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CN112957355A - Vildagliptin tablet and preparation method thereof - Google Patents

  • ️Tue Jun 15 2021

CN112957355A - Vildagliptin tablet and preparation method thereof - Google Patents

Vildagliptin tablet and preparation method thereof Download PDF

Info

Publication number
CN112957355A
CN112957355A CN202110369789.8A CN202110369789A CN112957355A CN 112957355 A CN112957355 A CN 112957355A CN 202110369789 A CN202110369789 A CN 202110369789A CN 112957355 A CN112957355 A CN 112957355A Authority
CN
China
Prior art keywords
vildagliptin
parts
tablet
magnesium stearate
preparation
Prior art date
2021-04-07
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202110369789.8A
Other languages
Chinese (zh)
Inventor
韩志鹏
张凤云
冯占美
张加泽
胡雪芳
范林
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Yantai Valiant Pharmaceutical Co ltd
Original Assignee
Yantai Valiant Pharmaceutical Co ltd
Priority date (The priority date 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 date listed.)
2021-04-07
Filing date
2021-04-07
Publication date
2021-06-15
2021-04-07 Application filed by Yantai Valiant Pharmaceutical Co ltd filed Critical Yantai Valiant Pharmaceutical Co ltd
2021-04-07 Priority to CN202110369789.8A priority Critical patent/CN112957355A/en
2021-06-15 Publication of CN112957355A publication Critical patent/CN112957355A/en
Status Pending legal-status Critical Current

Links

  • SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 title claims abstract description 84
  • 229960001254 vildagliptin Drugs 0.000 title claims abstract description 84
  • 238000002360 preparation method Methods 0.000 title claims abstract description 23
  • HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 76
  • 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 38
  • 238000000034 method Methods 0.000 claims abstract description 24
  • 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 abstract description 22
  • 229930195725 Mannitol Natural products 0.000 claims abstract description 22
  • CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims abstract description 22
  • 229930006000 Sucrose Natural products 0.000 claims abstract description 22
  • 239000000594 mannitol Substances 0.000 claims abstract description 22
  • 235000010355 mannitol Nutrition 0.000 claims abstract description 22
  • 239000005720 sucrose Substances 0.000 claims abstract description 22
  • 238000002156 mixing Methods 0.000 claims abstract description 19
  • 229920002785 Croscarmellose sodium Polymers 0.000 claims abstract description 18
  • VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 18
  • DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical group [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims abstract description 18
  • 229960001681 croscarmellose sodium Drugs 0.000 claims abstract description 18
  • 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims abstract description 18
  • 239000003814 drug Substances 0.000 claims abstract description 15
  • 239000000314 lubricant Substances 0.000 claims abstract description 14
  • 229940075614 colloidal silicon dioxide Drugs 0.000 claims abstract description 13
  • 239000003085 diluting agent Substances 0.000 claims abstract description 12
  • 239000007884 disintegrant Substances 0.000 claims abstract description 12
  • 229940079593 drug Drugs 0.000 claims abstract description 10
  • 239000000463 material Substances 0.000 claims abstract description 10
  • 239000000203 mixture Substances 0.000 claims abstract description 10
  • 239000002994 raw material Substances 0.000 claims abstract description 7
  • 238000005580 one pot reaction Methods 0.000 claims abstract description 6
  • 230000008569 process Effects 0.000 abstract description 11
  • 239000011248 coating agent Substances 0.000 abstract description 4
  • 238000000576 coating method Methods 0.000 abstract description 4
  • 238000005265 energy consumption Methods 0.000 abstract description 2
  • 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
  • 238000005550 wet granulation Methods 0.000 abstract description 2
  • 230000000052 comparative effect Effects 0.000 description 15
  • 238000012360 testing method Methods 0.000 description 13
  • 239000000126 substance Substances 0.000 description 8
  • 238000004090 dissolution Methods 0.000 description 7
  • NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical class N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 7
  • 238000007873 sieving Methods 0.000 description 7
  • WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 5
  • 239000008103 glucose Substances 0.000 description 5
  • 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 4
  • 238000009472 formulation Methods 0.000 description 4
  • 229940057948 magnesium stearate Drugs 0.000 description 4
  • 229960001855 mannitol Drugs 0.000 description 4
  • 238000004519 manufacturing process Methods 0.000 description 4
  • 230000000291 postprandial effect Effects 0.000 description 4
  • 229960004793 sucrose Drugs 0.000 description 4
  • AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 3
  • IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 3
  • 102000004877 Insulin Human genes 0.000 description 3
  • 108090001061 Insulin Proteins 0.000 description 3
  • 239000008119 colloidal silica Substances 0.000 description 3
  • 238000006731 degradation reaction Methods 0.000 description 3
  • 238000001514 detection method Methods 0.000 description 3
  • 229940097043 glucuronic acid Drugs 0.000 description 3
  • 239000000859 incretin Substances 0.000 description 3
  • 229940125396 insulin Drugs 0.000 description 3
  • 238000004806 packaging method and process Methods 0.000 description 3
  • 238000003860 storage Methods 0.000 description 3
  • XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
  • 108010004460 Gastric Inhibitory Polypeptide Proteins 0.000 description 2
  • 102100039994 Gastric inhibitory polypeptide Human genes 0.000 description 2
  • 102000051325 Glucagon Human genes 0.000 description 2
  • 108060003199 Glucagon Proteins 0.000 description 2
  • VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
  • 239000008280 blood Substances 0.000 description 2
  • 210000004369 blood Anatomy 0.000 description 2
  • 206010012601 diabetes mellitus Diseases 0.000 description 2
  • 230000000694 effects Effects 0.000 description 2
  • 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 2
  • 229960004666 glucagon Drugs 0.000 description 2
  • 238000004128 high performance liquid chromatography Methods 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
  • 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 2
  • 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
  • 235000019796 monopotassium phosphate Nutrition 0.000 description 2
  • PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
  • 230000009467 reduction Effects 0.000 description 2
  • 238000011160 research Methods 0.000 description 2
  • 230000028327 secretion Effects 0.000 description 2
  • 230000035945 sensitivity Effects 0.000 description 2
  • 239000000243 solution Substances 0.000 description 2
  • 206010067484 Adverse reaction Diseases 0.000 description 1
  • 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 1
  • 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 1
  • 229940122355 Insulin sensitizer Drugs 0.000 description 1
  • 108010076181 Proinsulin Proteins 0.000 description 1
  • 239000004480 active ingredient Substances 0.000 description 1
  • 230000006838 adverse reaction Effects 0.000 description 1
  • XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
  • 229910052782 aluminium Inorganic materials 0.000 description 1
  • 230000009286 beneficial effect Effects 0.000 description 1
  • 230000015556 catabolic process Effects 0.000 description 1
  • 210000004027 cell Anatomy 0.000 description 1
  • 230000003915 cell function Effects 0.000 description 1
  • 230000008859 change Effects 0.000 description 1
  • 230000007012 clinical effect Effects 0.000 description 1
  • 239000011247 coating layer Substances 0.000 description 1
  • 239000002131 composite material Substances 0.000 description 1
  • 239000013256 coordination polymer Substances 0.000 description 1
  • 230000007547 defect Effects 0.000 description 1
  • 230000001419 dependent effect Effects 0.000 description 1
  • 239000002274 desiccant Substances 0.000 description 1
  • 238000007865 diluting Methods 0.000 description 1
  • 229940090124 dipeptidyl peptidase 4 (dpp-4) inhibitors for blood glucose lowering Drugs 0.000 description 1
  • ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
  • 239000012738 dissolution medium Substances 0.000 description 1
  • 238000007922 dissolution test Methods 0.000 description 1
  • 238000010828 elution Methods 0.000 description 1
  • 238000005516 engineering process Methods 0.000 description 1
  • 238000011156 evaluation Methods 0.000 description 1
  • 230000003203 everyday effect Effects 0.000 description 1
  • 239000000945 filler Substances 0.000 description 1
  • 239000011888 foil Substances 0.000 description 1
  • 230000006870 function Effects 0.000 description 1
  • 230000009229 glucose formation Effects 0.000 description 1
  • 238000000227 grinding Methods 0.000 description 1
  • 230000002440 hepatic effect Effects 0.000 description 1
  • 230000003284 homeostatic effect Effects 0.000 description 1
  • 201000001421 hyperglycemia Diseases 0.000 description 1
  • 230000006872 improvement Effects 0.000 description 1
  • 238000000338 in vitro Methods 0.000 description 1
  • 238000001727 in vivo Methods 0.000 description 1
  • 230000005764 inhibitory process Effects 0.000 description 1
  • 230000003914 insulin secretion Effects 0.000 description 1
  • 235000012054 meals Nutrition 0.000 description 1
  • 238000000691 measurement method Methods 0.000 description 1
  • 239000002609 medium Substances 0.000 description 1
  • 238000012986 modification Methods 0.000 description 1
  • 230000004048 modification Effects 0.000 description 1
  • YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
  • 239000008194 pharmaceutical composition Substances 0.000 description 1
  • 239000008363 phosphate buffer Substances 0.000 description 1
  • 239000008055 phosphate buffer solution Substances 0.000 description 1
  • 229920000915 polyvinyl chloride Polymers 0.000 description 1
  • 239000004800 polyvinyl chloride Substances 0.000 description 1
  • 230000003389 potentiating effect Effects 0.000 description 1
  • 230000002265 prevention Effects 0.000 description 1
  • 230000001737 promoting effect Effects 0.000 description 1
  • 230000009257 reactivity Effects 0.000 description 1
  • 238000005070 sampling Methods 0.000 description 1
  • 238000012216 screening Methods 0.000 description 1
  • 239000000377 silicon dioxide Substances 0.000 description 1
  • 229940126589 solid medicine Drugs 0.000 description 1
  • 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
  • 238000012795 verification Methods 0.000 description 1

Classifications

    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Emergency Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Endocrinology (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention relates to a vildagliptin tablet and a preparation method thereof, belonging to the technical field of pharmaceutical preparations, wherein the vildagliptin tablet is obtained by adopting a one-pot method for mixing, uniformly mixing raw materials and auxiliary materials, and then performing tabletting operation by using a tabletting machine; the vildagliptin tablet comprises the following raw and auxiliary materials in parts by weight: 20-25 parts of vildagliptin bulk drug, 65-75 parts of diluent, 2-4 parts of disintegrant, 0.5-2 parts of glidant and 0.5-1 part of lubricant. The diluent is a mixture of mannitol and sucrose, the disintegrant is croscarmellose sodium, the glidant is colloidal silicon dioxide, and the lubricant is magnesium stearate. The invention adopts the one-pot method for mixing, compared with the traditional process, premixing and coating are not needed, the influence of moisture and high temperature in the wet granulation process on the stability of vildagliptin is avoided, the process is simplified, the process period and the operation cost are shortened, and the energy consumption is reduced.

Description

Vildagliptin tablet and preparation method thereof

Technical Field

The invention relates to a vildagliptin tablet and a preparation method thereof, belonging to the technical field of pharmaceutical preparations.

Background

Vildagliptin belongs to the class of insulin sensitizers, which is a highly potent selective dipeptidyl-peptidase-4 (DPP-4) inhibitor.

After the vildagliptin is administrated, the DPP-4 activity can be rapidly and completely inhibited, and the content of fasting and postprandial endogenous incretin GLP-1 (glucagon-like polypeptide-1) and GIP (glucose-dependent insulinotropic polypeptide) is increased.

By increasing the content of endogenous incretins, vildagliptin can increase the sensitivity of beta cells to glucose, thereby promoting the secretion of glucose-dependent insulin. After 50-100 mg vildagliptin is taken by a type 2 diabetes patient every day, the beta-cell function including HOMA-beta (homeostatic mode assessment method beta cell function index), the ratio of proinsulin to insulin and the beta cell reactivity obtained by multiple sampling tests in a meal tolerance test can be obviously improved. In non-diabetic people, vildagliptin does not stimulate insulin secretion, nor does vildagliptin reduce blood glucose levels.

By increasing the content of endogenous GLP-1, vildagliptin can also increase the sensitivity of alpha cells to glucose, so that the secretion amount of glucagon is increased. During hyperglycemia, the product can increase the ratio of insulin to glucagon by increasing the content of incretin, resulting in a decrease in fasting and postprandial hepatic glucose production, and thus, a decrease in blood glucose. Nowadays, with the improvement of living standard and the weakness of prevention consciousness of people, the prevalence rate of diabetes is continuously and greatly increased, and due to the good clinical effect of vildagliptin, adverse reactions are less and more concerned by people.

CN101618216B discloses a preparation method and a pharmaceutical formulation of vildagliptin tablets. However, the lubricant magnesium stearate used in the process has a degradation reaction with the active ingredient, which leads to a reduction in the stability during preparation or storage.

CN104856970B discloses that a proper amount of glucuronic acid is added in the prescription, and the glucuronic acid can inhibit the degradation reaction caused by the coordination of magnesium stearate and vildagliptin, but the cost of the glucuronic acid is high, and the production cost of the medicine is greatly increased.

CN106924207A discloses that adding a raw material medicine into a coating layer and then adding a moisture-proof coating increases the chemical stability of the raw material medicine. However, the coating operation is relatively complicated, which increases the production cost.

Disclosure of Invention

Aiming at the defects in the prior art, the invention provides the vildagliptin tablet which is short in production period, low in cost, stable and controllable in quality.

The technical scheme for solving the technical problems is as follows: the vildagliptin tablet comprises the following raw and auxiliary materials in parts by weight: 20-25 parts of vildagliptin bulk drug, 65-75 parts of diluent, 2-4 parts of disintegrant, 0.5-2 parts of glidant and 0.5-1 part of lubricant.

Preferably, the diluent is a mixture of mannitol and sucrose, and the weight ratio of mannitol to sucrose is 1 (1-2).

Preferably, the disintegrant is croscarmellose sodium.

Preferably, the glidant is colloidal silicon dioxide.

Preferably, the lubricant is magnesium stearate, and the weight ratio of the vildagliptin to the magnesium stearate is (40-50): 1.

the invention also discloses a preparation method of the vildagliptin tablet, which comprises the steps of mixing by adopting a one-pot method, uniformly mixing the raw materials and the auxiliary materials, and tabletting by using a tabletting machine to obtain the vildagliptin tablet;

the vildagliptin tablet comprises the following raw and auxiliary materials in parts by weight: 20-25 parts of vildagliptin bulk drug, 65-75 parts of diluent, 2-4 parts of disintegrant, 0.5-2 parts of glidant and 0.5-1 part of lubricant.

Further, the preparation method comprises the following steps: the vildagliptin bulk drug is added into a mixer after being screened by a 60-mesh sieve, then the diluent, the disintegrant, the glidant and the lubricant are sequentially added into the mixer after being screened by the 60-mesh sieve, the raw materials and the auxiliary materials are uniformly mixed in the mixer, the mixing uniformity is verified, and then a tabletting machine is used for tabletting operation to obtain the vildagliptin tablet.

Further, the diluent is a mixture of mannitol and sucrose, and the weight ratio of mannitol to sucrose is 1 (1-2).

Further, the disintegrant is croscarmellose sodium, and the glidant is colloidal silicon dioxide.

Further, the lubricant is magnesium stearate, and the weight ratio of the vildagliptin to the magnesium stearate is (40-50): 1.

the invention has the beneficial effects that:

(1) the invention adopts the one-pot method for mixing, compared with the traditional process, the one-pot method does not need premixing and coating, also avoids the influence of water and high temperature in the wet granulation process on the stability of the vildagliptin, simplifies the process, is simple to operate, shortens the process period and the operation cost, reduces the energy consumption, and has more stable quality of the vildagliptin in the preparation and storage processes;

(2) in the process of developing vildagliptin tablets, screening research is carried out on the prescription amount of magnesium stearate serving as a lubricant, and the fact that the degradation of the magnesium stearate on vildagliptin can be inhibited to a certain extent by reducing the prescription amount of the magnesium stearate is surprisingly found, so that the stability of the vildagliptin tablets is improved;

(3) by optimizing the prescription proportion of the bulk drug and the magnesium stearate, the inhibition effect of the magnesium stearate on the vildagliptin bulk drug is reduced, the stability of the tablet in production and storage is improved, the in-vitro dissolution consistency of the self-grinding tablet and a reference preparation is ensured, and a prescription process which is bioequivalent to the reference preparation is screened out through the verification of the in-vivo bioequivalence consistency;

(4) in the formula, the glidant is added, and the dosage of the glidant is tested and screened, so that the problem that the risk of sticking during tabletting is increased due to the reduction of the prescription amount of magnesium stearate can be effectively solved.

Detailed Description

The present invention will be described in detail with reference to the following embodiments in order to make the aforementioned objects, features and advantages of the invention more comprehensible. In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

Example 1

Components mg/tablet Prescription ratio/%)
Vildagliptin 50 25
Mannitol 68 34
Sucrose 74 37
Croscarmellose sodium 5 2.5
Colloidal silica 2 1
Magnesium stearate 1 0.5

The preparation method comprises the following steps:

sieving vildagliptin with a 60-mesh sieve, adding the prescribed amount of sucrose, mannitol, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate which are sieved with the 60-mesh sieve, uniformly mixing, and tabletting by using a conventional tabletting machine.

Example 2

Components mg/tablet Prescription ratio/%)
Vildagliptin 50 25
Mannitol 67.9 33.94
Sucrose 73.9 36.94
Croscarmellose sodium 5 2.5
Colloidal silica 2 1
Magnesium stearate 1.24 0.62

The preparation method comprises the following steps:

sieving vildagliptin with a 60-mesh sieve, adding the prescribed amount of sucrose, mannitol, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate which are sieved with the 60-mesh sieve, uniformly mixing, and tabletting by using a conventional tabletting machine.

Example 3

Figure BDA0003008824650000031

Figure BDA0003008824650000041

The preparation method comprises the following steps:

sieving vildagliptin with a 60-mesh sieve, adding the prescribed amount of sucrose, mannitol, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate which are sieved with the 60-mesh sieve, uniformly mixing, and tabletting by using a conventional tabletting machine.

Example 4

Components mg/tablet Prescription ratio/%)
Vildagliptin 50 25
Mannitol 68 34.19
Sucrose 75 37.19
Croscarmellose sodium 5 2.5
Colloidal silica 1 0.5
Magnesium stearate 1 0.62

The preparation method comprises the following steps:

sieving vildagliptin with a 60-mesh sieve, adding the prescribed amount of sucrose, mannitol, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate which are sieved with the 60-mesh sieve, uniformly mixing, and tabletting by using a conventional tabletting machine.

Comparative example 1

Components mg/tablet Prescription ratio/%)
Vildagliptin 50 25
Mannitol 68 34
Sucrose 74 37
Croscarmellose sodium 7 3.5
Magnesium stearate 1 0.5

The preparation method comprises the following steps:

sieving vildagliptin with a 60-mesh sieve, adding the formula amount of sucrose, mannitol, croscarmellose sodium and magnesium stearate which are sieved with the 60-mesh sieve, uniformly mixing, and tabletting by using a conventional tabletting machine.

Comparative example 2

Components mg/tablet Prescription ratio/%)
Vildagliptin 50 25
Mannitol 67.9 33.94
Sucrose 73.9 36.94
Croscarmellose sodium 7 3.5
Magnesium stearate 1.24 0.62

The preparation method comprises the following steps:

sieving vildagliptin with a 60-mesh sieve, adding the formula amount of sucrose, mannitol, croscarmellose sodium and magnesium stearate which are sieved with the 60-mesh sieve, uniformly mixing, and tabletting by using a conventional tabletting machine.

Comparative example 3

Components mg/tablet Prescription ratio/%)
Vildagliptin 50 25
Mannitol 67.7 33.85
Sucrose 73.64 36.82
Croscarmellose sodium 7 3.5
Magnesium stearate 1.66 0.83

The preparation method comprises the following steps:

sieving vildagliptin with a 60-mesh sieve, adding the formula amount of sucrose, mannitol, croscarmellose sodium and magnesium stearate which are sieved with the 60-mesh sieve, uniformly mixing, and tabletting by using a conventional tabletting machine.

Example 5 examination of the relevant Properties of the tablets according to the invention

TABLE 1 test results for relevant Properties of the tablets of examples 1 to 4 and comparative examples 1 to 3

Figure BDA0003008824650000051

As seen from the results of table 1: (1) the mixing uniformity of the examples 1-4 and the comparative examples 1-3 is verified, and the mixing uniformity meets the requirements. (2) In the process of developing vildagliptin tablets, when the dosage ratio of vildagliptin to magnesium stearate is respectively 50:1 (example 1), 40:1 (example 2) and 30:1 (example 3) and colloidal silicon dioxide with the prescription ratio of 1.0% is added, normal tabletting can be ensured, but when the dosage ratio of vildagliptin to magnesium stearate is 40:1 and colloidal silicon dioxide with the prescription ratio of 0.5% is added (example 4), the sticking phenomenon occurs during tabletting; (3) when the dosage ratio of the vildagliptin to the magnesium stearate is 30:1 (comparative example 3), the addition of the glidant, namely colloidal silicon dioxide is not needed, and all tabletting is normal; when the dosage ratio of vildagliptin to magnesium stearate is 50:1 (comparative example 1) and 40:1 (comparative example 2), no glidant colloidal silicon dioxide is added, the tablet is sticky and has rough and dented surfaces.

EXAMPLE 6 dissolution determination

The dissolution rates of examples 1 to 4 and comparative examples 1 to 3 were measured in accordance with the dissolution rate and release rate measurement method (second method of CP general rule 0931) using 1000ml of 0.01mol/L hydrochloric acid solution as a dissolution medium at a rotation speed of 50 rpm for 5 minutes, 15 minutes and 30 minutes under the medium.

Selection of reference formulation: the primary medicine on the market at home is preferred. The original manufacturer of vildagliptin tablets is Novartis, domestic imported medicines are available, the trade name is Galvus (Jiaweile), and the specification is 50 mg.

TABLE 2 dissolution test results of tablets of examples 1 to 4 and comparative examples 1 to 3

Figure BDA0003008824650000061

From the results in Table 2, the dissolution rates of the original ground product and the tablets in examples 1 to 4 and comparative examples 1 to 3 are all more than 85% in 15min, and all the dissolution rates are close to full dissolution within 30 min.

Example 7 detection test of vildagliptin tablet-related substances before and after accelerated test

Taking the vildagliptin tablets prepared in examples 1 to 4 and comparative examples 1 to 3 as samples, packaging the samples with aluminum foil for medicine packaging and polyvinyl chloride solid medicine hard sheets (additionally provided with composite film bag packaging and drying agents), and carrying out an accelerated 6-month test under accelerated test conditions: detecting related substances at 40 + -2 deg.C and relative humidity of 75 + -5% at 0 month, 1 month, 2 months, 3 months and 6 months respectively;

the related substances in the tablets are detected by a conventional HPLC method, which comprises the following steps:

the checking method comprises the following steps: HPLC method.

Chromatographic conditions are as follows:

a chromatographic column: octadecylsilane chemically bonded silica is used as filler

Mobile phase: the mobile phase A is phosphate buffer solution [ taking 1.3g of anhydrous potassium dihydrogen phosphate, adding water for dissolving and diluting to 1000ml, adjusting the pH value to 6.50 +/-0.05 by using dipotassium hydrogen phosphate solution (taking 1.5g of anhydrous potassium dihydrogen phosphate, adding 10ml of water for dissolving) to water-acetonitrile-methanol (400: 600: 15), the mobile phase B is phosphate buffer solution-acetonitrile-methanol (400: 200), and gradient elution is carried out according to the following procedures:

Figure BDA0003008824650000071

detection wavelength: 210 nm;

flow rate: 1.8 ml/min;

sample introduction volume: 10 mu l of the mixture;

column temperature: at 30 ℃.

The results of the accelerated test of the tablets of examples 1 to 4 and comparative examples 1 to 3 are shown in Table 3.

TABLE 3 examination data of the relevant substances of the tablets of examples 1 to 4 and comparative examples 1 to 3

Figure BDA0003008824650000072

Figure BDA0003008824650000081

From the accelerated test results shown in table 3, (1) the dosage ratios of vildagliptin and magnesium stearate are respectively 50:1 (example 1) and 40:1 (example 2), and after the vildagliptin and magnesium stearate are placed for 6 months under the conditions of temperature of 40 +/-2 ℃ and relative humidity of 75 +/-5%, the relevant substances have no significant change;

(2) the dosage ratio of the vildagliptin to the magnesium stearate is 30:1 (comparative example 3), and after the vildagliptin and the magnesium stearate are placed for 6 months under the conditions of the temperature of 40 +/-2 ℃ and the relative humidity of 75 +/-5%, the related substances have significant changes.

Example 8 bioequivalence test

The vildagliptin tablets prepared in examples 1-2 were used as samples, and bioequivalence tests were performed according to the guidance of human bioequivalence research technology for chemical drug-simulated pharmacy using pharmacokinetic parameters as end-point evaluation indexes.

Selection of reference formulation: the original manufacturer of vildagliptin tablets is Novartis, the trade name is Galvus (Jiaweile), and the specification is 50 mg.

The detection method comprises the following steps: the concentration of vildagliptin in the plasma of the subject was determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS).

Quantitative range: 1.00ng/mL to 500ng/mL minimum lower limit of quantitation (LLOQ): 1.00ng/mL

The postprandial bioequivalence test results for examples 1-2 and the reference formulation are shown in Table 4.

TABLE 4 test data for postprandial bioequivalence of examples 1-2 and reference formulations

Figure BDA0003008824650000091

The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.

The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims (10)

1. The vildagliptin tablet is characterized in that the vildagliptin tablet comprises the following raw and auxiliary materials in parts by weight: 20-25 parts of vildagliptin bulk drug, 65-75 parts of diluent, 2-4 parts of disintegrant, 0.5-2 parts of glidant and 0.5-1 part of lubricant.

2. The vildagliptin tablet as claimed in claim 1, wherein the diluent is a mixture of mannitol and sucrose, and the weight ratio of mannitol to sucrose is 1 (1-2).

3. The vildagliptin tablet of claim 1, wherein the disintegrant is croscarmellose sodium.

4. The vildagliptin tablet of claim 1, wherein the glidant is colloidal silicon dioxide.

5. The vildagliptin tablet according to claim 1, wherein the lubricant is magnesium stearate, and the weight ratio of the vildagliptin to the magnesium stearate is (40-50): 1.

6. a preparation method of vildagliptin tablets according to any one of claims 1-5, characterized by mixing in a one-pot method, uniformly mixing raw materials and auxiliary materials, and performing tabletting operation by a tabletting machine to obtain the vildagliptin tablets;

the vildagliptin tablet comprises the following raw and auxiliary materials in parts by weight: 20-25 parts of vildagliptin bulk drug, 65-75 parts of diluent, 2-4 parts of disintegrant, 0.5-2 parts of glidant and 0.5-1 part of lubricant.

7. The preparation method of vildagliptin tablets as claimed in claim 6, wherein the preparation method comprises the following steps: the vildagliptin bulk drug is added into a mixer after being screened by a 60-mesh sieve, then the diluent, the disintegrant, the glidant and the lubricant are sequentially added into the mixer after being screened by the 60-mesh sieve, the raw materials and the auxiliary materials are uniformly mixed in the mixer, the mixing uniformity is verified, and then a tabletting machine is used for tabletting operation to obtain the vildagliptin tablet.

8. The preparation method of vildagliptin tablets as claimed in claim 6, wherein the diluent is a mixture of mannitol and sucrose, and the weight ratio of mannitol to sucrose is 1 (1-2).

9. The method for preparing vildagliptin tablets as claimed in claim 6, wherein the disintegrant is croscarmellose sodium and the glidant is colloidal silicon dioxide.

10. The preparation method of vildagliptin tablets as claimed in claim 6, wherein the lubricant is magnesium stearate, and the weight ratio of vildagliptin to magnesium stearate is (40-50): 1.

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