CN115154432B - Repaglinide tablet and preparation method thereof - Google Patents
Repaglinide tablet and preparation method thereof Download PDFInfo
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- CN115154432B CN115154432B CN202210871242.2A CN202210871242A CN115154432B CN 115154432 B CN115154432 B CN 115154432B CN 202210871242 A CN202210871242 A CN 202210871242A CN 115154432 B CN115154432 B CN 115154432B
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- repaglinide
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- microcrystalline cellulose
- lactose
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- FAEKWTJYAYMJKF-QHCPKHFHSA-N GlucoNorm Chemical compound C1=C(C(O)=O)C(OCC)=CC(CC(=O)N[C@@H](CC(C)C)C=2C(=CC=CC=2)N2CCCCC2)=C1 FAEKWTJYAYMJKF-QHCPKHFHSA-N 0.000 title claims abstract description 77
- 229960002354 repaglinide Drugs 0.000 title claims abstract description 77
- 238000002360 preparation method Methods 0.000 title claims abstract description 43
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 claims abstract description 35
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims abstract description 25
- 239000008101 lactose Substances 0.000 claims abstract description 25
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 24
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 21
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 21
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 21
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 21
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229920002261 Corn starch Polymers 0.000 claims abstract description 17
- 239000008120 corn starch Substances 0.000 claims abstract description 17
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000011591 potassium Substances 0.000 claims abstract description 16
- 229910052700 potassium Inorganic materials 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 14
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 12
- 239000000203 mixture Substances 0.000 claims abstract description 10
- 238000009472 formulation Methods 0.000 claims abstract description 9
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims abstract description 8
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims abstract description 8
- 235000019700 dicalcium phosphate Nutrition 0.000 claims abstract description 5
- 238000002156 mixing Methods 0.000 claims description 20
- 238000007873 sieving Methods 0.000 claims description 18
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 9
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 9
- 239000000463 material Substances 0.000 claims description 9
- 229960003194 meglumine Drugs 0.000 claims description 9
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 8
- 239000011575 calcium Substances 0.000 claims description 8
- 229910052791 calcium Inorganic materials 0.000 claims description 8
- 229920001983 poloxamer Polymers 0.000 claims description 8
- 229960000502 poloxamer Drugs 0.000 claims description 8
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 8
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 8
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 7
- 229960000540 polacrilin potassium Drugs 0.000 claims description 7
- WVWZXTJUCNEUAE-UHFFFAOYSA-M potassium;1,2-bis(ethenyl)benzene;2-methylprop-2-enoate Chemical compound [K+].CC(=C)C([O-])=O.C=CC1=CC=CC=C1C=C WVWZXTJUCNEUAE-UHFFFAOYSA-M 0.000 claims description 7
- 229940069328 povidone Drugs 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 229920003081 Povidone K 30 Polymers 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 229920001993 poloxamer 188 Polymers 0.000 claims description 3
- 229940044519 poloxamer 188 Drugs 0.000 claims description 3
- 239000008213 purified water Substances 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 230000008569 process Effects 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000004090 dissolution Methods 0.000 description 27
- 239000012738 dissolution medium Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- 239000007884 disintegrant Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 4
- 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 4
- 239000000243 solution Substances 0.000 description 4
- 229940100389 Sulfonylurea Drugs 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000003914 insulin secretion Effects 0.000 description 3
- 238000010299 mechanically pulverizing process Methods 0.000 description 3
- 239000008055 phosphate buffer solution Substances 0.000 description 3
- 230000000580 secretagogue effect Effects 0.000 description 3
- 238000001694 spray drying Methods 0.000 description 3
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical group CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- 102000004257 Potassium Channel Human genes 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 201000001421 hyperglycemia Diseases 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 210000004153 islets of langerhan Anatomy 0.000 description 2
- 235000012054 meals Nutrition 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 229960005455 polacrilin Drugs 0.000 description 2
- 108020001213 potassium channel Proteins 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 108090000312 Calcium Channels Proteins 0.000 description 1
- 102000003922 Calcium Channels Human genes 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 101000748159 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 35 Proteins 0.000 description 1
- 102000016924 KATP Channels Human genes 0.000 description 1
- 108010053914 KATP Channels Proteins 0.000 description 1
- 102100040048 Ubiquitin carboxyl-terminal hydrolase 35 Human genes 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000003177 cardiotonic effect Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 230000000916 dilatatory effect Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 238000009506 drug dissolution testing Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000028161 membrane depolarization Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- BNYHRGTXRPWASY-UHFFFAOYSA-N nonylsulfonylurea Chemical compound CCCCCCCCCS(=O)(=O)NC(N)=O BNYHRGTXRPWASY-UHFFFAOYSA-N 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- -1 pre-preparation Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000013585 weight reducing agent Substances 0.000 description 1
- 238000005550 wet granulation 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
-
- 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
- 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
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
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- 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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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
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- 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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Abstract
The invention relates to a repaglinide tablet and a preparation method thereof, wherein the repaglinide tablet comprises the following components: repaglinide pre-formulation, anhydrous calcium hydrogen phosphate, lactose, microcrystalline cellulose, corn starch, potassium polycryline, magnesium stearate and ferric oxide; the repaglinide tablet comprises, by taking the total mass of 100%, 5% of potassium polycryline, 10% of anhydrous calcium hydrogen phosphate, 27-32% of lactose, 31.91% of microcrystalline cellulose, 20% of corn starch, 0.5% of magnesium stearate, 0-0.2% of iron oxide and the balance of a repaglinide pre-preparation. The repaglinide tablet provided by the invention is good in stability, simple in process and suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to repaglinide tablets and a preparation method thereof.
Background
Defects in insulin secretion play a key role in the development of type II diabetes. Evidence-based medicine has also demonstrated that long-term, intensive hypoglycemic therapy based on secretagogues can reduce macrovascular and microvascular complications. The secretagogues promote insulin secretion mainly by closing ATP-dependent potassium ion channels on pancreatic islet beta cell membranes, and mainly comprise traditional sulfonylureas and novel non-sulfonylureas. The repaglinide non-sulfonylurea secretagogue has stronger selectivity on potassium ion channels on pancreatic islet beta cells, and therefore, the specificity is higher.
Repaglinide tablets (trade name: norathon) are a drug successfully developed by danish norathnide for the treatment of type II diabetes, and were approved by the U.S. FDA in 12 months in 1997, and were marketed in the united states and european countries in 1998 one after another. Clinically, repaglinide tablets are mainly used for treating type II diabetes (non-insulin dependent type) patients who have diet control, weight reduction and exercise and can not effectively control hyperglycemia. Repaglinide is combined with a specific receptor on an islet beta cell membrane, so that an ATP sensitive potassium channel coupled with the receptor is promoted to be closed, outflow of potassium ions from beta cells is inhibited, cell membrane depolarization is inhibited, a calcium channel is opened, calcium ions flow inwards, and insulin secretion is promoted. The effect is faster than sulfonylureas, so the effect of reducing blood sugar after meal is faster; a glucose regulating drug to be taken at the first meal; the biggest advantage is that the physiological secretion of insulin can be simulated, thereby effectively controlling the postprandial hyperglycemia.
Repaglinide is white or off-white crystalline powder, odorless, soluble in chloroform, slightly soluble in ethanol or acetone, almost insoluble in water, and slightly soluble in 0.1mol/L hydrochloric acid solution; its poor solubility is a key factor affecting the difference in clinical efficacy. The content of active substances in the repaglinide tablets is not more than 2 percent, and the content uniformity is less than 15.0 according to the specification of an appendix XE of 2010 version of Chinese pharmacopoeia; the pH of the dissolution medium for repaglinide tablets in the united states pharmacopeia 35 edition (USP 35) is 5.0. However, the solubility of repaglinide in a medium with pH of 5.0 is small (0.012 mg/mL), the dissolution speed is slow, and the dissolution of repaglinide is difficult to reach 70 percent (Q) of the marked amount within 30 min; in addition, USP35 version has high requirements on the stability limit of the product, the content of single impurities does not exceed 0.2%, and the total impurities does not exceed 0.5%.
Currently, the commercial products are generally prepared by wet granulation; CN201210369291.2 discloses a composition and a preparation method of repaglinide tablets (with slow release effect); the patent CN200780036006.2 discloses a preparation method of repaglinide tablets, which adopts a spray dryer to carry out spray drying granulation: repaglinide, meglumine, poloxamer and polyvidone are prepared into spray-dried granule pre-preparation, so that the solubility of the spray-dried granule pre-preparation is improved. CN201310565684.5 discloses a preparation method of repaglinide tablets, but the dissolution curve of the repaglinide tablets is not consistent with that of the original preparation.
Therefore, providing the repaglinide tablet which has the same dissolution curve with the original preparation, has lower cost and is suitable for industrial production is one of the research hotspots.
Disclosure of Invention
In order to solve the technical problems, the invention provides repaglinide tablets and a preparation method thereof.
The research shows that the dissolution of the product can be influenced by adjusting the addition amount of the polacrilin potassium in the product, but the experiment shows that 5 percent of polacrilin potassium can meet the dissolution requirement of the tablet at the pH value of 5, but can not meet the dissolution requirement of the tablet at the pH value of 6.8. Although studies have shown that the ratio of repaglinide to meglumine improves the dissolution of the drug at different pH values. However, meglumine is also a pharmaceutical ingredient which increases the contractile force of cardiac muscle, has a cardiotonic effect, and also has the effects of dilating peripheral blood vessels and reducing cardiac load. Therefore, the content thereof has a large influence in repaglinide formulations; considering the influence of the drug effect and the national requirement for drug consistency evaluation, the proportion of the two most main components is adjusted, and the national approval requirement is difficult to meet. In order to solve the technical problem, the inventors have conducted intensive studies and finally found that the dissolution requirement can be satisfied by specifically designing the auxiliary materials. In particular, this problem can be solved by determining the content of potassium polycryline at 5% and selecting lactose as one of the fillers, while balancing the content of lactose and anhydrous dibasic calcium phosphate (anhydrous dibasic calcium phosphate represents 10% of the total weight of the tablet, while the lactose content is 25-35%, preferably 27-32%).
In a first aspect, the invention provides a repaglinide tablet, which comprises the following components: the repaglinide preparation comprises repaglinide, anhydrous calcium hydrophosphate, lactose, microcrystalline cellulose, corn starch, polacrilin potassium, magnesium stearate and ferric oxide, wherein the repaglinide preparation consists of repaglinide, meglumine, poloxamer and povidone;
wherein, based on the total mass of the repaglinide tablet as 100%, the content of the potassium polycryline is 5%, the content of anhydrous calcium hydrophosphate is 10%, the content of lactose is 27-32%, the content of microcrystalline cellulose is 31.91%, the content of corn starch is 20%, the content of magnesium stearate is 0.5%, the content of ferric oxide is 0-0.2%, such as 0.05%, 0.1%, 0.15% and the like, and the balance is a repaglinide pre-preparation.
The repaglinide pre-formulation consists of 44% of repaglinide, 22% of meglumine, 21% of poloxamer and 13% of povidone by taking the total mass of the repaglinide pre-formulation as 100%.
Generally, for tablets, the higher the content of a disintegrant (such as potassium polycryline), the faster the disintegration speed of the tablets, but the invention has surprisingly found that, when the addition amount of potassium polycryline is 5%, the in vitro dissolution behavior of the prepared repaglinide tablets in phosphate buffer with pH =5.0 is consistent with the original research, but the disintegration speed is remarkably reduced with the increase of the addition amount of potassium polycryline, and the dissolution speed of the repaglinide tablets is further reduced.
In a preferred embodiment of the present invention, the iron oxide is red iron oxide or yellow iron oxide.
As a preferred technical solution of the present invention, the poloxamer is poloxamer 188; the povidone is povidone K30; the microcrystalline cellulose is microcrystalline cellulose SH-112.
In a second aspect, the invention discloses a preparation method of repaglinide tablets, which comprises the following steps:
(1) Preparing a pre-preparation: weighing the raw and auxiliary materials required by the pre-preparation according to the prescription amount, heating purified water, and then sequentially adding the weighed raw and auxiliary materials, stirring and dissolving; spray drying and heating drying for later use;
(2) Pretreatment: drying and sieving the pre-preparation; mechanically pulverizing ferric oxide (red ferric oxide or yellow ferric oxide), and sieving; sieving microcrystalline cellulose, corn starch and lactose;
(3) Mixing and tabletting: mixing corn starch, pre-preparation, potassium polycryline, lactose, ferric oxide and anhydrous calcium hydrogen phosphate, mixing with microcrystalline cellulose and magnesium stearate, mixing, and tabletting.
As a specific embodiment of the present invention, the step (2) is: sieving the dried pre-preparation with a 80-mesh sieve; mechanically pulverizing ferric oxide (red ferric oxide or yellow ferric oxide), and sieving with 120 mesh sieve; sieving microcrystalline cellulose, corn starch and lactose with 60 mesh sieve.
As a specific embodiment of the present invention, the step (3) is: uniformly mixing corn starch, a pre-preparation, potassium polacrilin, lactose, ferric oxide and anhydrous calcium hydrophosphate, and sieving by a 60-mesh sieve; mixing the sieved materials with microcrystalline cellulose, mixing uniformly, adding magnesium stearate, mixing uniformly, and tabletting.
Compared with the prior art, the technical scheme provided by the embodiment of the invention has the following advantages:
(1) According to the invention, 5% of potassium polycryline is selected as a disintegrating agent, so that the dissolution behavior of the obtained repaglinide tablet in an in-vitro environment with the pH value of 5.0 is consistent with that of the original research;
(2) According to the invention, lactose is introduced into the diluent, and the proportion of lactose and anhydrous calcium hydrogen phosphate is controlled, so that the dissolution behavior of the obtained repaglinide tablet in an in-vitro environment with the pH value of 6.8 is consistent with that of the original research under the condition that the addition amount of the potassium polycryline is 5%;
(3) The repaglinide tablet provided by the invention has good stability, the dissolution curve is consistent with that of the original preparation, and meanwhile, the process requirement is low, so that the repaglinide tablet is suitable for industrial production.
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 repaglinide tablet, which comprises the following components of a repaglinide pre-preparation, anhydrous calcium hydrophosphate, lactose, microcrystalline cellulose SH-112, corn starch SH-H, polacrilin potassium, magnesium stearate and ferric oxide, wherein the repaglinide pre-preparation comprises repaglinide, meglumine, poloxamer 188 and povidone K30.
The preparation method comprises the following steps:
(1) Preparing a pre-preparation: weighing raw and auxiliary materials required by the pre-preparation according to the prescription amount, heating purified water to 60 ℃, sequentially adding the raw and auxiliary materials, stirring and dissolving; spray drying the solution by using a spray dryer; then dried using a hot air circulation oven at 50 ℃.
(2) Pretreating raw materials and auxiliary materials: sieving the dried pre-preparation with a 80-mesh sieve; mechanically pulverizing ferric oxide (red ferric oxide or yellow ferric oxide), and sieving with 120 mesh sieve; sieving microcrystalline cellulose, corn starch and lactose with 60 mesh sieve;
(3) Uniformly mixing corn starch, a pre-preparation, potassium polacrilin, lactose, ferric oxide and anhydrous calcium hydrophosphate, and sieving by a 60-mesh sieve; mixing the sieved material with microcrystalline cellulose, mixing well, adding magnesium stearate, mixing well and tabletting.
Example 2
This example investigates the effect of polacrilin potassium on disintegration.
(1) Referring to the preparation method provided in the example, repaglinide tablets were prepared according to the formula provided in table 1:
TABLE 1
Taking phosphate buffer solution with pH of 5.0 as dissolution medium, rotating speed of 50rpm, referring to determination method of dissolution rate and release rate of 2015 edition Chinese pharmacopoeia 0931, sampling and detecting and calculating dissolution amount of each tablet after 5, 10, 15, 30, 45, 60, 90 and 120min, and the result is shown in Table 2;
TABLE 2
As can be seen from table 2, under the dissolution medium with ph5.0, the repaglinide tablet provided by the present invention does not show the phenomenon that the dissolution behavior is always accelerated along with the increase of the usage amount of the disintegrant, and after the usage amount of the disintegrant is higher than 5%, the disintegration rate is rather reduced, and the content is higher, the difference is larger than that of the reference preparation; therefore, the specific selective disintegrant of potassium polycaprolin is added in an amount of 5%, so that the in-vitro dissolution behavior of the obtained repaglinide tablets can be consistent with that of the original research.
(2) Referring to the method provided in (1), the dissolution behavior of repaglinide tablets was investigated by changing the dissolution medium to phosphate buffer solution with ph6.8, and the results are shown in table 3:
TABLE 3
As can be seen from table 3, when 5% of potassium polycryline is selected as a disintegrant, the present invention has significant difference from the reference formulation, and cannot meet the requirement of drug approval.
Example 3
This example examined the effect of lactose and anhydrous dibasic calcium phosphate on dissolution testing.
(1) In vitro dissolution test
Referring to the preparation provided in example 1, repaglinide tablets were prepared according to the formulation provided in table 4:
TABLE 4
Taking phosphate buffer solution with pH6.8 as dissolution medium, rotating speed is 50rpm, referring to the determination method of dissolution rate and release rate of 2015 version Chinese pharmacopoeia 0931, sampling and detecting and calculating dissolution amount of each tablet after 5, 10, 15, 30, 45, 60, 90 and 120min, and the result is shown in Table 5;
TABLE 5
As can be seen from tables 4 and 5, the addition of lactose to the repaglinide tablets increased the dissolution of repaglinide, and when the amount of added lactose was 27.61%, the dissolution endpoint of the repaglinide tablets provided by the present invention was comparable to the dissolution endpoint of the reference preparation.
The dissolution of repaglinide tablets provided by formula 3 in phosphate buffer at ph5.0 was verified, and the results are shown in table 6:
TABLE 6
As can be seen from Table 6, the repaglinide tablets provided by the present invention have similar or even better dissolution rate than the reference formulation in the dissolution medium with pH 5.0.
In addition, 1 mg/tablet and 0.5 mg/tablet specifications were examined, with the 1 mg/tablet and 0.5 mg/tablet specifications consisting of Table 7:
TABLE 7
The results show that the dissolution of the compound is similar to the 2 mg/tablet specification under the conditions of pH5.0 and pH6.8, and the compound meets the requirements.
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," "8230," or "comprising" 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 (5)
1. The repaglinide tablet is characterized by comprising the following components in parts by weight: the repaglinide preparation comprises repaglinide, anhydrous calcium hydrophosphate, lactose, microcrystalline cellulose, corn starch, polacrilin potassium, magnesium stearate and ferric oxide, wherein the repaglinide preparation consists of repaglinide, meglumine, poloxamer and povidone;
the repaglinide tablet comprises, by taking the total mass of the repaglinide tablet as 100%, 5% of potassium polycryline, 10% of anhydrous calcium hydrophosphate, 27-32% of lactose, 31.91% of microcrystalline cellulose, 20% of corn starch, 0.5% of magnesium stearate, 0-0.2% of iron oxide and the balance of a repaglinide pre-preparation;
the repaglinide pre-formulation is composed of 44% of repaglinide, 22% of meglumine, 21% of poloxamer and 13% of povidone by taking the total mass of the repaglinide pre-formulation as 100%;
the poloxamer is poloxamer 188; the povidone is povidone K30; the microcrystalline cellulose is microcrystalline cellulose SH-112.
2. Repaglinide tablets according to claim 1, wherein the iron oxide is red or yellow iron oxide.
3. The method for preparing repaglinide tablets according to claim 1 or 2, comprising:
(1) Preparing a pre-preparation: heating purified water, adding repaglinide, meglumine, poloxamer and povidone for dissolving, and drying to obtain the repaglinide prefabricated agent;
(2) Pretreatment: sieving the dried repaglinide pre-preparation, crushing and sieving iron oxide powder, and sieving microcrystalline cellulose, corn starch and lactose;
(3) Mixing and tabletting: mixing corn starch, repaglinide pre-preparation, potassium polycaprolate, lactose, ferric oxide and anhydrous calcium hydrogen phosphate uniformly, mixing with microcrystalline cellulose and magnesium stearate sequentially, mixing uniformly, and tabletting.
4. The method according to claim 3, wherein the step (2) is: sieving the dried repaglinide pre-preparation by a sieve of 80 meshes; mechanically crushing the ferric oxide and then sieving the crushed ferric oxide by a 120-mesh sieve; sieving microcrystalline cellulose, corn starch and lactose with 60 mesh sieve.
5. The method according to claim 4, wherein the step (3) is: uniformly mixing corn starch, repaglinide pre-preparation, polacrilin potassium, lactose, ferric oxide and anhydrous calcium hydrophosphate, and sieving by using a 60-mesh sieve; mixing the sieved material with microcrystalline cellulose, mixing well, adding magnesium stearate, mixing well and tabletting.
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