 1.2mg/ml. Slowly stirring until the medicine powder is completely dissolved, controlling the temperature at 20-30 ℃, regulating the pH value of the solution to a target value range of pH 7.9+/-0.5 by using dilute hydrochloric acid/sodium hydroxide, and then filtering the preparation solution by a filter with the size of 0.22 mu m to obtain a target preparation solution, wherein the preparation is colorless and clear solution without visible foreign matters.
Table 11 Table of the composition and the ratio of the composite components
The prepared preparation is respectively placed in a cold white light environment with 5000 Lux+/-500 Lux (containing ultraviolet light), the temperature is controlled to be 3-8 ℃, the acceleration condition (23-27 ℃) and the long-term condition (2-8 ℃), the main peak purity (area normalization method) of the monomer content (SEC-HPLC) and related substances (RP-HPLC) is detected, and the results are as follows:
TABLE 12 detection results of the monomer content and the purity of the main peaks of the related substances under the illumination condition
TABLE 13 detection results of the monomer content and the purity of the main peaks of the related substances under accelerated conditions
TABLE 14 results of measurements of the monomer content and the purity of the main peaks of the related substances under long-term conditions
Through 9 groups of prescription experiments, the moderate methionine addition can be seen, and the degradation of the main peak purity of the preparation is relatively well inhibited. All prescriptions were colorless, clear solutions during the study period, with no visible foreign body.
The purity of the active component of the medicine can be maintained to be more than 90% in the accelerating condition (23-27 ℃) for 3 months, and the monomer content of the active component of the medicine and the purity of the active component of the medicine are still maintained to be more than 90% and the purity of the active component of the medicine to be more than 95% in the condition of strong light within 1 week, so that the stability of the medicine during long-term storage can be relatively well maintained.
EXAMPLE 6 drug efficacy of candidate drug formulations in STZ diabetes model mice
STZ diabetes model mice are type II diabetes models constructed using a high-glucose high-fat diet in combination with low-dose Streptozotocin (STZ) to induce C57BL/6J mice, with significant increases in blood glucose levels, but no significant differences in body weight, over normal mice. The candidate drug formulation was selected from the formulation in example 5 and was administered subcutaneously once every three days on the experimental schedule at two doses of 3nmol/kg and 10nmol/kg for a total of four weeks.
The present example is divided into 10 treatment groups, specifically:
g1: WT mice injected with solvent control
And G2: injection solvent control for STZ diabetes model mice
And G3: stavudine control (41.14 μg/kg)
And G4: norand nod triple agonists [1] Control group (14.67 mug/kg)
And G5: the P1 formulation low dose group (14.70. Mu.g/kg) in Table 11
G6: high dose group of P1 formulation in Table 11 (48.99 μg/kg)
And G7: the P3 formulation low dose group in Table 11 (14.66. Mu.g/kg)
G8: high dose group of P3 formulations in Table 11 (48.85 μg/kg)
And G9: the P4 formulation low dose group (14.59. Mu.g/kg) in Table 11
G10: high dose group of P4 formulation in Table 11 (48.64. Mu.g/kg)
Blood glucose was measured on days 7 and 14 of dosing with 6h fast (fig. 1a and b), blood glucose was measured on days 28 of dosing with two days fast (fig. 1C), postprandial blood glucose was measured on day 21 of dosing with one day (fig. 1D), and postprandial blood glucose was measured on day 22 of dosing with two days (fig. 1E).
The fasting blood sugar on the day of administration can be reduced to normal level by other drugs and dosage except G9, and the fasting blood sugar has very good suppressing effect after two days of administration (figures 1, A and B, C). Postprandial blood glucose also has a similar trend, and high dose groups of G6, G8, G10, semaglutin can maintain blood glucose at normal levels for less than two days of administration (fig. 1, d, E). Since the drug candidate of the Likemaglutide can lower the blood sugar to the lower limit, namely normal blood sugar value, at the dosage of 10nmol/kg every three days, the difference between the drug candidate and the Likemaglutide is not obvious, and the risk of hypoglycemia is further shown that the drug candidate and the Likemaglutide are not in existence in the process of the combination of the Likemaglutide and the three agonists.
EXAMPLE 7 acute toxicity test results of candidate drug formulations in ICH mice
In order to verify the biological safety of candidate medicines of the VS-S103A pharmaceutical preparation, a P3 pharmaceutical preparation with mature production process, high yield and good drug effect is selected as a first candidate medicine, and acute toxicity research is carried out in ICH mice. Similarly, we selected semaglutin as the control drug for head-to-head comparison. A total of two doses were used for investigation, the low dose being 15mg/kg, approximately 350 times the therapeutic dose; the high dose is 25mg/kg, approximately 650 times the therapeutic dose. With a single subcutaneous injection, the high dose P3 and semaglutin were injected first, one week after dosing was observed, the adverse effects of the mice were recorded, body weight, food intake were recorded, then the low dose P3 and semaglutin were injected, one week after dosing was observed, the adverse effects, body weight, food intake were also recorded, and after two weeks the mice were dissected and the viscera were observed.
The observation of the behavior of mice shows that no matter how high the dosage of the P3 pharmaceutical preparation and the semeglutide is, the reactions such as retardation, bow back, somnolence and the like generally appear three days before injection, gradually disappear from the fourth day, no gastrointestinal adverse reaction common to GLP-1 analogue medicines appears, and the overall adverse reaction is slight. There was no significant difference between the P3 drug formulation and semaglutin from the perspective of food intake and body weight, nor was there any significant difference found in organ anatomy. Therefore, the P3 pharmaceutical preparation is similar to semaglutin in acute toxicity, and has better biological safety.
Reference to the literature
[1]Finan,B.et al.A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents.Nat Med 21,27-36,doi:10.1038/nm.3761(2015).
Claims (15)
1. A pharmaceutical formulation comprising VS-S103A, characterized in that the pharmaceutical formulation comprises VS-S103A and a pharmaceutically acceptable buffer, wherein the VS-S103A is dissolved in the pharmaceutically acceptable buffer, and wherein the pH of the pharmaceutical formulation comprising VS-S103A is in the range of 6.5 to 9.5, preferably in the range of 7.0 to 8.8, more preferably in the range of 7.4 to 8.4.
2. The pharmaceutical formulation comprising VS-S103A according to claim 1, wherein VS-S103A is the only active ingredient of the pharmaceutical formulation.
3. The pharmaceutical formulation comprising VS-S103A according to claim 1, wherein the buffer is selected from the group consisting of sodium phosphate buffer, tris-HCL buffer, sodium citrate buffer, arginine hydrochloride buffer, glycine hydrochloride buffer, sodium phosphate buffer, sodium acetate buffer, and combinations thereof.
4. The pharmaceutical formulation comprising VS-S103A according to claim 1, wherein the concentration of the buffer is in the range of 5mM/L to 200mM/L, preferably 5mM/L to 100mM/L, most preferably 10mM/L to 50mM/L.
5. The pharmaceutical formulation comprising VS-S103A according to claim 1, wherein the concentration of VS-S103A in the buffer is in the range of 0.1mg/ml to 10mg/ml.
6. The pharmaceutical formulation comprising VS-S103A according to claim 1, further comprising a pharmaceutically acceptable preservative selected from the group consisting of phenol, m-cresol, o-cresol, p-cresol, methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate, butyl p-hydroxybenzoate, at a concentration in the pharmaceutical formulation in the range of 1mg/ml to 10mg/ml.
7. The pharmaceutical formulation comprising VS-S103A according to claim 1, further comprising a pharmaceutically acceptable osmolality adjusting agent selected from one of glycerol, propylene glycol, trehalose, sucrose, mannitol, xylitol, lactose, sodium chloride, sorbitol or a combination of different osmolality adjusting agents, said osmolality adjusting agent being present in the pharmaceutical formulation in a concentration ranging from 0.5mg/ml to 200mg/ml.
8. The pharmaceutical formulation comprising VS-S103A according to claim 1, further comprising a pharmaceutically acceptable antioxidant selected from the group consisting of methionine, sodium thiosulfate, sodium sulfite and combinations of different antioxidants, wherein the concentration of the antioxidant in the pharmaceutical formulation is in the range of 0.5mg/ml to 50mg/ml.
9. The pharmaceutical preparation containing VS-S103A according to claim 1, characterized in that it contains 0.1mg/ml to 30mg/ml of VS-S103A as an active ingredient; contains disodium hydrogen phosphate buffer solution with pH range of 7.0-8.8 and concentration of 5 mM-200 mM or Tris-HCL buffer solution with concentration of 5 mM-200 mM as buffer solution; contains 10 mg/ml-50 mg/ml propylene glycol or 10 mg/ml-100 mg/ml mannitol and 10 mg/ml-200 mg/ml trehalose as osmotic pressure regulator; methionine of 0.5mg/ml to 50mg/ml as an antioxidant; contains 1mg/ml to 10mg/ml of phenol or m-cresol as a preservative.
10. The pharmaceutical preparation containing VS-S103A according to claim 1, characterized in that it contains 0.1mg/ml to 20mg/ml of VS-S103A as an active ingredient; comprises disodium hydrogen phosphate buffer solution with the pH range of 7.4-8.4 and the concentration of 10 mM-50 mM as buffer solution; contains propylene glycol with the concentration of 8mg/ml to 20mg/ml or trehalose with the concentration of 10mg/ml to 150mg/ml as an osmotic pressure regulator; methionine of 0.5mg/ml to 30mg/ml as an antioxidant; phenol or m-cresol with the concentration of 2mg/ml to 8mg/ml is used as a preservative; preferably, the specific prescription of the pharmaceutical preparation containing VS-S103A is any one of the following:
11. the pharmaceutical preparation containing VS-S103A according to claim 1, characterized in that it contains 0.1mg/ml to 20mg/ml of VS-S103A as an active ingredient; contains Tris-HCL buffer solution with pH of 7.4-8.4 and concentration of 5-50 mM as buffer solution; contains 8 mg/ml-20 mg/ml of glycerin or 10 mg/ml-150 mg/ml of trehalose as osmotic pressure regulator; 0.5mg/ml to 30mg/ml of methionine or one or more compositions of sodium thiosulfate as an antioxidant; phenol or m-cresol with the concentration of 2mg/ml to 8mg/ml is used as a preservative; preferably, the specific prescription of the pharmaceutical preparation containing VS-S103A is any one of the following:
12. the pharmaceutical preparation containing VS-S103A according to claim 1, characterized in that it contains 0.1mg/ml to 20mg/ml of VS-S103A as an active ingredient; comprises disodium hydrogen phosphate buffer solution and/or arginine hydrochloride buffer solution with the pH range of 7.4-8.4 and the concentration of 10-50 mM as buffer solution; contains 8 mg/ml-20 mg/ml sorbitol or 1 mg/ml-10 mg/ml sodium chloride as osmotic pressure regulator; methionine of 0.5mg/ml to 30mg/ml as an antioxidant; phenol or m-cresol with the concentration of 2mg/ml to 8mg/ml is used as a preservative; preferably, the specific prescription of the pharmaceutical preparation containing VS-S103A is any one of the following:
13. the method for preparing the pharmaceutical preparation containing the VS-S103A according to claims 1 to 12, characterized in that the VS-S103A, the preservative, the osmotic pressure regulator and the antioxidant are dissolved in a pharmaceutically acceptable buffer according to the prescribed amount.
14. The preparation method according to claim 13, wherein the active substance is premixed with the preservative, the osmotic pressure regulator and the antioxidant for 10-20 min and diluted with the buffer solution to a concentrated solution; preferably, the concentrated solution is 60% -80% of the target capacity.
15. The method according to claim 13, wherein the buffer used in the preparation has a pH of 8.0 to 9.0.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111644995.1A CN116407614A (en) | 2021-12-29 | 2021-12-29 | Stable preparation of novel tri-agonist innovative biological medicine |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111644995.1A CN116407614A (en) | 2021-12-29 | 2021-12-29 | Stable preparation of novel tri-agonist innovative biological medicine |
Publications (1)
Publication Number | Publication Date |
---|---|
CN116407614A true CN116407614A (en) | 2023-07-11 |
Family
ID=87058132
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202111644995.1A Pending CN116407614A (en) | 2021-12-29 | 2021-12-29 | Stable preparation of novel tri-agonist innovative biological medicine |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN116407614A (en) |
-
2021
- 2021-12-29 CN CN202111644995.1A patent/CN116407614A/en active Pending
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20080248999A1 (en) | Amylin formulations | |
US20180161400A1 (en) | Antidiabetic oral insulin biguanide combination | |
WO1996006635A1 (en) | Pharmaceutical compositions containing a bile salt and a buffer for increased bioavailability of an active compound | |
EP3295952B1 (en) | Pharmaceutical formulation comprising glp-1 analogue and preparation method thereof | |
EP3532029B1 (en) | Liquid pharmaceutical composition | |
JP2005537232A (en) | Formulation of amylin agonist peptide | |
US8410052B2 (en) | Oral administration of a calcitonin | |
US20240065978A1 (en) | Formulations of glucagon-like-peptide-2 (glp-2) analogues | |
EP0726075A1 (en) | Pharmaceutical non-inorganic saline solutions for endonasal administration | |
KR20220020821A (en) | Pharmaceutical parenteral composition of dual GLP1/2 agonist | |
CN116407614A (en) | Stable preparation of novel tri-agonist innovative biological medicine | |
EP3856767B1 (en) | Formulations of glucagon-like-peptide-2 (glp-2) analogues | |
WO2013071396A1 (en) | Oral leptin formulations and uses thereof | |
EP3402505B1 (en) | Pharmaceutical formulations for the treatment of diabetes | |
WO2018188565A1 (en) | Polypeptide and composition thereof for treating diseases of metabolic system | |
US11471512B2 (en) | Pharmaceutical compositions of a peptide | |
US20230151073A1 (en) | Fibrillation resistant calcitonin peptides and uses thereof | |
RU2815643C2 (en) | Pharmaceutical parenteral composition of double agonist glp1/2 | |
JP2024501256A (en) | Therapeutic peptide preparations | |
WO1995022342A1 (en) | Pharmaceutical formulations of ciliary neurotrophic factor | |
NZ773548A (en) | Stable intranasal formulations of carbetocin | |
US20160095904A1 (en) | Stabilized liquid formulation | |
MXPA97001455A (en) | Pharmaceutical compositions containing a salvage and a regulator to increase the biodisponibility of a compound act | |
NZ617828B2 (en) | Controlled release peptide formulations |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |