CN115501195A - Linagliptin tablet and preparation method thereof - Google Patents
Linagliptin tablet and preparation method thereof Download PDFInfo
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- CN115501195A CN115501195A CN202211286356.7A CN202211286356A CN115501195A CN 115501195 A CN115501195 A CN 115501195A CN 202211286356 A CN202211286356 A CN 202211286356A CN 115501195 A CN115501195 A CN 115501195A
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- Prior art keywords
- linagliptin
- granules
- mannitol
- tablet
- compression roller
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- LTXREWYXXSTFRX-QGZVFWFLSA-N Linagliptin Chemical compound N=1C=2N(C)C(=O)N(CC=3N=C4C=CC=CC4=C(C)N=3)C(=O)C=2N(CC#CC)C=1N1CCC[C@@H](N)C1 LTXREWYXXSTFRX-QGZVFWFLSA-N 0.000 title claims abstract description 52
- 229960002397 linagliptin Drugs 0.000 title claims abstract description 52
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 238000000034 method Methods 0.000 claims description 32
- 238000002156 mixing Methods 0.000 claims description 30
- 239000008187 granular material Substances 0.000 claims description 29
- 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 20
- 229930195725 Mannitol Natural products 0.000 claims description 20
- 238000007906 compression Methods 0.000 claims description 20
- 230000006835 compression Effects 0.000 claims description 20
- 239000000594 mannitol Substances 0.000 claims description 20
- 235000010355 mannitol Nutrition 0.000 claims description 20
- 239000000463 material Substances 0.000 claims description 18
- 238000000576 coating method Methods 0.000 claims description 17
- 239000011248 coating agent Substances 0.000 claims description 16
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 13
- 229920000881 Modified starch Polymers 0.000 claims description 12
- 229920001531 copovidone Polymers 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 11
- 229920002261 Corn starch Polymers 0.000 claims description 10
- 239000008120 corn starch Substances 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- 239000002245 particle Substances 0.000 claims description 10
- 238000005469 granulation Methods 0.000 claims description 9
- 238000007908 dry granulation Methods 0.000 claims description 7
- 230000003179 granulation Effects 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- 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
- 230000004584 weight gain Effects 0.000 claims description 5
- 235000019786 weight gain Nutrition 0.000 claims description 5
- 238000004090 dissolution Methods 0.000 abstract description 10
- 239000012535 impurity Substances 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 7
- 238000011160 research Methods 0.000 description 5
- 238000005550 wet granulation Methods 0.000 description 5
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 description 4
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 description 3
- 108010004460 Gastric Inhibitory Polypeptide Proteins 0.000 description 3
- 102100039994 Gastric inhibitory polypeptide Human genes 0.000 description 3
- 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 3
- 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
- 102100040918 Pro-glucagon Human genes 0.000 description 3
- 230000001276 controlling effect Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 230000028327 secretion Effects 0.000 description 3
- 102000051325 Glucagon Human genes 0.000 description 2
- 108060003199 Glucagon Proteins 0.000 description 2
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive effect 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
- 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
- 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 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 235000020985 whole grains Nutrition 0.000 description 2
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical group O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 1
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000008199 coating composition Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 229920006158 high molecular weight polymer Polymers 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 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 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000002571 pancreatic alpha cell Anatomy 0.000 description 1
- 230000002572 peristaltic effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- A61K9/2095—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
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
-
- 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
-
- 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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2893—Tablet coating processes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Obesity (AREA)
- Emergency Medicine (AREA)
- Hematology (AREA)
- Endocrinology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a linagliptin tablet and a preparation method thereof. The linagliptin tablet prepared by the preparation method provided by the invention has better dissolution behavior and excellent stability.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a linagliptin tablet and a preparation method thereof.
Background
Linagliptin is an oral selective DPP-4 (dipeptidyl peptidase 4) inhibitor with a xanthine skeleton, has high selectivity on DPP-4, has long action duration and can achieve expected curative effect after being taken once a day. In humans, DPP-4 is capable of degrading incretin-like polypeptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), while linagliptin is capable of increasing the concentration of active incretin, stimulating insulin release in a glucose-dependent manner, and reducing circulating glucagon levels. The incretin secretion is maintained at a lower basal level in one day and is increased immediately after a meal; under conditions of normal or elevated glucose levels, both GLP-1 and GIP increase the biosynthesis and secretion of pancreatic β -cell insulin; in addition, GLP-1 also reduces glucagon secretion from pancreatic alpha cells and hepatic glucose output.
Linagliptin tablets (Linagliptin) were developed by the company brigling invager, and were approved by the FDA to be marketed in the united states at the earliest 5 months in 2011 at a specification of 5mg, and then, the Linagliptin tablets of brigling invager were approved in the european union and japan in various countries/regions and were approved to be imported into china in 2013. The linagliptin tablet is white or similar to white after being coated, and the original patent 200780016227.3 discloses the components of the linagliptin tablet, wherein the linagliptin tablet comprises linagliptin and diluent mannitol thereof, pre-crosslinked starch, adhesive copolymerized polyvinylpyrrolidone, disintegrant corn starch, lubricant magnesium stearate and a coating, the coating contains hydroxypropyl methylcellulose, polyethylene glycol, talcum powder, titanium dioxide, iron oxide and the like, and the auxiliary materials are common auxiliary materials for wet granulation. Because linagliptin belongs to a high-solubility medicine, the adjustment of auxiliary materials and a process can influence the product and the quality thereof, and can mainly influence the increase of impurities.
The main impurities of linagliptin are N and O. The impurity N is a main degradation product in the preparation, and is generated by the reaction of linagliptin and auxiliary materials in the preparation at high temperature or high temperature and high humidity, and the specific generation process is as follows:
and impurity O is generated by the acid degradation of linagliptin:
the original patented process is wet granulation, which is difficult to control the growth of impurity N. The applicant of the invention establishes a formula and a process of a linagliptin tablet in earlier research, the related formula and process are described in patent 202211154627.3, and the formula described in the patent is matched with dry granulation and an internal and external dual-granulation process, so that the linagliptin tablet has good dissolution and stability. However, the formulations described in the above patents are quite different from the original formulations. In further research, the applicant further uses the process in the research of similar formulas in the original research, and obtains a preparation process of the linagliptin tablet with excellent stability and dissolution performance through research and adjustment.
Disclosure of Invention
In order to solve the technical problems, the invention provides a linagliptin tablet and a preparation method thereof. According to the preparation method, a dry granulation process is adopted in the preparation method of the linagliptin tablet, and a special multi-granule preparation process is designed, so that the effects of effectively controlling the dissolution of linagliptin and the increase of impurities are realized.
Based on the above findings, the present invention provides, in a first aspect, a linagliptin tablet, comprising a coating and an elemental tablet, wherein the elemental tablet comprises, in parts by weight:
as a preferred technical scheme of the invention, the plain tablets comprise the following components in parts by weight:
the composition also comprises a coating, and the weight increment of the coating is controlled to be 2-5 percent of the weight of the tablet, preferably about 3 percent by controlling the coating process; the coating composition may include various components such as high molecular weight polymers, plasticizers, colorants, and the like, preferably opadry II.
Wherein the copovidone is preferably copovidone VA64 copovidone.
In a second aspect, the present invention provides a preparation method of the linagliptin tablet described in the first aspect, including the following steps:
(1) Mixing linagliptin, pregelatinized starch and part of mannitol, and performing dry granulation to obtain inner granules;
(2) Mixing the inner granules with corn starch, the rest mannitol and copovidone, and performing dry granulation to obtain medicine granules;
(3) Mixing the medicinal granules with calcium stearate, and tabletting;
(4) And (4) coating.
The multiple dry method granule preparation form adopted by the linagliptin tablet can also effectively control the problems of dissolution of linagliptin and impurity growth.
The invention integrally adopts a dry granulation process and designs a special multi-granule process, so that the problems of the dissolution of the linagliptin tablet and the increase of impurities can be effectively controlled.
As a preferred technical solution of the present invention, the step (1) is: the linagliptin, the pregelatinized starch and 30-50wt% of mannitol are uniformly mixed, and the inner granules are prepared by a dry-process granulator.
As a preferred technical solution of the present invention, the step (1) is: uniformly mixing linagliptin, pregelatinized starch and 30-50wt% of mannitol to obtain a mixed material, placing the mixed material in a hopper of a dry granulating machine, and setting the compression roller speed, the compression roller gap, the finishing speed and the mesh aperture to prepare the inner particles.
As a preferred technical scheme of the invention, the step (1) is as follows: uniformly mixing linagliptin, pregelatinized starch and 50wt% mannitol, placing the mixture in a hopper of a dry-process granulator, and preparing the inner granule, wherein the compression roller speed is 10rpm, the compression roller gap is 1.0mm, the granulation speed is 100rpm, and the mesh aperture is 0.8 mm.
As a preferred technical scheme of the invention, the step (2) is as follows: and uniformly mixing the inner granules with the corn starch, the rest mannitol and the copovidone, and preparing the medicine granules by a dry granulating machine.
As a preferred technical solution of the present invention, the step (2) is: and (3) uniformly mixing the inner particles with the corn starch, the rest mannitol and the copovidone, placing the mixed material into a hopper of a dry-process granulator, and obtaining the medicine particles, wherein the compression roller speed is 10rpm, the compression roller gap is 1.0mm, the whole granulation speed is 100rpm, and the mesh opening size is 1.2 mm.
As a preferred technical solution of the present invention, the step (3) is: mixing the medicinal granules with calcium stearate for more than 5min, and tabletting.
As a preferred technical scheme of the invention, in the step (4), the weight gain of the coating is controlled to be 2.0-5.0%, preferably 2.0-4.0%, and more preferably about 3%; the coating of the present invention may optionally be coated with an opadry water soluble film coating material, such as opadry I or opadry II.
As a specific embodiment of the present invention, the preparation method comprises:
(1) Weighing linagliptin and each auxiliary material component according to the prescription amount;
(2) Putting linagliptin, pregelatinized starch and 50% mannitol into a hopper of a mixing tank, uniformly mixing, placing the uniformly mixed material into a hopper of a dry-process granulator, and preparing to obtain inner granules, wherein the compression roller speed is 10rpm, the compression roller gap is 1.0mm, the whole-granulating speed is 100rpm, and the mesh size is 0.8 mm;
(3) Putting the prepared inner particles, corn starch, residual mannitol and copovidone into a hopper of a mixing tank, uniformly mixing, putting the uniformly mixed material into the hopper of a dry-process granulator, and preparing to obtain medicine particles, wherein the compression roller speed is 10rpm, the compression roller gap is 1.0mm, the whole-grain speed is 100rpm, and the mesh opening is 1.2 mm;
(4) Mixing the prepared medicinal granules with additional calcium stearate for more than 5min, and tabletting;
(5) Coating: the weight gain was about 3% (about 5.4 mg/tablet).
Compared with the prior art, the technical scheme provided by the embodiment of the invention has the following advantages:
the linagliptin tablet provided by the invention has better dissolution behavior, meets the requirement of the consistency of the imitation drugs, has excellent stability, and does not cause the increase of impurities under the high-temperature and high-humidity environment.
Detailed Description
In order that the above objects, features and advantages of the present invention may be more clearly understood, a solution of the present invention will be further described below. It should be noted that the embodiments of the present invention and features of the embodiments may be combined with each other without conflict.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways than those described herein; it is to be understood that the embodiments described in this specification are only some embodiments of the invention, and not all embodiments.
Example 1
The embodiment provides a linagliptin tablet and a preparation method thereof.
The composition of the linagliptin tablet is shown in table 1:
TABLE 1
The preparation method comprises the following steps:
(1) Weighing linagliptin and each auxiliary material component according to the prescription amount;
(2) Putting linagliptin, pregelatinized starch and 50% mannitol into a hopper of a mixing tank, uniformly mixing, putting the uniformly mixed material into a hopper of a dry-process granulator, and preparing inner granules, wherein the compression roller speed is 10rpm, the compression roller gap is 1.0mm, the granulating speed is 100rpm, and the mesh size is 0.8 mm;
(3) Putting the prepared inner particles, corn starch, the rest mannitol and the copovidone VA64 into a hopper of a mixing tank, uniformly mixing, putting the uniformly mixed materials into a hopper of a dry-process granulator, and preparing the medicine particles, wherein the compression roller speed is 10rpm, the compression roller gap is 1.0mm, the whole-grain speed is 100rpm, and the screen mesh aperture is 1.2 mm;
(4) Mixing the prepared medicinal granules with calcium stearate for more than 5min, and tabletting;
(5) Coating: the weight gain of the coating was controlled to be about 3% and the coating material used was opadry II.
Comparative example 1
The comparative example provides a formulation and a process of the original patent.
The original patent formula is shown in a table 2:
TABLE 2
The preparation method comprises the following steps:
(1) Sequentially putting the mannitol, linagliptin, corn starch and pregelatinized starch in the formula amount into a granulator, mixing for 5min, and then adding an adhesive (copovidone) solution in a liquid spraying manner through a peristaltic pump for granulation, wherein the granulation parameters are as follows: stirring for 3r/s, and shearing for 25r/s;
(2) Wet granulation is carried out on the wet granules after granulation is finished through a6 multiplied by 6mm screen;
(3) Transferring the finished wet granules into a fluidized bed for drying, setting the air inlet temperature to be 55-65 ℃, setting the moisture to be less than 2.0%, installing a 1.2mm screen, and finishing the dried granules by using a granulator;
(4) Adding the granules into a mixing tank, adding magnesium stearate, mixing for 5min, and tabletting;
(5) Coating, and controlling the weight gain to be 3%.
Comparative example 2
The comparative example provides a linagliptin tablet and a preparation method thereof.
The difference from example 1 is that in this comparative example, pregelatinized starch was added in step (3), and the rest of the process was the same.
Performance testing
(1) The tablets are placed for 6 months under the conditions of temperature of 40 +/-2 ℃, relative humidity of 75 +/-5% and RH constant temperature and humidity, the impurity contents of the tablets before and after 1, 2, 3 and 6 months of the tablets are respectively detected according to a method for measuring the VD content in the appendix II of the 2010 version of Chinese pharmacopoeia, the reference preparation adopts the commercial tablets, and the results are shown in Table 3.
TABLE 3
As can be seen from table 3, the stability of the linagliptin tablets obtained according to the present invention was also significantly better than that of the wet granulation (comparative example 1), both in terms of control of impurity N and overall impurity control. Meanwhile, the effect was slightly improved as compared with comparative example 2, but it was not remarkable. However, as can be seen from the results, the stability of the linagliptin tablet can be increased by using the multi-granulation process provided by the present invention, compared to a method in which the ingredients are directly mixed for wet granulation and total mixing. This result is consistent with previous findings.
(2) 900mL of 0.1M HCl was used as a dissolution medium, and 50 rotations of the Paddle method were performed according to 0931, the first method of the four general guidelines of the 2020 edition of Chinese pharmacopoeia: the dissolution and release determination method comprises sampling and detecting the samples at 5, 10, 15, 30, 45 and 60min, and calculating the dissolution (%) of linagliptin, the results are shown in Table 4;
TABLE 4
As can be seen from table 4, the dissolution behavior of the linagliptin tablet provided by the present invention is close to that of the reference preparation, and completely meets the relevant regulatory requirements. This result is also consistent with the previous findings of the applicant.
It is noted that, in this document, relational terms such as "first" and "second," and the like, may be used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Also, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus. Without further limitation, an element defined by the phrases "comprising a" \8230; "does not exclude the presence of additional like elements in a process, method, article, or apparatus that comprises the element.
The foregoing are merely exemplary embodiments of the present invention, which enable those skilled in the art to understand or practice the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (9)
1. The preparation method of the linagliptin tablet is characterized in that the linagliptin tablet comprises a coating and an elemental tablet, and the elemental tablet comprises the following components in parts by weight:
the preparation method comprises the following steps:
(1) Mixing linagliptin, pregelatinized starch and part of mannitol, and performing dry granulation to obtain inner granules;
(2) Mixing the inner granules with corn starch, the rest mannitol and copovidone, and performing dry granulation to obtain medicine granules;
(3) Mixing the medicinal granules with calcium stearate, and tabletting;
(4) And (4) coating.
2. The preparation method according to claim 1, wherein the plain sheet consists of the following components in parts by weight:
3. the method according to claim 1, wherein the step (1) is: the linagliptin, the pregelatinized starch and 30-50wt% of mannitol are uniformly mixed, and the inner granules are prepared by a dry-process granulator.
4. The method according to claim 3, wherein the step (1) is: uniformly mixing linagliptin, pregelatinized starch and 30-50wt% of mannitol to obtain a mixed material, placing the mixed material in a hopper of a dry granulating machine, and setting the compression roller speed, the compression roller gap, the finishing speed and the mesh aperture to prepare the inner particles.
5. The method according to claim 4, wherein the step (1) is: uniformly mixing linagliptin, pregelatinized starch and 50wt% mannitol, placing the mixture in a hopper of a dry-process granulator, and preparing the inner granule, wherein the compression roller speed is 10rpm, the compression roller gap is 1.0mm, the granulation speed is 100rpm, and the mesh aperture is 0.8 mm.
6. The method according to claim 1, wherein the step (2) is: and uniformly mixing the inner granules with the corn starch, the rest mannitol and the copovidone, and preparing the medicine granules by a dry granulating machine.
7. The method according to claim 6, wherein the step (2) is: and (3) uniformly mixing the inner particles with the corn starch, the rest mannitol and the copovidone, placing the mixed material into a hopper of a dry-process granulator, and obtaining the medicine particles, wherein the compression roller speed is 10rpm, the compression roller gap is 1.0mm, the whole granulation speed is 100rpm, and the mesh opening size is 1.2 mm.
8. The method according to claim 1, wherein the step (3) is: mixing the medicinal granules with calcium stearate for more than 5min, and tabletting.
9. The method according to any one of claims 1 to 8, wherein in the step (4), the weight gain of the coating is controlled to be 2.0 to 3.5%.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104644563A (en) * | 2013-11-23 | 2015-05-27 | 天津市汉康医药生物技术有限公司 | Linagliptin composition and preparation method thereof |
| CN106138059A (en) * | 2015-03-27 | 2016-11-23 | 天津汉瑞药业有限公司 | A kind of stable Li Gelieting pharmaceutical composition |
| CN106389364A (en) * | 2016-10-28 | 2017-02-15 | 迪沙药业集团有限公司 | Trajenta tablet composition and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104644563A (en) * | 2013-11-23 | 2015-05-27 | 天津市汉康医药生物技术有限公司 | Linagliptin composition and preparation method thereof |
| CN106138059A (en) * | 2015-03-27 | 2016-11-23 | 天津汉瑞药业有限公司 | A kind of stable Li Gelieting pharmaceutical composition |
| CN106389364A (en) * | 2016-10-28 | 2017-02-15 | 迪沙药业集团有限公司 | Trajenta tablet composition and preparation method thereof |
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Denomination of invention: A ligagliptin tablet and its preparation method Effective date of registration: 20231013 Granted publication date: 20230512 Pledgee: Jilin Bank Co.,Ltd. Tonghua Meihekou Branch Pledgor: Jilin Huisheng Biopharmaceutical Co.,Ltd. Registration number: Y2023220000102 |
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Denomination of invention: A type of ligagliptin tablets and their preparation method Granted publication date: 20230512 Pledgee: Industrial and Commercial Bank of China Limited Meihekou Branch Pledgor: Jilin Huisheng Biopharmaceutical Co.,Ltd. Registration number: Y2024220000070 |