CN114042051A - Pharmaceutical composition containing sitagliptin and metformin and preparation method thereof - Google Patents
Pharmaceutical composition containing sitagliptin and metformin and preparation method thereof Download PDFInfo
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- CN114042051A CN114042051A CN202111375470.2A CN202111375470A CN114042051A CN 114042051 A CN114042051 A CN 114042051A CN 202111375470 A CN202111375470 A CN 202111375470A CN 114042051 A CN114042051 A CN 114042051A
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- sitagliptin
- metformin
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- 229960004034 sitagliptin Drugs 0.000 title claims abstract description 101
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 title claims abstract description 101
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 title claims abstract description 88
- 229960003105 metformin Drugs 0.000 title claims abstract description 75
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 238000013268 sustained release Methods 0.000 claims abstract description 38
- 239000012730 sustained-release form Substances 0.000 claims abstract description 38
- 239000000853 adhesive Substances 0.000 claims abstract description 19
- 230000001070 adhesive effect Effects 0.000 claims abstract description 19
- 239000000463 material Substances 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 16
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims abstract description 15
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 15
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 15
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 14
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims abstract description 14
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 13
- 239000000314 lubricant Substances 0.000 claims abstract description 13
- 229960004329 metformin hydrochloride Drugs 0.000 claims abstract description 13
- OETHQSJEHLVLGH-UHFFFAOYSA-N metformin hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N OETHQSJEHLVLGH-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000000080 wetting agent Substances 0.000 claims abstract description 12
- 230000008569 process Effects 0.000 claims abstract description 10
- 239000003085 diluting agent Substances 0.000 claims abstract description 7
- 239000008187 granular material Substances 0.000 claims description 44
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 18
- 238000002156 mixing Methods 0.000 claims description 17
- 239000007779 soft material Substances 0.000 claims description 15
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 14
- 238000000576 coating method Methods 0.000 claims description 13
- 239000011259 mixed solution Substances 0.000 claims description 13
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 claims description 12
- 235000006708 antioxidants Nutrition 0.000 claims description 12
- 239000011248 coating agent Substances 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 12
- 235000019359 magnesium stearate Nutrition 0.000 claims description 9
- 239000011230 binding agent Substances 0.000 claims description 8
- 238000005507 spraying Methods 0.000 claims description 8
- 239000002211 L-ascorbic acid Substances 0.000 claims description 7
- 235000000069 L-ascorbic acid Nutrition 0.000 claims description 7
- 229960005070 ascorbic acid Drugs 0.000 claims description 7
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 7
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 7
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 7
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 6
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 6
- 235000013539 calcium stearate Nutrition 0.000 claims description 6
- 239000008116 calcium stearate Substances 0.000 claims description 6
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 6
- 238000003825 pressing Methods 0.000 claims description 6
- 239000000473 propyl gallate Substances 0.000 claims description 6
- 235000010388 propyl gallate Nutrition 0.000 claims description 6
- 229940075579 propyl gallate Drugs 0.000 claims description 6
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 5
- 229930195725 Mannitol Natural products 0.000 claims description 5
- 239000000594 mannitol Substances 0.000 claims description 5
- 235000010355 mannitol Nutrition 0.000 claims description 5
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000000654 additive Substances 0.000 claims description 4
- 230000000996 additive effect Effects 0.000 claims description 4
- 239000012729 immediate-release (IR) formulation Substances 0.000 claims description 4
- 229960001021 lactose monohydrate Drugs 0.000 claims description 4
- 238000010008 shearing Methods 0.000 claims description 4
- 238000005550 wet granulation Methods 0.000 claims description 3
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- RPWFJAMTCNSJKK-UHFFFAOYSA-N Dodecyl gallate Chemical compound CCCCCCCCCCCCOC(=O)C1=CC(O)=C(O)C(O)=C1 RPWFJAMTCNSJKK-UHFFFAOYSA-N 0.000 claims description 2
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 claims description 2
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- 235000010385 ascorbyl palmitate Nutrition 0.000 claims description 2
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 claims description 2
- 239000000555 dodecyl gallate Substances 0.000 claims description 2
- 235000010386 dodecyl gallate Nutrition 0.000 claims description 2
- 229940080643 dodecyl gallate Drugs 0.000 claims description 2
- 238000005469 granulation Methods 0.000 claims description 2
- 230000003179 granulation Effects 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- 239000000574 octyl gallate Substances 0.000 claims description 2
- 235000010387 octyl gallate Nutrition 0.000 claims description 2
- NRPKURNSADTHLJ-UHFFFAOYSA-N octyl gallate Chemical compound CCCCCCCCOC(=O)C1=CC(O)=C(O)C(O)=C1 NRPKURNSADTHLJ-UHFFFAOYSA-N 0.000 claims description 2
- 235000019422 polyvinyl alcohol Nutrition 0.000 claims description 2
- OKODKVMXHLUQSW-JITBQSAISA-M sodium;(e)-4-hydroxy-4-oxobut-2-enoate;octadecanoic acid Chemical compound [Na+].OC(=O)\C=C\C([O-])=O.CCCCCCCCCCCCCCCCCC(O)=O OKODKVMXHLUQSW-JITBQSAISA-M 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 claims description 2
- 229960003943 hypromellose Drugs 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 8
- 239000012535 impurity Substances 0.000 abstract description 5
- 238000004090 dissolution Methods 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 229940090124 dipeptidyl peptidase 4 (dpp-4) inhibitors for blood glucose lowering Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000000843 powder Substances 0.000 description 5
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 102100025101 GATA-type zinc finger protein 1 Human genes 0.000 description 2
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 description 2
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 2
- 102000017011 Glycated Hemoglobin A Human genes 0.000 description 2
- 108010014663 Glycated Hemoglobin A Proteins 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000000889 atomisation Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 229960004937 saxagliptin Drugs 0.000 description 2
- QGJUIPDUBHWZPV-SGTAVMJGSA-N saxagliptin Chemical compound C1C(C2)CC(C3)CC2(O)CC13[C@H](N)C(=O)N1[C@H](C#N)C[C@@H]2C[C@@H]21 QGJUIPDUBHWZPV-SGTAVMJGSA-N 0.000 description 2
- 108010033693 saxagliptin Proteins 0.000 description 2
- 238000007613 slurry method Methods 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- 229960001254 vildagliptin Drugs 0.000 description 2
- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 208000016097 disease of metabolism Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000009506 drug dissolution testing Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000002641 glycemic effect Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 210000004153 islets of langerhan Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000007119 pathological manifestation Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229960001967 tacrolimus Drugs 0.000 description 1
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000011144 upstream manufacturing Methods 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
- A61K9/20—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
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
-
- 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
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Engineering & Computer Science (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a pharmaceutical composition containing sitagliptin and metformin, which consists of a metformin sustained-release layer and a sitagliptin quick-release layer, wherein the metformin sustained-release layer consists of the following raw and auxiliary materials in parts by weight: 200 portions of metformin hydrochloride and 300 portions of; 50-100 parts of hydroxypropyl methylcellulose; 8-20 parts of an adhesive; 30-50 parts of a wetting agent; 1-3 parts of a lubricant; 1-5 parts of an antioxidant; the sitagliptin quick release layer comprises the following raw and auxiliary materials in parts by weight: 20-60 parts of sitagliptin; 40-100 parts of hydrophilic diluent; 1-5 parts of an adhesive; 10-20 parts of a wetting agent; 0.05-1 part of lubricant; 0.1-1 part of antioxidant. The sitagliptin metformin composition has the advantages that the stability of the sitagliptin is improved and the impurity content is obviously superior to that of the original preparation by optimizing the prescription and the process.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition containing sitagliptin and metformin and a preparation method thereof.
Background
The main pathological manifestation of type 2diabetes mellitus (T2 DM) is progressive impairment of pancreatic islet beta cell function, which is a metabolic disease with chronic hyperglycemia as a main characteristic in clinical manifestation. The World Health Organization (WHO) statistics show that there are 3.47 billion diabetic patients worldwide, 90% of which belong to T2 DM. Strict glycemic control is critical for treatment of T2 DM.
Metformin (MET) is a first-line therapeutic drug recommended by many guidelines for diabetes treatment, and its effectiveness and safety have been clinically confirmed. DPP-4 is an enzyme in the human body, whose main function is to break down proteins in the body, and is an upstream regulator of GLP-1. DPP-4 inhibitors can achieve similar therapeutic effects as GLP-1 agonists. Since the DPP-4 inhibitor has good curative effect and can be orally taken, the DPP-4 inhibitor is one of the main development directions of diabetes drugs since 2019, and currently approved DPP-4 inhibitors on the market in the world include sitagliptin (sitagliptin), Saxagliptin (Saxagliptin), Vildagliptin (Vildagliptin) and the like. Clinical studies show that the traditional combined use of metformin and a DPP-4 inhibitor can effectively reduce the blood glucose index (glycosylated hemoglobin (HbA1 c)) and the fasting blood glucose index (FBG) level, so that the blood glucose of patients can be well controlled.
Sitagliptin metformin tablet (trade name: tacrolimus) is the first fixed compound preparation of DPP-4 inhibitor and metformin developed and produced by Moshadong company, and is used for treating type 2diabetes patients who still have poor blood sugar control or are receiving combined treatment of the two through metformin monotherapy. The formula and the process of the medicine are disclosed in original patent CN 101932241A, however, the medicine is found to have the problem of stability during development, the stability is obviously reduced after the medicine is stored under the conditions of high temperature, high humidity and illumination, and the content of related substances is obviously increased.
Disclosure of Invention
Based on the technical problems, the invention provides a pharmaceutical composition containing sitagliptin and metformin and a preparation method thereof, wherein the sitagliptin and metformin composition has the advantages of increased stability and obviously better impurity content than the original preparation by optimizing the prescription and process.
The specific scheme of the invention is as follows:
the invention provides a pharmaceutical composition containing sitagliptin and metformin, which consists of a metformin sustained-release layer and a sitagliptin quick-release layer, wherein the metformin sustained-release layer consists of the following raw and auxiliary materials in parts by weight: 200 portions of metformin hydrochloride and 300 portions of; 50-100 parts of hydroxypropyl methylcellulose; 8-20 parts of an adhesive; 30-50 parts of a wetting agent; 1-3 parts of a lubricant; 1-5 parts of an antioxidant; the sitagliptin quick release layer comprises the following raw and auxiliary materials in parts by weight: 20-60 parts of sitagliptin; 40-100 parts of hydrophilic diluent; 1-5 parts of an adhesive; 10-20 parts of a wetting agent; 0.05-1 part of lubricant; 0.1-1 part of antioxidant.
Preferably, the adhesive is selected from any one or more of polyvinyl alcohol, hydroxypropyl methylcellulose and polyvinylpyrrolidone; more preferably, the binder is polyvinylpyrrolidone.
Preferably, the wetting agent is pure water or ethanol.
Preferably, the antioxidant is selected from any one or more of L-ascorbic acid, ascorbyl palmitate, propyl gallate, octyl gallate, dodecyl gallate, di-tert-butyl-p-cresol and butyl hydroxy anisole.
Preferably, the lubricant is selected from one or more of magnesium stearate, calcium stearate, stearic acid, zinc stearate, and sodium fumarate stearate.
Preferably, the hydrophilic diluent in the sitagliptin quick-release layer is selected from one or more of lactose monohydrate, mannitol and sorbitol.
Preferably, the method comprises the following steps: the raw and auxiliary materials are subjected to wet granulation to respectively obtain the metformin sustained-release mixed granules and the sitagliptin quick-release mixed granules, and then the pharmaceutical composition containing the sitagliptin and the metformin is obtained through double-layer tabletting and coating.
Preferably, the preparation of the metformin sustained-release mixed granule specifically comprises the following steps: mixing metformin hydrochloride and hydroxypropyl methylcellulose, and spraying adhesive mixed solution to obtain a soft material; shearing, granulating, drying and finishing the soft material, and mixing with a lubricant to obtain metformin sustained-release mixed granules; the binder mixed solution consists of an adhesive, a wetting agent and an antioxidant; more preferably, the soft mass is dried at 40-70 ℃ to a moisture content of less than 3% while drying; granulating with 18-20 mesh sieve, and grading with 30-40 mesh sieve.
Preferably, the preparation of the sitagliptin immediate-release mixed granules specifically comprises the following steps: mixing sitagliptin and a hydrophilic diluent, and spraying an adhesive mixed solution to obtain a soft material; the soft material is subjected to shearing granulation, drying and granule finishing and then is mixed with a lubricant to obtain sitagliptin quick-release mixed granules; the binder mixed solution consists of an adhesive, a wetting agent and an antioxidant; more preferably, the soft mass is dried at 40-60 ℃ to a moisture content of less than 3% while drying; granulating with 18-20 mesh sieve, and grading with 30-40 mesh sieve.
Preferably, the metformin sustained-release mixed granules are used as a substrate, and the sitagliptin quick-release mixed granules are used as an additive and are added at the concentration of 2-5kg/cm2Pressing under a pre-pressing pressure; the weight ratio of the metformin sustained-release mixed granules to the sitagliptin quick-release mixed granules is 5-20: 1.
Compared with the prior art, the invention has the beneficial effects that:
according to the invention, through the optimization of the formulas of the metformin sustained-release layer and the sitagliptin quick-release layer and the matching of a double-layer tablet preparation process, the stability of the sitagliptin is obviously improved, the generation of related substances of the sitagliptin is effectively reduced, the content uniformity of the sitagliptin is ensured, and the quality of the product is effectively improved. In particular, the amount of the solvent to be used,
(1) in the metformin sustained release layer, glidants in the original grinding prescription are saved, the content of a lubricant is reduced, and a small amount of antioxidant is added, so that the design of the prescription can ensure that the sustained release performance is consistent with the original grinding, and the powder index of the metformin intermediate particles is better, thereby being beneficial to tabletting;
(2) in the sitagliptin quick release layer, the composition of the prescription of the sitagliptin quick release layer is changed, so that the sitagliptin quick release layer is adapted to the double-layer tablet process, the stability of the sitagliptin is obviously improved, the generation of related substances of the sitagliptin is effectively reduced, the content uniformity of the sitagliptin is easier to ensure, and the quality of a product is effectively improved;
(3) compared with the coating and medicine application process (generally 20-40h) of sitagliptin, the process for double-layer tabletting with the matched prescription greatly shortens the coating time, obviously improves the production efficiency and avoids the influence of the temperature in the coating process on related substances of the sitagliptin and antioxidants in the prescription.
Detailed Description
Hereinafter, the technical solution of the present invention will be described in detail by specific examples, but these examples should be explicitly proposed for illustration, but should not be construed as limiting the scope of the present invention.
In the following embodiment, the metformin hydrochloride raw material is uniformly pretreated firstly, specifically, the metformin hydrochloride raw material is crushed by using a universal crusher provided with 100-mesh gongs, so that the fine powder with the particle size of more than 80 meshes is larger than 95%, which is beneficial to improving the mixing uniformity of the raw material and the auxiliary material in the subsequent wet granulation process.
In the following examples, sitagliptin phosphate monohydrate is specifically used when sitagliptin is fed; the feeding amount of the sitagliptin phosphate monohydrate is 20-60 parts by weight of sitagliptin.
In the following examples, the pharmaceutical composition containing sitagliptin and metformin obtained by the double-layer tabletting process is a sitagliptin and metformin double-layer tablet, and the first layer is a metformin sustained-release layer; the second time is a sitagliptin quick-release layer.
Example 1
A pharmaceutical composition containing sitagliptin and metformin comprises a metformin sustained-release layer and a sitagliptin quick-release layer; the metformin sustained-release layer is composed of the following raw and auxiliary materials in parts by weight: 200 parts of metformin hydrochloride; 55 parts of hydroxypropyl methylcellulose; 9 parts of polyvinylpyrrolidone; 36 parts of pure water; 3 parts of magnesium stearate; 1.5 parts of L-ascorbic acid; the sitagliptin quick release layer comprises the following raw and auxiliary materials in parts by weight: 50 parts of sitagliptin; 100 parts of lactose monohydrate; 1.5 parts of hydroxypropyl methylcellulose; 20 parts of pure water; 0.75 part of magnesium stearate; 0.38 portion of L-ascorbic acid.
The preparation method comprises the following steps:
(1) preparing metformin sustained-release mixed granules:
uniformly mixing 200 parts of metformin hydrochloride and 55 parts of hydroxypropyl methylcellulose in a high-efficiency wet granulator, and spraying an adhesive mixed solution formed by mixing 36 parts of pure water, 9 parts of polyvinylpyrrolidone and 1.5 parts of L-ascorbic acid by using a high-pressure atomization two-fluid spray gun to obtain a soft material; granulating with 18 mesh sieve, drying in fluidized bed at 60 deg.C until the water content is less than 3%, grading with 30 mesh sieve, adding 3 parts of magnesium stearate, and mixing to obtain metformin sustained-release mixed granule;
(2) preparing sitagliptin quick-release mixed granules:
in a high-efficiency wet granulator, 50 parts of sitagliptin and 100 parts of lactose monohydrate are uniformly mixed, and then 1.5 parts of hydroxypropyl methylcellulose and 0.38 part of L-ascorbic acid are sprayed into adhesive mixed solution prepared by dissolving in 20 parts of pure water to prepare soft material; granulating with 18 mesh sieve, drying at 50 deg.C in fluidized bed to water content of less than 3%, grading with 30 mesh sieve, adding 0.75 part of magnesium stearate, and mixing to obtain sitagliptin quick-release mixed granule;
(3) double-layer tabletting and coating:
using a double-layer tablet press, using the metformin sustained-release mixed granules as a base material and the sitagliptin quick-release mixed granules as an additive, controlling the ratio of the metformin sustained-release mixed granules to the sitagliptin quick-release mixed granules to be 10:1 and controlling the ratio of the metformin sustained-release mixed granules to the sitagliptin quick-release mixed granules to be 3kg/cm2Pressing into plain tablets by a rotary tablet press under the prepressing pressure; taking 105 parts
II coating premix, dissolving in 595 parts of pure water, and dissolving completelyCoating the obtained product in a high-efficiency coating machine to increase the weight by 3% to obtain the pharmaceutical composition containing sitagliptin and metformin. The obtained sample has good appearance, uniform color and complete and unbroken film coat through observation.
Example 2
A pharmaceutical composition containing sitagliptin and metformin comprises a metformin sustained-release layer and a sitagliptin quick-release layer; the composition of the metformin sustained-release layer is the same as that of the embodiment 1; the sitagliptin quick release layer comprises the following raw and auxiliary materials in parts by weight: 50 parts of sitagliptin; 100 parts of mannitol; 1.5 parts of hydroxypropyl methylcellulose; 20 parts of pure water; 0.75 part of magnesium stearate; 0.38 portion of L-ascorbic acid. It was prepared according to this formulation in the same manner as in example 1. The obtained sample has good appearance, uniform color and complete and unbroken film coat through observation.
Example 3
A pharmaceutical composition containing sitagliptin and metformin comprises a metformin sustained-release layer and a sitagliptin quick-release layer; the metformin sustained-release layer is composed of the following raw and auxiliary materials in parts by weight: 300 parts of metformin hydrochloride; 100 parts of hydroxypropyl methylcellulose; 20 parts of polyvinyl alcohol; 50 parts of pure water; 2.5 parts of calcium stearate; 3 parts of propyl gallate; the sitagliptin quick release layer comprises the following raw and auxiliary materials in parts by weight: 60 parts of sitagliptin; 80 parts of mannitol; 3 parts of polyvinyl alcohol; 15 parts of pure water; 0.8 part of calcium stearate; 0.8 part of propyl gallate.
The preparation method comprises the following steps:
(1) preparing metformin sustained-release mixed granules:
uniformly mixing 300 parts of metformin hydrochloride and 100 parts of hydroxypropyl methylcellulose in a high-efficiency wet granulator, and spraying an adhesive mixed solution formed by mixing 50 parts of pure water, 20 parts of polyvinyl alcohol and 3 parts of propyl gallate by using a high-pressure atomization two-fluid spray gun to obtain a soft material; granulating with 18 mesh sieve, drying at 70 deg.C in fluidized bed to water content of less than 3%, grading with 30 mesh sieve, adding 2.5 parts of calcium stearate, and mixing to obtain metformin sustained-release mixed granule;
(2) preparing sitagliptin quick-release mixed granules:
uniformly mixing 60 parts of sitagliptin and 80 parts of mannitol in a high-efficiency wet granulator, and spraying into a binder mixed solution prepared by dissolving 3 parts of polyvinyl alcohol and 0.8 part of propyl gallate in 15 parts of pure water to prepare a soft material; granulating with 18 mesh sieve, drying in fluidized bed at 40 deg.C until water content is less than 3%, grading with 30 mesh sieve, adding 0.8 part of calcium stearate, and mixing to obtain sitagliptin quick-release mixed granule;
(3) double-layer tabletting and coating:
using a double-layer tablet press, using the metformin sustained-release mixed granules as a base material and the sitagliptin quick-release mixed granules as an additive, controlling the ratio of the metformin sustained-release mixed granules to the sitagliptin quick-release mixed granules to be 5:1 at 5kg/cm2Pressing into plain tablets by a rotary tablet press under the prepressing pressure; taking 105 parts
II, dissolving the coating premix in 595 parts of pure water to obtain a coating solution after complete dissolution, and coating the plain tablets in a high-efficiency coating machine to increase the weight by 3 percent to obtain the pharmaceutical composition containing sitagliptin and metformin. The obtained sample has good appearance, uniform color and complete and unbroken film coat through observation.
And (3) performance testing:
1. content uniformity
According to the content uniformity inspection method of 0941 in the four parts of the 2020 edition of the Chinese pharmacopoeia, 10 samples of the pharmaceutical composition containing sitagliptin and metformin prepared in example 1 are taken, and the content data of the sitagliptin is determined as shown in the following table 1.
Table 1, results of measuring uniformity of sitagliptin content in example 1 sample
The above results indicate that the sample obtained in example 1 has good content uniformity of sitagliptin.
2. Dissolution rate
According to the second method (slurry method) of the dissolution and release determination method of 0931 in the four parts of the year 2020 edition, a sample of the pharmaceutical composition containing sitagliptin and metformin prepared in example 1 was subjected to dissolution testing under the conditions of the second method (slurry method), 75 revolutions and 900 ml of phosphate buffer medium with pH6.8, and the specific data are shown in Table 2 below.
Table 2 dissolution data
The results show that the sitagliptin in the sample in the example 1 is released rapidly, belongs to 'very rapid dissolution', and the metformin hydrochloride is released slowly, is consistent with the release of the original preparation (jietan), and meets the requirement of in vitro dissolution consistency.
3. Related substances
The pharmaceutical composition containing sitagliptin and metformin obtained in example 1 (hereinafter, referred to as a self-made preparation) was examined for the substance data of sitagliptin stored for 0 month, 1 month and 2 months respectively with the original formulation at 40 ℃ under the condition of relative humidity of 75%, and the detailed data are shown in Table 3.
TABLE 3 data of the materials of the home-made formulation and the original formulation in example 1
Note: the original preparation used in the test of the invention is sitagliptin metformin tablet (trade name: jietangsu) of the company of Moshadong on the market. The total impurities are the sum of known impurities and unknown impurities.
The results show that the content of the related substances of the sitagliptin in the self-made preparation is obviously superior to that of the original preparation.
4. Powder characteristic of metformin sustained-release mixed granules
Sample 1 is the metformin sustained-release mixed granules obtained in example 1;
sample 2 is: granulating 200 parts of metformin hydrochloride by using a high-efficiency wet granulator, and spraying an adhesive mixed solution formed by 36 parts of pure water and 9 parts of polyvinylpyrrolidone to prepare a soft material; granulating with 18 mesh sieve, drying at 60 deg.C until the water content is less than 3%, and grading with 30 mesh sieve to obtain intermediate I; and adding 55 parts of hydroxypropyl methylcellulose, 1.5 parts of silicon dioxide and 3 parts of magnesium stearate into the intermediate I, and uniformly mixing to obtain a sample 2.
The powder characteristics of the above samples 1 and 2 were tested, and the experimental data are shown in table 4 below.
TABLE 4 characterization data of the metformin sustained release mixed granule powder morphology
The above results show that: the density of the sample 1 obtained by the invention is close to that of the comparative sample 2; according to the invention, all auxiliary materials are added into the granules together, so that the process complexity is reduced, the glidant is removed, the dosage of magnesium stearate is reduced, good compressibility and flowability can be maintained, and the dissolution of the medicine is not influenced.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.
Claims (10)
1. A pharmaceutical composition containing sitagliptin and metformin is composed of a metformin sustained release layer and a sitagliptin quick release layer, and is characterized in that the metformin sustained release layer is composed of the following raw and auxiliary materials in parts by weight: 200 portions of metformin hydrochloride and 300 portions of; 50-100 parts of hydroxypropyl methylcellulose; 8-20 parts of an adhesive; 30-50 parts of a wetting agent; 1-3 parts of a lubricant; 1-5 parts of an antioxidant; the sitagliptin quick release layer comprises the following raw and auxiliary materials in parts by weight: 20-60 parts of sitagliptin; 40-100 parts of hydrophilic diluent; 1-5 parts of an adhesive; 10-20 parts of a wetting agent; 0.05-1 part of lubricant; 0.1-1 part of antioxidant.
2. The pharmaceutical composition containing sitagliptin and metformin according to claim 1, wherein the binder is selected from any one or a combination of polyvinyl alcohol, hypromellose, polyvinylpyrrolidone; preferably, the binder is polyvinylpyrrolidone.
3. The pharmaceutical composition containing sitagliptin and metformin according to claim 1 or 2, characterized in that the wetting agent is pure water or ethanol.
4. The pharmaceutical composition containing sitagliptin and metformin according to any one of claims 1 to 3, wherein the antioxidant is selected from any one or more of L-ascorbic acid, ascorbyl palmitate, propyl gallate, octyl gallate, dodecyl gallate, di-tert-butyl-p-cresol, butyl hydroxyanisole in combination.
5. The pharmaceutical composition containing sitagliptin and metformin according to any one of claims 1 to 4, characterized in that the lubricant is selected from a combination of one or more of magnesium stearate, calcium stearate, stearic acid, zinc stearate, sodium fumarate stearate.
6. The pharmaceutical composition containing sitagliptin and metformin according to any one of claims 1 to 5, wherein the hydrophilic diluent in the immediate release sitagliptin layer is selected from a combination of one or more of lactose monohydrate, mannitol and sorbitol.
7. The process for the preparation of a pharmaceutical composition containing sitagliptin and metformin according to any one of claims 1 to 6, comprising: the raw and auxiliary materials are subjected to wet granulation to respectively obtain the metformin sustained-release mixed granules and the sitagliptin quick-release mixed granules, and then the pharmaceutical composition containing the sitagliptin and the metformin is obtained through double-layer tabletting and coating.
8. The method for preparing a pharmaceutical composition containing sitagliptin and metformin according to claim 7, wherein the metformin sustained-release mixed granule is prepared by specifically comprising: mixing metformin hydrochloride and hydroxypropyl methylcellulose, and spraying adhesive mixed solution to obtain a soft material; shearing, granulating, drying and finishing the soft material, and mixing with a lubricant to obtain metformin sustained-release mixed granules; the binder mixed solution consists of an adhesive, a wetting agent and an antioxidant; preferably, the soft material is dried at 40-70 deg.C until the moisture content is less than 3%; granulating with 18-20 mesh sieve, and grading with 30-40 mesh sieve.
9. The preparation method of the pharmaceutical composition containing sitagliptin and metformin according to claim 7 or 8, wherein the preparation of the sitagliptin immediate-release mixed granules specifically comprises the following steps: mixing sitagliptin and a hydrophilic diluent, and spraying an adhesive mixed solution to obtain a soft material; the soft material is subjected to shearing granulation, drying and granule finishing and then is mixed with a lubricant to obtain sitagliptin quick-release mixed granules; the binder mixed solution consists of an adhesive, a wetting agent and an antioxidant; preferably, the soft material is dried at 40-60 ℃ until the moisture content is less than 3% during drying; granulating with 18-20 mesh sieve, and grading with 30-40 mesh sieve.
10. According to claim 7-9 the process for the preparation of a pharmaceutical composition containing sitagliptin and metformin according to any one of claims, characterized in that the metformin sustained-release mixed granules are used as a base material and the sitagliptin immediate-release mixed granules are used as an additive in an amount of 2-5kg/cm2Pressing under a pre-pressing pressure; the weight ratio of the metformin sustained-release mixed granules to the sitagliptin quick-release mixed granules is 5-20: 1.
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