CN107684550A - Treating diabetes product and its preparation and application - Google Patents
Treating diabetes product and its preparation and application Download PDFInfo
- Publication number
- CN107684550A CN107684550A CN201610629475.6A CN201610629475A CN107684550A CN 107684550 A CN107684550 A CN 107684550A CN 201610629475 A CN201610629475 A CN 201610629475A CN 107684550 A CN107684550 A CN 107684550A
- Authority
- CN
- China
- Prior art keywords
- treating diabetes
- acid
- combination
- delivery formulations
- oral
- 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
- 206010012601 diabetes mellitus Diseases 0.000 title claims abstract description 71
- 238000002360 preparation method Methods 0.000 title abstract description 18
- 239000000203 mixture Substances 0.000 claims abstract description 78
- 238000009472 formulation Methods 0.000 claims abstract description 71
- 235000016709 nutrition Nutrition 0.000 claims abstract description 66
- 239000004615 ingredient Substances 0.000 claims abstract description 63
- 229920000642 polymer Polymers 0.000 claims abstract description 52
- 210000003405 ileum Anatomy 0.000 claims abstract description 50
- 210000001072 colon Anatomy 0.000 claims abstract description 46
- 210000004347 intestinal mucosa Anatomy 0.000 claims abstract description 40
- 238000011282 treatment Methods 0.000 claims abstract description 20
- 230000004060 metabolic process Effects 0.000 claims abstract description 19
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 42
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 39
- 239000000047 product Substances 0.000 claims description 36
- 229920001661 Chitosan Polymers 0.000 claims description 28
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 claims description 28
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 26
- 238000006177 thiolation reaction Methods 0.000 claims description 23
- 239000004475 Arginine Substances 0.000 claims description 21
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 21
- 235000019260 propionic acid Nutrition 0.000 claims description 21
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 21
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 claims description 20
- 239000003814 drug Substances 0.000 claims description 19
- 230000001360 synchronised effect Effects 0.000 claims description 15
- 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 claims description 14
- 239000008103 glucose Substances 0.000 claims description 14
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 14
- 208000008589 Obesity Diseases 0.000 claims description 12
- 235000020824 obesity Nutrition 0.000 claims description 11
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 10
- 150000004668 long chain fatty acids Chemical class 0.000 claims description 9
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 claims description 8
- 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 claims description 8
- 239000003613 bile acid Substances 0.000 claims description 8
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 6
- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 6
- 206010036049 Polycystic ovaries Diseases 0.000 claims description 6
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 6
- 235000021407 appetite control Nutrition 0.000 claims description 6
- 201000010065 polycystic ovary syndrome Diseases 0.000 claims description 6
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 claims description 5
- 206010018429 Glucose tolerance impaired Diseases 0.000 claims description 5
- 208000001280 Prediabetic State Diseases 0.000 claims description 5
- 201000009104 prediabetes syndrome Diseases 0.000 claims description 5
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 3
- 206010018473 Glycosuria Diseases 0.000 claims description 3
- 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 3
- 102000004856 Lectins Human genes 0.000 claims description 3
- 108090001090 Lectins Proteins 0.000 claims description 3
- 239000004793 Polystyrene Substances 0.000 claims description 3
- 229920002125 Sokalan® Polymers 0.000 claims description 3
- 229910021529 ammonia Inorganic materials 0.000 claims description 3
- 229960001631 carbomer Drugs 0.000 claims description 3
- 239000000017 hydrogel Substances 0.000 claims description 3
- 229920001477 hydrophilic polymer Polymers 0.000 claims description 3
- 239000002523 lectin Substances 0.000 claims description 3
- 229920002223 polystyrene Polymers 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 239000007857 degradation product Substances 0.000 claims description 2
- 230000017854 proteolysis Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- 229920002807 Thiomer Polymers 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 206010025482 malaise Diseases 0.000 claims 1
- 210000001198 duodenum Anatomy 0.000 abstract description 17
- 230000002183 duodenal effect Effects 0.000 abstract description 13
- 230000000694 effects Effects 0.000 abstract description 12
- 210000004877 mucosa Anatomy 0.000 abstract description 9
- 238000010521 absorption reaction Methods 0.000 abstract description 6
- 238000004088 simulation Methods 0.000 abstract description 3
- 238000007876 drug discovery Methods 0.000 abstract description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
- 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 24
- 210000002784 stomach Anatomy 0.000 description 23
- 210000004027 cell Anatomy 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 238000005516 engineering process Methods 0.000 description 18
- 102100040918 Pro-glucagon Human genes 0.000 description 17
- 210000001035 gastrointestinal tract Anatomy 0.000 description 16
- 238000000034 method Methods 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical class 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 14
- 210000004369 blood Anatomy 0.000 description 14
- 239000008280 blood Substances 0.000 description 14
- 102000004877 Insulin Human genes 0.000 description 12
- 108090001061 Insulin Proteins 0.000 description 12
- 229940125396 insulin Drugs 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 230000001225 therapeutic effect Effects 0.000 description 12
- 210000000936 intestine Anatomy 0.000 description 10
- 239000000463 material Substances 0.000 description 10
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 9
- 239000006187 pill Substances 0.000 description 9
- 230000028327 secretion Effects 0.000 description 9
- 230000008685 targeting Effects 0.000 description 9
- 108010004460 Gastric Inhibitory Polypeptide Proteins 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 239000002702 enteric coating Substances 0.000 description 8
- 238000009505 enteric coating Methods 0.000 description 8
- 229940088597 hormone Drugs 0.000 description 8
- 239000005556 hormone Substances 0.000 description 8
- 239000011806 microball Substances 0.000 description 8
- 230000003232 mucoadhesive effect Effects 0.000 description 8
- YNXLOPYTAAFMTN-SBUIBGKBSA-N C([C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)C1=CC=C(O)C=C1 Chemical compound C([C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)C1=CC=C(O)C=C1 YNXLOPYTAAFMTN-SBUIBGKBSA-N 0.000 description 7
- 229920003141 Eudragit® S 100 Polymers 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 235000013305 food Nutrition 0.000 description 7
- 239000003629 gastrointestinal hormone Substances 0.000 description 7
- 239000004005 microsphere Substances 0.000 description 7
- 102100039994 Gastric inhibitory polypeptide Human genes 0.000 description 6
- 206010022489 Insulin Resistance Diseases 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 235000008935 nutritious Nutrition 0.000 description 6
- 101800000221 Glucagon-like peptide 2 Proteins 0.000 description 5
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 230000003914 insulin secretion Effects 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 230000004936 stimulating effect Effects 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 108010077544 Chromatin Proteins 0.000 description 4
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 4
- 102400000326 Glucagon-like peptide 2 Human genes 0.000 description 4
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 235000001014 amino acid Nutrition 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 4
- 239000012876 carrier material Substances 0.000 description 4
- 210000003483 chromatin Anatomy 0.000 description 4
- 230000001419 dependent effect Effects 0.000 description 4
- 238000012377 drug delivery Methods 0.000 description 4
- TWSALRJGPBVBQU-PKQQPRCHSA-N glucagon-like peptide 2 Chemical compound C([C@@H](C(=O)N[C@H](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]([C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O)[C@@H](C)CC)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=CC=C1 TWSALRJGPBVBQU-PKQQPRCHSA-N 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 239000004925 Acrylic resin Substances 0.000 description 3
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 3
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 3
- 206010033307 Overweight Diseases 0.000 description 3
- 102400000319 Oxyntomodulin Human genes 0.000 description 3
- 101800001388 Oxyntomodulin Proteins 0.000 description 3
- 102100029909 Peptide YY Human genes 0.000 description 3
- 235000004279 alanine Nutrition 0.000 description 3
- 235000019789 appetite Nutrition 0.000 description 3
- 230000036528 appetite Effects 0.000 description 3
- 210000003719 b-lymphocyte Anatomy 0.000 description 3
- 230000023852 carbohydrate metabolic process Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000003405 delayed action preparation Substances 0.000 description 3
- 235000005911 diet Nutrition 0.000 description 3
- 230000037213 diet Effects 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 238000002651 drug therapy Methods 0.000 description 3
- 230000002124 endocrine Effects 0.000 description 3
- 210000001630 jejunum Anatomy 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- PXZWGQLGAKCNKD-DPNMSELWSA-N molport-023-276-326 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(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)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 PXZWGQLGAKCNKD-DPNMSELWSA-N 0.000 description 3
- 230000035764 nutrition Effects 0.000 description 3
- 210000000496 pancreas Anatomy 0.000 description 3
- 239000000902 placebo Substances 0.000 description 3
- 229940068196 placebo Drugs 0.000 description 3
- 229920001184 polypeptide Polymers 0.000 description 3
- 210000000813 small intestine Anatomy 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 description 2
- 229940123208 Biguanide Drugs 0.000 description 2
- 101800000224 Glucagon-like peptide 1 Proteins 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- 101000684208 Homo sapiens Prolyl endopeptidase FAP Proteins 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 229940100389 Sulfonylurea Drugs 0.000 description 2
- 229940123464 Thiazolidinedione Drugs 0.000 description 2
- 229960002632 acarbose Drugs 0.000 description 2
- XUFXOAAUWZOOIT-UHFFFAOYSA-N acarviostatin I01 Natural products OC1C(O)C(NC2C(C(O)C(O)C(CO)=C2)O)C(C)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O XUFXOAAUWZOOIT-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 150000004283 biguanides Chemical class 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000009509 drug development Methods 0.000 description 2
- 235000020828 fasting Nutrition 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 230000030136 gastric emptying Effects 0.000 description 2
- 229960004580 glibenclamide Drugs 0.000 description 2
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 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 2
- 239000000859 incretin Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 210000004153 islets of langerhan Anatomy 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 210000004400 mucous membrane Anatomy 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 238000007410 oral glucose tolerance test Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 2
- 230000002980 postoperative effect Effects 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 229960004586 rosiglitazone Drugs 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical compound O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 description 1
- BOVGTQGAOIONJV-BETUJISGSA-N 1-[(3ar,6as)-3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-2-yl]-3-(4-methylphenyl)sulfonylurea Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1C[C@H]2CCC[C@H]2C1 BOVGTQGAOIONJV-BETUJISGSA-N 0.000 description 1
- LLJFMFZYVVLQKT-UHFFFAOYSA-N 1-cyclohexyl-3-[4-[2-(7-methoxy-4,4-dimethyl-1,3-dioxo-2-isoquinolinyl)ethyl]phenyl]sulfonylurea Chemical compound C=1C(OC)=CC=C(C(C2=O)(C)C)C=1C(=O)N2CCC(C=C1)=CC=C1S(=O)(=O)NC(=O)NC1CCCCC1 LLJFMFZYVVLQKT-UHFFFAOYSA-N 0.000 description 1
- 206010000087 Abdominal pain upper Diseases 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 208000008279 Dumping Syndrome Diseases 0.000 description 1
- 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 1
- 108010011459 Exenatide Proteins 0.000 description 1
- 208000003790 Foot Ulcer Diseases 0.000 description 1
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 1
- 102000051325 Glucagon Human genes 0.000 description 1
- 108060003199 Glucagon Proteins 0.000 description 1
- FAEKWTJYAYMJKF-QHCPKHFHSA-N GlucoNorm Chemical compound C1=C(C(O)=O)C(OCC)=CC(CC(=O)N[C@@H](CC(C)C)C=2C(=CC=CC=2)N2CCCCC2)=C1 FAEKWTJYAYMJKF-QHCPKHFHSA-N 0.000 description 1
- 229920002527 Glycogen Polymers 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 206010019909 Hernia Diseases 0.000 description 1
- 108091016366 Histone-lysine N-methyltransferase EHMT1 Proteins 0.000 description 1
- 101001039966 Homo sapiens Pro-glucagon Proteins 0.000 description 1
- 206010021135 Hypovitaminosis Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 229940122199 Insulin secretagogue Drugs 0.000 description 1
- 102100024295 Maltase-glucoamylase Human genes 0.000 description 1
- IBAQFPQHRJAVAV-ULAWRXDQSA-N Miglitol Chemical compound OCCN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO IBAQFPQHRJAVAV-ULAWRXDQSA-N 0.000 description 1
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- 108010088847 Peptide YY Proteins 0.000 description 1
- 208000032395 Post gastric surgery syndrome Diseases 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 102000007156 Resistin Human genes 0.000 description 1
- 108010047909 Resistin Proteins 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- LPQOADBMXVRBNX-UHFFFAOYSA-N ac1ldcw0 Chemical compound Cl.C1CN(C)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN3CCSC1=C32 LPQOADBMXVRBNX-UHFFFAOYSA-N 0.000 description 1
- 239000000370 acceptor Substances 0.000 description 1
- 230000009858 acid secretion Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 108010028144 alpha-Glucosidases Proteins 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical class [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- 239000011805 ball Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 239000012490 blank solution Substances 0.000 description 1
- 208000034158 bleeding Diseases 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 235000020805 dietary restrictions Nutrition 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 229960001519 exenatide Drugs 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 229960000346 gliclazide Drugs 0.000 description 1
- 229960004346 glimepiride Drugs 0.000 description 1
- WIGIZIANZCJQQY-RUCARUNLSA-N glimepiride Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)N[C@@H]2CC[C@@H](C)CC2)C=C1 WIGIZIANZCJQQY-RUCARUNLSA-N 0.000 description 1
- ZJJXGWJIGJFDTL-UHFFFAOYSA-N glipizide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZJJXGWJIGJFDTL-UHFFFAOYSA-N 0.000 description 1
- 229960001381 glipizide Drugs 0.000 description 1
- 229960003468 gliquidone Drugs 0.000 description 1
- 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 1
- 229960004666 glucagon Drugs 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 230000002641 glycemic effect Effects 0.000 description 1
- 229940096919 glycogen Drugs 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 206010022498 insulinoma Diseases 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000004130 lipolysis Effects 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229960001110 miglitol Drugs 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 229960000698 nateglinide Drugs 0.000 description 1
- OELFLUMRDSZNSF-BRWVUGGUSA-N nateglinide Chemical compound C1C[C@@H](C(C)C)CC[C@@H]1C(=O)N[C@@H](C(O)=O)CC1=CC=CC=C1 OELFLUMRDSZNSF-BRWVUGGUSA-N 0.000 description 1
- YCIMNLLNPGFGHC-UHFFFAOYSA-N o-dihydroxy-benzene Natural products OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 208000021255 pancreatic insulinoma Diseases 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 229960005095 pioglitazone Drugs 0.000 description 1
- 229920000307 polymer substrate Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229960003611 pramlintide Drugs 0.000 description 1
- 108010029667 pramlintide Proteins 0.000 description 1
- NRKVKVQDUCJPIZ-MKAGXXMWSA-N pramlintide acetate Chemical compound C([C@@H](C(=O)NCC(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CS)NC(=O)[C@@H](N)CCCCN)[C@@H](C)O)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 NRKVKVQDUCJPIZ-MKAGXXMWSA-N 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 229960002354 repaglinide Drugs 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 239000000837 restrainer Substances 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
-
- 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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
-
- 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
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
- A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention belongs to Field of Drug Discovery, and in particular to a kind for the treatment of diabetes product and its preparation and application.The treating diabetes product contains in orally positioning delivery formulations contain nutritional ingredient described in terminal ileum and the oral positioning delivery formulations of colon specific.The present invention is by in-depth study extensively, find first, using the treating diabetes product of the present invention, nutritional ingredient is positioned to terminal ileum and colon and discharged, or combine to position intestinal mucosa sticky polymers to duodenum simultaneously and discharged, with allow the intestinal mucosa sticky polymers be attached to duodenal mucosa formed shielding, prevent duodenal absorption, can more perfect simulation and reach metabolism operation effect.
Description
Technical field
The invention belongs to Field of Drug Discovery, and in particular to a kind for the treatment of diabetes product and its preparation and application.
Background technology
Diabetes B affects health of the whole world more than 4.15 hundred million populations at present, more seriously in coming 10 years
The interior death rate related to diabetes can be increased beyond 50%.Planning commission's issue data are defended according to China to show, at present diabetes mellitus in China
Adult's diabetes B illness rate has reached 11.4%, soars to No. 1 in the world, reaches 1.4 hundred million people, caused by diabetes
The generation of complication such as heart disease, renal failure, blindness, foot ulcers etc. also linear ascendant trend.In addition, China also has
20% population is in prediabetes, and the glycometabolism of this groups of people is abnormal.
Diabetes B mainly from based on insulin resistance with hypoinsulinism to hypoinsulinism with pancreas
Insulin resistance.And type 1 diabetes are primarily due to B cell destruction, insulin definitely lacks and caused, and the overwhelming majority is autoimmunity
Property disease.
Meanwhile the whole world has nearly 1/3rd people overweight or fat.In China, obesity is in explosive growth.It there are about at present
43.6%, i.e., 600,000,000 Chinese are overweight or fat.Obesity turns into global a great problem.Obesity can cause a system
Row complication or relevant disease, and then influence our life-span or cause quality of life to decline.Diabetes generally with obesity
And deposit.The number with diabetes accounts for the pathogenic factor of the fat often diabetes of 41.5%. in fat person.
The treatment of diabetes B at present is mainly drug therapy, and the species of medicine is various, for example (such as diformazan is double for biguanides
Guanidine), sulfonylureas (such as Glimepiride, glibenclamide, gliclazide and gliquidone), thiazolidinediones (such as Rosiglitazone and
Pioglitazone), benzoic acid derivative class, insulin secretagogue, alpha-glucosidase restrainer (such as acarbose and Fu Gelie
Ripple sugar), GLP-1 analogs, DPPIV etc..
But these medicines have a certain degree of side effect, for example many patients can produce stomach when taking melbine
The side effect in road and can not use, DPPIV medicines are then found that the risk of heart failure can be increased；Long-term use of diabetes medicament
Be also easy to produce drug resistance, thus often the uncontrollable blood glucose of medicine, it is necessary to which dressing or drug combination, are eventually transitioned into as pancreas islet
Plain dependent diabetes；These medicines are required for the metabolism discharge of liver kidney, and the patient of hepatic and kidney function obstacle can not use；Obviously
, these medicines and insulin are merely able to control blood glucose, cured the symptoms, not the disease, it is necessary to use all the life.
Develop the exploitation focus that various new Remedies for diabetes are always each drugmaker and research institution.
The metabolism operative treatment diabetes B guide that the first more tissue joints in the whole world on May 24th, 2016 are formulated -- it is international
Diabetic tissue, which is combined, has delivered metabolism operative treatment diabetes B American Diabetes Association (ADA), IDF
(IDF), U.K. Diabetes association (DUK), diabetology branch of Chinese Medical Association (CDS) and India's diabetology meeting (DI) etc. 45
The accreditation to guideline representation of individual international organization.Metabolism operation should turn into diabetes B therapeutic strategy.This guide is nearly one
What diabetes B therapy field occurred since century most sexually revises at all.
Show according to being counted all over the world to the clinical research that metabolism is performed the operation in the past few decades, 80%-95% diabetes
People is being metabolized Post operation, and without any drug therapy and special diet, blood glucose, insulin, glycosylation hemalbumin recover normal.It is right
The postoperative 5-10 for many years of these patients follow-up finds that the patients with NIDDM blood sugar recovery more than 80% is normal, and is not required to
Any drug therapy and dietary restriction are wanted, diabetic symptom can obtain significantly to alleviate and even up to cure and can tie up for a long time completely
Hold, and the effect for changing the gastric bypass operation of intestines and stomach order will be substantially better than simple stomach volume limitation operation, that is,
Say, metabolism operation turns into a kind of unique therapeutic strategy that can cure diabetes.
The core performed the operation with stomach turn of tidal stream as the metabolism therapeutic method of surgery of representative is that the normal physiological for changing food flows to, and is reached
To the purpose Post operation for curing diabetes, the food of upper digestive tract has turn of tidal stream, and they are no longer pass through the both ends of stomach, duodenum
With jejunum upper end.
The main reason for diet is reduced, weight loss is not metabolism operative treatment diabetes, glycemic control and diabetes
Symptom improves will be much earlier than Body weight loss.Main research shows at present, and metabolism operation changes the endocrine hormone of intestines and stomach,
It is the main mechanism that postoperative diabetes are cured for a long time.It should be evident, however, that metabolism operation is the surgical operation of a duplication, surgery is cured
Raw skill set requirements are higher, and multiple complications risk also be present, such as internal bleeding, stomachache, hernia, constipation or diarrhoea,
Dumping syndrome, infection, hypovitaminosis etc..
K cells are mainly distributed on small intestine epimere, are included sugar, protein by food nourishment composition, fat secretes GIP after stimulating
Pancreas islet such as (glucose dependent insulin release peptide Glucose-dependent insulinotropic polypeptide)
Plain resistance factor.L cells are mainly distributed on small intestine hypomere and colorectal mucosa, if subjected to glucose, amino acid, aliphatic acid etc. pierce
GLP-1 (glucagon-like-peptide-1 Glucagon-like peptide-1) can be produced after swashing, the endocrine such as GLP-2, PYY swashs
Element, so as to strengthen insulin secretion, insulin resistance is reduced, improves glycometabolism.
GIP is duodenum and the synthesis of jejunum epimere K cells, a kind of incretin of secretion, is mainly pierced by diet
Swash its secretion.Its excessive secretion can cause lipid in peripheral tissues' (liver, muscle etc.) and the deposition of B cell, so that
Insulin resistance and secreting function is caused to be damaged, and the secretion for suppressing GIP can be obviously improved and fat 2 related type glycosurias
Disease.
GLP-1 is distal ileum and the synthesis of large intestine L cells, a kind of incretin of secretion, glucose, ammonia in food
Base acid and fat are the main nutriments for stimulating it to discharge, and GLP-1 can promote Glycogen synthesis and lipolysis, suppress stomach
Emptying and glucagon secretion, increase the gene expression of insulin and the synthesis of insulin precurosor, while also promote B cell to increase
Raw and suppression apoptosis.Many drug developments concentrate on treats the illness such as diabetes, obesity using GLP-1, but human body is natural
GLP-1 is very unstable, can be degraded by dipeptidyl peptidase IV (DPP IV), half-life period is only 1~2 minute.Swashed by GLP-1 acceptors
Dynamic agent, either directly synthesis long-acting GLP-1 analog or the degraded for passing through little molecules in inhibiting GLP-1 are the heat of drug development
Point.
GLP-2 (glucagon-like-peptide-2 glucagon-like peptide-2) is 33 amino secreted by L cells
The polypeptide of acid.GLP-2 is newly discovered enteric epithelium specificity growth factor, has many effects to intestines and stomach, including promote
Enter the growth and development of normal small intestine, protect and repair the intestinal mucosa damaged in various intestines problems, the secretion of gastric acid inhibitory and
The motion of stomach and intestine, increase blood supply of enteron aisle etc..
PYY is also the polypeptide for 36 amino acid secreted by L cells.It can reduce appetite.
Oxyntomodulin (OXM) is the polypeptide for 37 amino acid secreted by L cells, can reduce appetite, suppresses stomach
Acid secretion.
Post operation is metabolized, the upper digestive tract including duodenum no longer receives food stimulus, is mainly distributed on and disappears
The resistins such as GIP would not be secreted by changing the K cells of mucous membrane, and the Insulin resistance of body will eliminate.Together
When, without the food digested completely, lower digestive tract in can entering earlier, distribution inside lower digestive tract mucous membrane will be stimulated
L cells, secrete the hormone such as PYY, GLP1, GLP2, OXM.These hormones play the role of common：First, it is directly hypoglycemic；Second,
Eliminate the apoptosis of islet cells；3rd, insulinoma cell proliferation can be stimulated.These hormones can also protect islet cells not by picture
The harm of sugared toxicity, Fatty toxicity and some other inflammation；4th, appetite is reduced, reduces food intake.
The content of the invention
In order to overcome the problems of in the prior art, it is an object of the invention to provide a kind for the treatment of diabetes product
And its preparation and application.
To achieve these goals and other related purposes, the present invention adopt the following technical scheme that：
The first aspect of the present invention provides a kind for the treatment of diabetes product, and the treating diabetes product contains in ileum
End and the oral positioning delivery formulations of colon specific, the oral positioning delivery formulations contain nutritional ingredient.
The terminal ileum refers to ileum close to the position of colon.
Preferably, the nutritional ingredient is selected from：Any of carbohydrate, fat or protein degradation products are more
The combination of kind.
Preferably, the nutritional ingredient is selected from：Acetic acid, propionic acid, butyric acid, bile acid, long chain fatty acids, glucose, paddy ammonia
Any of acid amides or arginine or a variety of combinations.
Preferably, the nutritional ingredient is：Propionic acid and arginic combination, the combination of propionic acid and glutamine, acetic acid and
Arginic combination, the combination of acetic acid and glutamine, combination, the courage of butyric acid and arginic combination, butyric acid and glutamine
Combination, long chain fatty acids and the arginic combination of the sour and arginic combination of juice, bile acid and glutamine, or long-chain fat
The combination of acid and glutamine.
The long chain fatty acids contain more than 14 carbon atoms.
Preferably, in each combination, the mass ratio between two kinds of nutritional ingredients is (1~10)：(1~10).
In the embodiment of the present invention, in each combination, the mass ratio between two kinds of nutritional ingredients is 1:1.
The use it is a discovery of the invention that two nutritional ingredients in each combination are put together, discharge stomach stimulating L cells
During intestinal hormones, there is collaboration facilitation between each other, the effect that 0.5+0.5 is more than 1 can be obtained.
Preferably, the nutritional ingredient is wrapped in intestinal mucosa sticky polymers.
The intestinal mucosa sticky polymers are prior art.
For example, Curr Drug Deliv 2015；12(2):139-56.
Mucoadhesive polymeric platform for drug delivery；a comprehensive
review.Disigned Monomers and Polymers 12(2009),483-495Polymers in
Mucoadhesive Drug Delivery System:Described in A Brief Note.
The preferred intestinal mucosa adhesion of intestinal mucosa sticky polymers is relatively strong, has no toxic side effect, bio-compatible
The good polymer of property.
Preferably, the intestinal mucosa sticky polymers are selected from hydrophilic polymer, Hydrogels polymer, Thiolation poly-
Any one or more combination in compound, lectin polymer.
Preferably, the intestinal mucosa sticky polymers are selected from chitosan, polystyrene, carbomer, the poly- Guang of carbomer-half
Propylhomoserin, polyacrylic acid-cysteine, polyacrylic acid-homocysteine, alginates-cysteine, the Guang of polymethylacrylic acid-half
Any one or more combination in propylhomoserin, sodium carboxymethylcellulose-cysteine.
It is further preferred that the intestinal mucosa sticky polymers are selected from Thiolation chitosan or chitosan-catechol
In any one or more combination.
Preferably, the intestinal mucosa sticky polymers can be prepared into the form of liquid microballoon.In terminal ileum and colon
After release, nutritional ingredient and the compactness and continuation of intestinal mucosa can be strengthened, be advantageous to the absorption of nutritional ingredient.
Preferably, the oral positioning delivery formulations for being set forth in terminal ileum and colon specific are enteric coated release
Preparation.
It is further preferred that be set forth in terminal ileum and the oral positioning delivery formulations of colon specific are sensitive for bag pH
The delivery formulations of type enteric coating.
Can be as requested, select the polymer of advantageous pH range dissolving.Ensure that nutritional ingredient is positioned at terminal ileum and knot
Enteric release.
Using polyacrylic resin Eudragit S100 as pH responsive type enteric coatings in one embodiment of the present invention.
Preferably, the treating diabetes product also includes oral Twelve-phase synchronous generator delivery formulations, and described oral 12
Contain intestinal mucosa sticky polymers in duodenum 12 positioning delivery formulations.
Preferably, the oral Twelve-phase synchronous generator delivery formulations position intestinal mucosa sticky polymers to duodenum
Discharged, the intestinal mucosa sticky polymers, which are attached in duodenal mucosa, forms shielding, duodenal to prevent
Absorption.
The intestinal mucosa sticky polymers are prior art.For example, Curr Drug Deliv 2015；12(2):139-
56.
Mucoadhesive polymeric platform for drug delivery；a comprehensive
review.Disigned Monomers and Polymers 12(2009),483-495Polymers in
Mucoadhesive Drug Delivery System:Described in A Brief Note.
The preferred intestinal mucosa adhesion of intestinal mucosa sticky polymers is relatively strong, has no toxic side effect, bio-compatible
The good polymer of property.
Preferably, the intestinal mucosa sticky polymers are selected from hydrophilic polymer, Hydrogels polymer, Thiolation poly-
Any of compound or lectin polymer or a variety of combinations.
Preferably, the intestinal mucosa sticky polymers are selected from chitosan, polystyrene, carbomer, the poly- Guang of carbomer-half
Propylhomoserin, polyacrylic acid-cysteine, polyacrylic acid-homocysteine, alginates-cysteine, the Guang of polymethylacrylic acid-half
Any one or more combination in propylhomoserin or sodium carboxymethylcellulose-cysteine.
It is further preferred that the intestinal mucosa sticky polymers are selected from Thiolation chitosan or chitosan-catechol
In any one or more combination.
Preferably, the intestinal mucosa sticky polymers can be prepared into the form of liquid microballoon.After duodenum release,
The contact area with intestinal mucosa can be increased, be easy to use.
Preferably, the oral Twelve-phase synchronous generator delivery formulations are enteric coated delivery formulations.
It is further preferred that release system of the oral Twelve-phase synchronous generator delivery formulations for bag pH responsive type enteric coatings
Agent.
Can be as requested, select advantageous pH range dissolving polymer, such as may be selected pH be more than 5.0 even more than
The polymer of quick release can be achieved when 3.0.Ensure that intestinal mucosa sticky polymers are positioned at duodenum release.
HPMCAM (HPMCAM) conduct is used in one embodiment of the present invention
Enteric coating.
Preferably, the treating diabetes product be used for type i diabetes, type ii diabetes, prediabetes, obesity,
Appetite control, metabolic syndrome or Stein-Leventhal syndrome treatment.
Preferably, the treating diabetes product is metabolism operative treatment substitute products.
No longer it can be treated using the patient of the treating diabetes product using metabolism operation.
It is further preferred that the treating diabetes are stomach turn of tidal stream operative treatment substitute products.
No longer it can be treated using the patient of the treating diabetes product using the operation of stomach turn of tidal stream.
The second aspect of the present invention, there is provided foregoing treating diabetes product prepare type i diabetes, type ii diabetes,
Purposes in prediabetes, obesity, appetite control, metabolic syndrome or Stein-Leventhal syndrome medicine.
Preferably, the medicine is metabolism operation alternative medicine.
Metabolism operative treatment can be no longer carried out using the patient of the medicine.
It is further preferred that the medicine is stomach turn of tidal stream operation alternative medicine.
Stomach turn of tidal stream operative treatment can be no longer carried out using the patient of the medicine.
The third aspect of the present invention, there is provided one kind treats type i diabetes, type ii diabetes, prediabetes, obesity
Disease, appetite control, the method for metabolic syndrome or Stein-Leventhal syndrome, including step：By the foregoing glycosuria of therapeutically effective amount
Sick treatment product is applied to corresponding subject.
Preferably, the method for application is oral.
Preferably, the alternative metabolism operative treatment of methods described.
It is further preferred that the alternative stomach turn of tidal stream operative treatment of methods described.
" therapeutically effective amount " means such any quantity, compared with no corresponding subject for receiving such quantity,
Cause improved treatment, healing, prevention or alleviation disease, illness or side effect, or reduce the progression rates of disease or illness.The art
Language also includes the quantity of effectively enhancing normal physiological function in the range of it.Therapeutically effective amount will produce " therapeutic effect ".
The present invention delay sustained release preparation of therapeutically effective amount will rely on many factors.For example, ethnic group/species of subject,
Definite situation and its order of severity, the property of preparation that age and body weight, needs are treated.Therapeutically effective amount finally should be by doctor
Judged.Anyway, for treating the present invention delay with diabetes or overweight condition and conditions associated patient
The effective dose of sustained release preparation, generally, it may be that 0.01 to 10g/kg recipients (mammal) body weight/day.More generally, effectively
Amount should be 30 to 300mg/kg body weight/days.Therefore, it is usual for the Adult Mammals of 70kg body weight, daily actual amount
It is from 2.1 to 21g.The quantity may be given with daily single dose or with daily some (such as 2,3,4,5 or more) divided doses to
Give so that total daily dose is identical.
Compared with prior art, the present invention has the advantages that：
The present invention has found, using the treating diabetes product of the present invention, by nutrition first by in-depth study extensively
Composition, which is positioned to terminal ileum and colon, to be discharged, or is combined to position intestinal mucosa sticky polymers to 12 simultaneously and referred to
Intestines are discharged, and are formed shielding to allow the intestinal mucosa sticky polymers to be attached to duodenal mucosa, are prevented duodenum
Absorption, can more perfect simulation and reach metabolism operation effect.
Brief description of the drawings
Fig. 1：In embodiment 1, the horizontal changes of GLP-1 in blood are analyzed.
Fig. 2：In embodiment 1, the horizontal changes of PYY in blood are analyzed.
Fig. 3：In embodiment 1, insulin level in blood is analyzed.
Fig. 4：In embodiment 1, blood glucose levels are analyzed.
Fig. 5：In embodiment 2, the microballoon that is prepared under component A Electronic Speculum.
Fig. 6：In embodiment 2, the microballoon that is prepared under B component Electronic Speculum.
Fig. 7：In embodiment 2, the horizontal changes of GLP-1 in blood are analyzed.
Fig. 8：In embodiment 2, insulin level in blood is analyzed.
Fig. 9：The mucoadhesive of CC microballoons and TC microballoons is tested respectively.
Embodiment
Present invention research finds some naturally occurring nutritional ingredients passing through upper digestive tract (Stomach duodenum, sky
Intestines) when do not discharge and reach terminal ileum and discharging during colon site, can treat more including diabetes, obesity etc.
Kind disease.It is acted on and therapy mechanism is similar to the operation of stomach turn of tidal stream, that is, avoid nutriment from stimulating upper digestive tract (stomach, 12
Duodenum 12, jejunum) K cells, suppress GIP (glucose dependent insulin release peptide Glucose-dependent
Insulinotropic polypeptide) etc. resistin secretion；Meanwhile the L of a large amount of stimulation lower digestive tracts is thin
Born of the same parents produce the endocrine hormones such as GLP-1 (glucagon-like-peptide-1 Glucagon-like peptide-1), GLP-2, PYY, from
And strengthen insulin secretion, insulin resistance is reduced, improves glycometabolism.
Natural nutritional ingredient includes aliphatic acid, monose or polysaccharide, amino acid；More satisfactory specific nutritional ingredient includes
Acetic acid, propionic acid, one or two is selected in butyric acid, bile acid, long chain fatty acids, glucose, glutamine or arginic group,
Even more than combination.Using the preparation that can deliver it to terminal ileum and colon, the stimulation nutrition of individual abundance is given
Material or its composition, it is sufficient to cause the L cells in individual lower digestive tract to discharge gastrointestinal hormone, and obtain desired result,
And avoid the stimulation of the K cells of upper digestive tract.
In currently available technology, there are a variety of formulation methods that material can be delivered to terminal ileum and colon progress
Release.In terminal ileum and the oral positioning delivery formulations of colon specific, after such delivery formulations is oral, kept in stomach
Completely, into after terminal ileum and colon, design requirement h substance can be pressed, reaches the purpose of quick-release and sustained release.For example, it can adopt
With enteric coated delivery formulations.That is, can be as requested, from the polymer of advantageous pH range dissolving.It is fixed to use
When delivery formulations, time and position by the length Drug controlled release that changes delivery formulations time lag.Due to the gastric emptying time
Influence, the purpose of terminal ileum and colon specific is not necessarily fully achieved in only application control delivery formulations time lag, can will
The technology and use enteric coating technology of control release time combines, to ensure that material only discharges in terminal ileum and colon.
Include but is not limited in the example of terminal ileum and the oral positioning delivery formulations of colon specific special in the U.S.
Sharp No.749307；3,845,770；3,916,899；3,536,809；3,598,123；4,008,719；5,674,533；5,
059,595；5,591,767；5,120,548；5,073,543；5,639,476；5,354,556；And described in 5,733,566
Those.Such formulation may be used in the HPMC of different proportion, other polymer substrates, gel, permeable
Film, osmosis system, multiple coatings, particulate, liposome, microsphere or its combination provide required release characteristics, to provide one
The release in terminal ileum and colon of kind or various active composition.
Preferably, we use and are prepared in terminal ileum and colon using the coating of commonplace pH value sensitive type at present
The oral positioning delivery formulations of release are positioned, naturally occurring nutrient compounds are delivered to terminal ileum and colon.It is set forth in
The oral positioning delivery formulations of terminal ileum and colon specific, it includes having the nutrient compounds comprising therapeutically effective amount
Core and the enteric coating being centered around around the core peroral dosage form.The pH sensitivity values of enteric coating can be set respectively
It is more preferably lasting at least about period of delay of 5 to 10 minutes after the pH of continuous contact 5.0,5.5,6.0,6.5 or 7.0
In the lag phase of at least about 15 or 20 minutes after pH needed for contact, still more preferably continue in contact terminal ileum and colon
Required pH after lag phase of at least about 25 or 30 minutes.In an especially preferred embodiment, the preparation ensures
Nutriment discharges again after terminal ileum and colon is reached by upper digestive tract, wherein at least about 6.0, more preferably at least
About 6.5, and (extendedrelease) slowly is discharged even more preferably from after the beginning lag phase under the pH of 6.8 or 7.0, prolong
The time that these long nutritional ingredients discharge in terminal ileum and colon.
Included but is not limited to by the situation of preparation for treating as intake, type i diabetes, type ii diabetes, diabetes
Early stage obesity, appetite control, Metabolic syndrome seek peace Stein-Leventhal syndrome.
In type ii diabetes are treated, preparation of the invention can combine with one or more pharmaceutically active agents, such as diformazan
Biguanides, sulfonylureas such as glibenclamide and Glipizide, Repaglinide, Nateglinide, thiazolidinedione such as Rosiglitazone and pyrrole lattice
Row ketone, acarbose, Miglitol, Exenatide (exanatide), pramlintide and insulin.
In addition, nutritional ingredient is positioned to terminal ileum and colon discharged while, intestinal mucosa viscosity is poly-
Compound, which is positioned to duodenum, to be discharged, and the intestinal mucosa sticky polymers are attached to duodenal mucosa and form shielding,
Prevent duodenal absorption, can more perfect simulation and reach metabolism operation effect.By the way that intestinal mucosa is glued
Property polymer position to duodenum and discharged, form a temporary transient barrier in duodenal mucosa, last for hours to
Ten a few houres, barrier food contact with duodenal mucosa.Avoid nutriment from stimulating duodenal K cells, suppress GIP
The secretion of resistins such as (glucose dependent insulin release peptides).
In currently available technology, there are a variety of formulation methods material can be delivered into duodenum and discharged.
Oral Twelve-phase synchronous generator delivery formulations, after such delivery formulations is oral, keep complete in stomach, into after duodenum, energy
By design requirement h substance, reach quick-release and the purpose being sustained.For example, enteric coated delivery formulations can be used.That is, can
As requested, from the polymer of advantageous pH range dissolving.Time release formulation can also be used, during by changing delivery formulations
The time of stagnant length Drug controlled release and position.Due to the influence in gastric emptying time, only application control delivery formulations time lag
The purpose of Twelve-phase synchronous generator release is not necessarily fully achieved, by the technology of control release time and enteric coating technology knot can be used
Close, to ensure that material only discharges in duodenum.
Before the specific embodiment of the invention is further described, it should be appreciated that protection scope of the present invention is not limited to down
State specific specific embodiment；It is also understood that the term used in the embodiment of the present invention is specific specific in order to describe
Embodiment, the protection domain being not intended to be limiting of the invention.The test method of unreceipted actual conditions in the following example,
Generally according to normal condition, or the condition proposed by according to each manufacturer.
When embodiment provides number range, it should be appreciated that except non-invention is otherwise noted, two ends of each number range
Any one numerical value can be selected between point and two end points.Unless otherwise defined, in the present invention all technologies for using and
Scientific terminology is identical with the meaning that those skilled in the art of the present technique are generally understood that.Except used in embodiment specific method, equipment,
Outside material, according to grasp of the those skilled in the art to prior art and the record of the present invention, it can also use and this
Any method, equipment and the material of the similar or equivalent prior art of method, equipment described in inventive embodiments, material come real
The existing present invention.
Unless otherwise indicated, disclosed in this invention experimental method, detection method, preparation method using this technology lead
Domain conventional molecular biology, biochemistry, chromatin Structure and analysis, analytical chemistry, cell culture, recombinant DNA technology and
The routine techniques of association area.These technologies existing perfect explanation in the prior art, for details, reference can be made to Sambrook etc.
MOLECULAR CLONING：A LABORATORY MANUAL, Second edition, Cold Spring Harbor
Laboratory Press, 1989and Third edition, 2001；Ausubel etc., CURRENT PROTOCOLS IN
MOLECULAR BIOLOGY, John Wiley＆Sons, New York, 1987and periodic updates；the
Series METHODS IN ENZYMOLOGY, Academic Press, San Diego；Wolffe, CHROMATIN
STRUCTURE AND FUNCTION, Third edition, Academic Press, San Diego, 1998；METHODS IN
ENZYMOLOGY, Vol.304, Chromatin (P.M.Wassarman and A.P.Wolffe, eds.), Academic
Press, San Diego, 1999；With METHODS IN MOLECULAR BIOLOGY, Vol.119, Chromatin
Protocols (P.B.Becker, ed.) Humana Press, Totowa, 1999 etc..
Embodiment 1
The present embodiment prepares the treating diabetes product containing B component, and the B component is in terminal ileum and site specific DDS for colon
The oral positioning delivery formulations of release, the oral positioning delivery formulations contain nutritional ingredient.
The present embodiment is prepared in the oral positioning delivery formulations of terminal ileum and colon specific with reference to prior art,
Nutritional ingredient is positioned to terminal ileum and colon and discharged.It is prepared in the oral positioning of terminal ileum and colon specific
Delivery formulations are prior art, such as refer to skill described in Application No. 201480003932.X application for a patent for invention
Art.
Specifically, the present embodiment is used as carrier material using Thiolation chitosan (Thiolated Chitosan, TC), system
Standby Thiolation chitosan microball.Then nutritional ingredient is dissolved or dispersed in Thiolation chitosan microball entity, prepares parcel
Nutritious Thiolation chitosan microball.Then nutritious Thiolation chitosan microball will be wrapped up again is wrapped in intestines
In solubleness carrier material polyacrylic resin Eudragit S100, it is prepared into the oral of terminal ileum and colon specific
Position delivery formulations.Known in those skilled in the art is the Thiolation many positions that can be added in chitosan, is had very strong
Mucoadhesive.Therefore, the present embodiment only with a kind of concrete form therein Thiolation chitosan as an example, but simultaneously
It is not limited to cited Thiolation chitosan.Specific Thiolation chitosan used in the present embodiment is：Chitosan -4- mercaptos
Base butylamine.
More specifically, (1) prepares the micro-sphere crosslinked solution for the TC for being surrounded by nutritional ingredient propionic acid and glutamine, including step
Suddenly：
Take 240mg TC to be dissolved in 12ml 1% acetum, obtain acidic polymer solution, then by 30mg arginine
It is dispersed in 30mg propionic acid in gained acidic polymer solution.Atoleine 50ml again plus containing 1%Span 80, is fully stirred
Mix；The toluene solution for adding formaldehyde saturation is sufficiently stirred, and the toluene solution for adding glutaraldehyde saturation is sufficiently stirred 20 hours.Produce
Microballoon cleaned for several times with n-hexane, acetone dehydration, room temperature blots, and must be enclosed with the Thiolation chitosan microball of nutritional ingredient.
(2) using Eudragit S100 parcel above-mentioned steps (1) thus obtained microspheres：500mg Eudragit S100 are dissolved in
Ethanol：Mixed solvent (the ethanol of acetone：Acetone volume ratio is 2:1) in.50mg is distributed to containing nutritious TC microballoons
In solution before 10ml.Add the atoleine 70ml containing 1%Span 80, be sufficiently stirred 3 hours, and volatile organic solvent.
Cleaned for several times with n-hexane, room temperature blots standby, is attained at terminal ileum and the oral positioning delivery formulations of colon specific.
Those skilled in the art understand that and confirm, be released in the oral positioning of terminal ileum and colon specific
Put preparation and be not limited to specific dosage form cited in embodiment, as long as nutriment can be positioned at terminal ileum
The oral formulations discharged with colon.
Prepared respectively effectively using oral positioning delivery formulations of the as above identical in terminal ileum and colon specific
Composition is (1) arginine；(2) glutamine；(3) propionic acid；(4) the oral positioning delivery formulations of arginine and propionic acid.
The oral positioning delivery formulations are respectively (1) oral arginine targeting release pill, and every oral arginine is determined
Contain 500mg arginine in the release tablet of position；(2) the oral targeting release pill of glutamine, every glutamine orally position
Contain 500mg glutamine in release tablet；(3) the oral targeting release pill of alanine, every alanine orally position release
Contain 500mg propionic acid in tablet；(4) compound oral targeting release pill, contain in every compound oral targeting release pill
500mg arginine and 500mg propionic acid.
Above-mentioned each oral positioning delivery formulations are in terminal ileum and colon specific.
The insulin-independent diabetes B patient of 15 overnight fastings is divided into 5 groups in the morning, and every 3 people is randomly divided into
One group, every group of patient gives above-mentioned delay sustained release preparation respectively：
After administration 4 hours, patient receives oral glucose tolerance test.Blood is collected at following time point：-30、0、
15th, 30,60,90,120 minutes.
Analyze the level of the hormone such as GLP-1, PYY, insulin, glucose in blood.With oral placebo (without any nutrition
The oral targeting release pill of blank of material, in terminal ileum and colon specific) control group compare, this four groups of patients'
Several indexs are all obviously improved.But under identical experiment condition, such as the 4th group is taken compound oral targeting release pill 2
Grain, be better than for independent form diabetes B therapeutic effect individually take oral arginine targeting release pill 4,
Individually take the therapeutic effect of the oral targeting release pill of alanine 4.
That is, as nutritional ingredient and individually, propionic acid as nutritional ingredient, uses compared to single arginine
Arginine and propionic acid are orally positioned delivery formulations technology using identical, are located to ileum end collectively as nutritional ingredient
End and colon are discharged, the L using arginine and propionic acid collectively as nutritional ingredient, arginine and propionic acid for lower digestive tract
Cell release gastrointestinal hormone has good synergy, can obtain the therapeutic effect that 0.5+0.5 is more than 1.
In addition, the present embodiment have studied referring also to above-mentioned experimental method：
Using acetic acid and arginine collectively as nutritional ingredient, compared to single acetic acid as nutritional ingredient and individually
Arginine as nutritional ingredient, delivery formulations technology is orally positioned using identical, is located to terminal ileum and colon
Discharged, as a result display discharges stomach and intestine using acetic acid and arginine collectively as L cells of the nutritional ingredient for lower digestive tract
Hormone has good synergy, can obtain the therapeutic effect that 0.5+0.5 is more than 1.
Using acetic acid and glutamine collectively as nutritional ingredient, compared to single acetic acid as nutritional ingredient, Yi Jidan
Only glutamine orally positions delivery formulations technology using identical as nutritional ingredient, be located to terminal ileum and
Colon is discharged, and as a result display is released using acetic acid and glutamine collectively as L cells of the nutritional ingredient for lower digestive tract
Putting gastrointestinal hormone has good synergy, can obtain the therapeutic effect that 0.5+0.5 is more than 1.
Nutritional ingredient is used as using propionic acid and glutamine jointly, compared to single propionic acid as nutritional ingredient and
Single glutamine is orally positioned delivery formulations technology using identical, is located to terminal ileum as nutritional ingredient
Discharged with colon, as a result display uses the L cells of propionic acid and glutamine collectively as nutritional ingredient for lower digestive tract
Release gastrointestinal hormone has good synergy, can obtain the therapeutic effect that 0.5+0.5 is more than 1.
Nutritional ingredient is used as using butyric acid and glutamine jointly, compared to single butyric acid as nutritional ingredient and
Single glutamine is orally positioned delivery formulations technology using identical, is located to terminal ileum as nutritional ingredient
Discharged with colon, as a result display uses the L cells of butyric acid and glutamine collectively as nutritional ingredient for lower digestive tract
Release gastrointestinal hormone has good synergy, can obtain the therapeutic effect that 0.5+0.5 is more than 1.
Nutritional ingredient is used as using butyric acid and arginine jointly, compared to single butyric acid as nutritional ingredient, Yi Jidan
Only arginine is orally positioned delivery formulations technology using identical, is located to terminal ileum and knot as nutritional ingredient
Intestines are discharged, and as a result display discharges stomach using butyric acid and arginine collectively as L cells of the nutritional ingredient for lower digestive tract
Intestinal hormones has good synergy, can obtain the therapeutic effect that 0.5+0.5 is more than 1.
Bile acid is respectively adopted and arginic combination is total to collectively as the combination of nutritional ingredient, bile acid and glutamine
It is same to be used as nutritional ingredient, long chain fatty acids and arginic combination collectively as nutritional ingredient, or long chain fatty acids and glutamy
The combination of amine also achieves treatments of the 0.5+0.5 more than 1 collectively as nutritional ingredient and imitated.
The present invention has no particular limits for the mass ratio between two kinds of nutritional ingredients in each combination.Each combination
In, the mass ratio between two kinds of nutritional ingredients is (1~10)：(1~10).
In addition, the present embodiment is referring also to above-mentioned preparation method and experimental method, using chitosan-catechol as carrier
Material, prepare chitosan-catechol microballoon.Then it is real nutritional ingredient to be dissolved or dispersed in chitosan-catechol microballoon
In body, prepare and wrap up nutritious chitosan-catechol microballoon.Then will wrap up again nutritious chitosan-
Catechol microballoon is wrapped in enteric solubility carrier material polyacrylic resin Eudragit S100, is prepared into terminal ileum
With the oral positioning delivery formulations of colon specific.Achieve good therapeutic effect.
Embodiment 2
The present embodiment prepares the treating diabetes product containing component A and B component, the B component be in terminal ileum and
The oral positioning delivery formulations of colon specific (with embodiment 1)；Component A is oral Twelve-phase synchronous generator delivery formulations, institute
State and contain intestinal mucosa sticky polymers in oral Twelve-phase synchronous generator delivery formulations.
The present embodiment prepares oral Twelve-phase synchronous generator delivery formulations with reference to prior art, by intestinal mucosa adhesive polymeric
Thing, which is positioned to duodenum, to be discharged, and the intestinal mucosa sticky polymers are attached to duodenal mucosa and form shielding, resistance
Only duodenal absorption.
Specifically, the present embodiment is glued using Thiolation chitosan (Thiolated Chitosan, TC) as intestinal mucosa
Property polymer, prepares Thiolation chitosan microball.Then Thiolation chitosan microball is wrapped in hydroxypropylmethylcellulose acetate Methyl cellulose
In plain maleate (HPMCAM), oral Twelve-phase synchronous generator delivery formulations are prepared into.It is known to one of skill in the art
Be the Thiolation many positions that can be added in chitosan, but effect is all similar.Therefore, the present embodiment is only with therein
A kind of Thiolation chitosan of concrete form as an example, but be not restricted to that cited Thiolation chitosan.The present embodiment
Used in specific Thiolation chitosan be：Chitosan -4- sulfydryl butylamine.
More specifically, (1) prepares TC micro-sphere crosslinked solution, including step：300mg TC are taken to be dissolved in 12ml
1% acetum, add the atoleine 50ml containing 1%Span 80, be sufficiently stirred；Add the toluene solution of formaldehyde saturation
It is sufficiently stirred, the toluene solution for adding glutaraldehyde saturation is sufficiently stirred 20 hours.Caused microballoon is cleaned for several times with n-hexane, and third
Ketone is dehydrated, and room temperature blots.
(2) using micro- obtained by HPMCAM (HPMCAM) parcel above-mentioned steps (1)
Ball：
200mg HPMCAM are dissolved in the mixed solvent (ethanol of 5ml ethanol and acetone：Acetone volume ratio is 2:1) in, add
Enter 40mgTC crosslinked microspheres, and 20mg aluminum stearates, instill 20ml liquid paraffins, be sufficiently stirred.Evaporating completely falls acetone and second
After alcohol, microballoon is cleaned for several times with n-hexane, and room temperature blots standby, obtains oral Twelve-phase synchronous generator delivery formulations, wherein microballoon
Electron microscopic picture it is as shown in Figure 5.
B component includes step with embodiment 1, specific preparation method：
(1) the micro-sphere crosslinked solution for the TC for being surrounded by nutritional ingredient propionic acid and glutamine, including step are prepared：
Take 240mg TC to be dissolved in 12ml 1% acetum, obtain acidic polymer solution, then by 30mg arginine
It is dispersed in 30mg propionic acid in gained acidic polymer solution.Atoleine 50ml again plus containing 1%Span 80, is fully stirred
Mix；The toluene solution for adding formaldehyde saturation is sufficiently stirred, and the toluene solution for adding glutaraldehyde saturation is sufficiently stirred 20 hours.Produce
Microballoon cleaned for several times with n-hexane, acetone dehydration, room temperature blots, and must be enclosed with the Thiolation chitosan microball of nutritional ingredient.
(2) using Eudragit S100 parcel above-mentioned steps (1) thus obtained microspheres：500mg Eudragit S100 are dissolved in
Ethanol：Mixed solvent (the ethanol of acetone：Acetone volume ratio is 2:1) in.50mg is distributed to containing nutritious TC microballoons
In solution before 10ml.Add the atoleine 70ml containing 1%Span 80, be sufficiently stirred 3 hours, and volatile organic solvent.
To be cleaned for several times with n-hexane, room temperature blots standby, is attained at terminal ileum and the oral positioning delivery formulations of colon specific,
Microballoon picture therein is as shown in Figure 6.
The component A prepared and B component are prepared into following 4 kinds of oral formulations respectively：
1st kind：6gA components are taken to be prepared into oral formulations；
2nd kind：6gB components are taken to be prepared into oral formulations；
3rd kind：Component A+B component respectively takes 3g according to 1:1 ratio is prepared into mixing oral formulations (obviously, mixing ratio
Example can be adjusted).
4th kind：Not plus the blank solution of microballoon prepares oral formulations as a control group.
The insulin-independent diabetes B patient of 8 overnight fastings is divided into 4 groups in the morning, and every 2 people is randomly divided into one
Group, every group of patient give above-mentioned 4 kinds of preparations, are respectively labeled as the 1st group, the 2nd group, the 3rd group, the 4th group respectively.
After oral formulations 30 minutes, patient receives oral glucose tolerance test.Blood is collected at following time point：-
30th, 0,15,30,60,90,120 minute.
Analyze the level of the hormone such as GLP-1, PYY, insulin, glucose in blood.With the control group phase of oral placebo
Than the 1st group, the 2nd group, several indexs of the 3rd group of patient are all obviously improved, maximum with the 3rd group of improved degree.
In addition, the present invention also research is glued using chitosan-catechol (Chitosan-Catechol, CC) as enteron aisle
Film sticky polymers, prepare chitosan-catechol microballoon.The mucoadhesive of CC microballoons and TC microballoons is tested respectively, as a result such as
Shown in Fig. 9, CC microballoons and TC microballoons are respectively provided with good mucoadhesive.
Therefore, referring also to the preparation method of TC microballoons, using chitosan-catechol (Chitosan-Catechol, CC)
As intestinal mucosa sticky polymers, chitosan-catechol microballoon is prepared, and then prepares oral Twelve-phase synchronous generator release system
Agent is as component A.With reference to above-mentioned experimental method, the component A prepared and B component are prepared into 4 kinds of oral formulations respectively, as a result
It has been shown that, compared with the control group of oral placebo, the 1st group, the 2nd group, several indexs of the 3rd group of patient are all obviously improved, with the 3rd
The degree that group improves is maximum.
Those skilled in the art are able to confirm that and what is known is：Examples detailed above is only a more excellent side being currently known
Case, however it is not limited to cited specific dosage form in embodiment, as long as it can incite somebody to action：
1. the oral Twelve-phase synchronous generator that intestinal mucosa cohesive material is attached to duodenal mucosa formation shielding action is released
Preparation is put as component A；
2. using nutritional ingredient in terminal ileum and the oral positioning delivery formulations of colon specific as B component.
It is described above, only presently preferred embodiments of the present invention, it is not any to the present invention in form and substantial limitation,
It should be pointed out that for those skilled in the art, on the premise of the inventive method is not departed from, can also make
Some improvement and supplement, these are improved and supplement also should be regarded as protection scope of the present invention.All those skilled in the art,
Without departing from the spirit and scope of the present invention, when made using disclosed above technology contents it is a little more
Dynamic, modification and the equivalent variations developed, it is the equivalent embodiment of the present invention；Meanwhile all substantial technologicals pair according to the present invention
The variation, modification and evolution for any equivalent variations that above-described embodiment is made, still fall within the scope of technical scheme
It is interior.
Claims (14)
1. a kind for the treatment of diabetes product, the treating diabetes product contains oral positioning delivery formulations, the oral positioning
Delivery formulations contain nutritional ingredient in terminal ileum and colon specific, the oral positioning delivery formulations.
2. treating diabetes product according to claim 1, it is characterised in that the nutritional ingredient is selected from：Carbon hydrate
Any of thing, fat or protein degradation products or a variety of combinations.
3. treating diabetes product according to claim 1, it is characterised in that the nutritional ingredient is selected from：Acetic acid, third
Any of acid, butyric acid, bile acid, long chain fatty acids, glucose, glutamine or arginine or a variety of combinations.
4. treating diabetes product according to claim 1, it is characterised in that the nutritional ingredient is：Propionic acid and smart ammonia
Combination, the combination of propionic acid and glutamine, acetic acid and the arginic combination of acid, the combination of acetic acid and glutamine, butyric acid and
Arginic combination, the combination of butyric acid and glutamine, the group of bile acid and arginic combination, bile acid and glutamine
Conjunction, long chain fatty acids and arginic combination, or the combination of long chain fatty acids and glutamine.
5. treating diabetes product according to claim 4, it is characterised in that in each combination, between two kinds of nutritional ingredients
Mass ratio be (1~10)：(1~10).
6. treating diabetes product according to claim 1, it is characterised in that the nutritional ingredient is wrapped in intestinal mucosa
In sticky polymers.
7. treating diabetes product according to claim 1, it is characterised in that be set forth in terminal ileum and colon released
The oral positioning delivery formulations put are enteric coated delivery formulations.
8. treating diabetes product according to claim 1, it is characterised in that the treating diabetes product also includes mouth
Twelve-phase synchronous generator delivery formulations are taken, contain intestinal mucosa sticky polymers in the oral Twelve-phase synchronous generator delivery formulations.
9. treating diabetes product according to claim 8, it is characterised in that the intestinal mucosa sticky polymers are selected from
Any of hydrophilic polymer, Hydrogels polymer, thiolated polymers or lectin polymer are a variety of
Combination.
10. treating diabetes product according to claim 8, it is characterised in that the intestinal mucosa sticky polymers choosing
From chitosan, polystyrene, carbomer, poly- carbomer-cysteine, polyacrylic acid-cysteine, polyacrylic acid-high half Guang
In propylhomoserin, alginates-cysteine, polymethylacrylic acid-cysteine or sodium carboxymethylcellulose-cysteine it is any or
A variety of combinations.
11. treating diabetes product according to claim 8, it is characterised in that the intestinal mucosa sticky polymers choosing
From Thiolation chitosan or chitosan-catechol.
12. according to any one of the claim 1~11 treating diabetes product, it is characterised in that the treating diabetes production
It is comprehensive that product are used for type i diabetes, type ii diabetes, prediabetes, obesity, appetite control, metabolic syndrome or polycystic ovary
Simulator sickness is treated.
13. according to any one of the claim 1~11 treating diabetes product, it is characterised in that the treating diabetes production
Product are metabolism operative treatment substitute products.
14. treating diabetes product is preparing type i diabetes, type ii diabetes, glycosuria as described in any one of claim 1~11
Purposes in sick early stage, obesity, appetite control, metabolic syndrome or Stein-Leventhal syndrome medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610629475.6A CN107684550B (en) | 2016-08-03 | 2016-08-03 | Diabetes treatment product and preparation and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610629475.6A CN107684550B (en) | 2016-08-03 | 2016-08-03 | Diabetes treatment product and preparation and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107684550A true CN107684550A (en) | 2018-02-13 |
| CN107684550B CN107684550B (en) | 2020-04-10 |
Family
ID=61151346
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610629475.6A Active CN107684550B (en) | 2016-08-03 | 2016-08-03 | Diabetes treatment product and preparation and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107684550B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116096352A (en) * | 2020-06-10 | 2023-05-09 | 阿帕亚知识产权公司 | Pharmaceutical composition containing multiple dosage forms of intestinal factor-releasing substance in combination with gelling agent |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050244367A1 (en) * | 2004-05-03 | 2005-11-03 | Ilypsa, Inc. | Phospholipase inhibitors localized in the gastrointestinal lumen |
| CN102159220A (en) * | 2008-04-24 | 2011-08-17 | 麦德托尼克公司 | Thiolated chitosan gel |
| CN102355896A (en) * | 2009-01-12 | 2012-02-15 | 拜奥基尔公司 | Composition and method for treatment of diabetes |
| CN103070844A (en) * | 2013-01-28 | 2013-05-01 | 万平 | Locating quick-release biological adhesive and application thereof |
-
2016
- 2016-08-03 CN CN201610629475.6A patent/CN107684550B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050244367A1 (en) * | 2004-05-03 | 2005-11-03 | Ilypsa, Inc. | Phospholipase inhibitors localized in the gastrointestinal lumen |
| CN102159220A (en) * | 2008-04-24 | 2011-08-17 | 麦德托尼克公司 | Thiolated chitosan gel |
| CN102355896A (en) * | 2009-01-12 | 2012-02-15 | 拜奥基尔公司 | Composition and method for treatment of diabetes |
| CN103070844A (en) * | 2013-01-28 | 2013-05-01 | 万平 | Locating quick-release biological adhesive and application thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116096352A (en) * | 2020-06-10 | 2023-05-09 | 阿帕亚知识产权公司 | Pharmaceutical composition containing multiple dosage forms of intestinal factor-releasing substance in combination with gelling agent |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107684550B (en) | 2020-04-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Arbit et al. | Oral insulin: the rationale for this approach and current developments | |
| Rameshrad et al. | An overview of glucagon-like peptide-1 receptor agonists for the treatment of metabolic syndrome: A drug repositioning | |
| CN112274633A (en) | Somalutide blood sugar-reducing and weight-reducing microneedle patch and preparation method and application thereof | |
| EP2771023A1 (en) | Oral formulations mimetic of roux-en-y gastric bypass actions on the ileal brake; compositions, methods of treatment, diagnostics and systems for treatment of metabolic syndrome manifestations including insulin resistance, fatty liver disease, hyperlipidemia, and t2d | |
| KR20110120866A (en) | Diabetic Therapeutic Compositions and Methods of Treatment | |
| WO2010027498A2 (en) | Compositions and methods for inducing satiety and treating non-insulin dependent diabetes emillitus, pre-diabetic symptoms, insulin resistance and related disease states and conditions | |
| TW200824706A (en) | Methods for administering long-lasting hypoglycemic agents | |
| CN104840415A (en) | Long-acting controlled-release liposome gel composition containing hypoglycemic active ingredient and preparation method thereof | |
| CN103702668A (en) | Composition and method for treatment of diabetes | |
| Reboredo et al. | Oral administration of zein-based nanoparticles reduces glycemia and improves glucose tolerance in rats | |
| US20120040048A1 (en) | Composition and Method for Control of Diabetes | |
| EP4164592B1 (en) | Pharmaceutical compositions containing enterokine-releasing substances in multiple dosage forms in combination with gelling agents | |
| EP3871692B1 (en) | Pharmaceutical composition with blood sugar lowering effect | |
| CN107684550A (en) | Treating diabetes product and its preparation and application | |
| WO2021036884A1 (en) | Application of hernandezine or pharmaceutically acceptable salt thereof in drugs for diabetes or diabetic complications | |
| CN118370728A (en) | A GLP-1RA drug-loaded nanoparticle and preparation and preparation method thereof | |
| AU2019229469B2 (en) | GLP-1 composition for treating obesity and weight management | |
| CN117899175A (en) | A Chinese medicine prescription for lowering blood sugar and uric acid and its preparation method | |
| CN107684551A (en) | Diabetes or fat disease treatment product and its preparation and application | |
| US20250177314A1 (en) | Compositions and methods for treating diabetes | |
| US20210085727A1 (en) | Preparation and application of grain worm for treating diabetes | |
| Abderrahmani et al. | Optimizing the Current Type 2 Diabetes Antidiabetics with Nanotechnologies: Where Do We Stand? | |
| LU103233B1 (en) | Treatment of obesity and related conditions by circadian administration of enterokine-stimulating compositions | |
| AU2025205229A1 (en) | Compositions and methods for treating diabetes | |
| WO2025119939A1 (en) | Treatment of obesity and related conditions by circadian administration of enterokine-stimulating compositions |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |