CN105343021A - Repaglinide tablet and preparation method thereof - Google Patents
Repaglinide tablet and preparation method thereof Download PDFInfo
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- CN105343021A CN105343021A CN201510760346.6A CN201510760346A CN105343021A CN 105343021 A CN105343021 A CN 105343021A CN 201510760346 A CN201510760346 A CN 201510760346A CN 105343021 A CN105343021 A CN 105343021A
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- repaglinide
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- 229960002354 repaglinide Drugs 0.000 title claims abstract description 122
- 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 81
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- -1 repaglinide compound Chemical class 0.000 claims description 42
- 239000008187 granular material Substances 0.000 claims description 35
- 238000003756 stirring Methods 0.000 claims description 20
- 238000001035 drying Methods 0.000 claims description 16
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 14
- 239000003795 chemical substances by application Substances 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 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 11
- 229960003194 meglumine Drugs 0.000 claims description 11
- LQJCZPBVFGWKML-UHFFFAOYSA-N chloroform;3-methylbutyl acetate Chemical compound ClC(Cl)Cl.CC(C)CCOC(C)=O LQJCZPBVFGWKML-UHFFFAOYSA-N 0.000 claims description 10
- 238000005520 cutting process Methods 0.000 claims description 10
- 239000012046 mixed solvent Substances 0.000 claims description 10
- 239000007779 soft material Substances 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 9
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 8
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 8
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical group C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 8
- 229920003081 Povidone K 30 Polymers 0.000 claims description 8
- 229920002472 Starch Polymers 0.000 claims description 8
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 8
- 235000019700 dicalcium phosphate Nutrition 0.000 claims description 8
- 239000003085 diluting agent Substances 0.000 claims description 8
- 239000000314 lubricant Substances 0.000 claims description 8
- 235000019359 magnesium stearate Nutrition 0.000 claims description 8
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 8
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 8
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 8
- 239000011734 sodium Substances 0.000 claims description 8
- 229910052708 sodium Inorganic materials 0.000 claims description 8
- 235000019698 starch Nutrition 0.000 claims description 8
- 239000008107 starch Substances 0.000 claims description 8
- 239000011230 binding agent Substances 0.000 claims description 7
- 239000008213 purified water Substances 0.000 claims description 7
- 238000010583 slow cooling Methods 0.000 claims description 7
- 239000000463 material Substances 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 239000013078 crystal Substances 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- 238000005550 wet granulation Methods 0.000 claims description 5
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 3
- 229910017488 Cu K Inorganic materials 0.000 claims description 2
- 229910017541 Cu-K Inorganic materials 0.000 claims description 2
- 230000005496 eutectics Effects 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 9
- 239000000126 substance Substances 0.000 abstract description 7
- 230000008859 change Effects 0.000 abstract description 5
- 238000004090 dissolution Methods 0.000 abstract description 3
- 238000012360 testing method Methods 0.000 description 12
- 230000003914 insulin secretion Effects 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 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 6
- MLFHJEHSLIIPHL-UHFFFAOYSA-N isoamyl acetate Chemical compound CC(C)CCOC(C)=O MLFHJEHSLIIPHL-UHFFFAOYSA-N 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 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 4
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 102000004877 Insulin Human genes 0.000 description 3
- 108090001061 Insulin Proteins 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 229940125396 insulin Drugs 0.000 description 3
- 229940117955 isoamyl acetate Drugs 0.000 description 3
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 3
- 229960003105 metformin Drugs 0.000 description 3
- 230000000291 postprandial effect Effects 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- 229940100389 Sulfonylurea Drugs 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 201000001421 hyperglycemia Diseases 0.000 description 2
- 230000002218 hypoglycaemic effect Effects 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 235000012054 meals Nutrition 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000012827 research and development Methods 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 238000009097 single-agent therapy Methods 0.000 description 2
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 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
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 229940122199 Insulin secretagogue Drugs 0.000 description 1
- 102000016924 KATP Channels Human genes 0.000 description 1
- 108010053914 KATP Channels Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102000004257 Potassium Channel Human genes 0.000 description 1
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 230000002641 glycemic effect Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000028161 membrane depolarization Effects 0.000 description 1
- 229940127017 oral antidiabetic Drugs 0.000 description 1
- 239000003538 oral antidiabetic agent Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 108020001213 potassium channel Proteins 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—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
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to a repaglinide tablet and a preparation method, and belongs to the technical field of a medicine. The finished repaglinide tablet prepared by the invention, under conditions that temperature is 40+/-2 DEG C and relative humidity is 75%+/-5%, can be preserved for 6 months; on 1st, 2nd, 3rd and 6th months, the repaglinide tablet is not sampled; and characters, dissolution rate, relative substances, content and laevo isomer are investigated. Compared with the repaglinide tablet on the 0th day, the repaglinide tablet, besides relative substances which are slightly increased (greatly less than a stipulated limit), is free from obvious change in various quality indexes, showing that the repaglinide tablet disclosed by the invention is good in stability.
Description
Technical field
The present invention relates to a kind of tablet and preparation method thereof, particularly relate to a kind of Repaglinide tablet and preparation method, belong to medical art.
Background technology
Defect of insulin secretion plays pivotal role for the generation development of type Ⅱdiabetes mellitus.Evidence-based medicine EBM also proves, can reduce trunk and microvascular complication by short long-term control blood sugar treatment of secreting based on agent.In view of Chinese patients with NIDDM obese degree is far away from west crowd, its hypoinsulinism plays a part very important in the process driving pathoglycemia to raise, therefore, Insulin secretagogues was proposed as a line medication of Type 2 Diabetes In China patient in diabetes mellitus in China guideline of prevention and treatment in 2007.
Short secrete agent and promote insulin secretion mainly through closing ATP dependent potassium on beta Cell of islet film, mainly comprise traditional sulphanylureas and novel non-sulphanylureas is short secretes agent.As the oral antidiabetic drug used the earliest, the status that sulfonylurea drugs has other drug not replace so far in Clinical practice.
It is stronger to the potassium-channel selectivity on beta Cell of islet that non-sulphanylureas urgees to secrete agent repaglinide, and thus, its specificity is higher.Just because of the feature on these mechanism of action, non-sulphanylureas is short to be secreted agent and has and directly can improve insulin early phase hyposecretion, thus has unique advantage to reduction post-prandial glycemia.Research finds, the I phase insulin secretion of Repaglinide in treatment of patients group can return to normal healthy controls group level.And repaglinide can also recover the secretion of insulin pulses formula, and improves insulin sensitivity to a certain extent.In view of repaglinide promotes insulin secretion with having concentration of glucose dependency, promote the ability of early phase insulin secretion especially specifically, therefore the peak value that insulin secretion peak value and post-prandial glycemia can be made to raise is coordinated more.Under the prerequisite that glycemic control is close, Repaglinide in treatment of patients group severe hypoglycemia incidence rate reduces by 60% than sulphanylureas treatment group.Moreover, existing research confirms, repaglinide does not increase mortality risk.
Meta analyzes display, and repaglinide can make HbA1c decline 1.5%-2.0%, and fasting glucose and post-prandial glycemia can reduce 1.8-3.9mmol/L and 3.7-7.2mmol/L respectively.The obese patient of metformin monotherapy poor blood glucose control, repaglinide and metformin use in conjunction, within three months, treatment compliance rate combines 2.7 and 3 times that group is repaglinide and metformin monotherapy group respectively.
Repaglinide (trade name: NovoNorm) is a kind of medicine for the treatment of type Ⅱdiabetes mellitus successfully developed by Novo Nordisk Co., Ltd of Denmark, obtains U.S. FDA approval, within 1998, successively go on the market in US and European various countries in December, 1997.Clinically, repaglinide is mainly used in type Ⅱdiabetes mellitus (non-insulin-depending type) patient that Therapeutic diet control, reduction body weight and motion exercise effectively can not control hyperglycemia.The specific receptor of repaglinide on beta Cell of islet film is combined, and promotes to close with the ATP sensitive potassium channel of coupled receptors, and suppress potassium ion from β cell drain, membrane depolarization, calcium channel is open, flow of calcium ions, promotes insulin secretion.Its effect is faster than sulfonylurea, therefore hypoglycemic activity is very fast after the meal.Be first glucose regulating taken when having meal.Maximum advantage to imitate the physiological secretion of insulin, effectively controls postprandial hyperglycemia thus.
Research and development repaglinide preparation, expanding its application is one of focus of repaglinide research and development.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of Repaglinide tablet, and this Repaglinide tablet improves has higher stability and bioavailability.
Another object of the present invention is to provide the method preparing above-mentioned Repaglinide tablet.
Object of the present invention is achieved through the following technical solutions.
A kind of Repaglinide tablet, it is prepared from by following parts by weight of component: repaglinide compound is in repaglinide 0.5 ~ 2, diluent 80 ~ 90, disintegrating agent 3 ~ 7, binding agent 3 ~ 7, lubricant 1 ~ 2, purified water 22 ~ 23; Wherein, described repaglinide compound, it has such as formula structure (I) Suo Shi, this repaglinide compound take repaglinide as active component, take meglumine as the pharmaceutical co-crystals of eutectic formation, a repaglinide molecule and a meglumine molecular composition basic structural unit
Wherein, A is meglumine, has formula (II) structure
Above-mentioned Repaglinide tablet, described diluent is the mixture of calcium hydrogen phosphate, microcrystalline Cellulose, starch; Described disintegrating agent is carboxymethylstach sodium; Described binding agent is PVP K30; Described lubricant is magnesium stearate.
Above-mentioned Repaglinide tablet, described repaglinide compound uses the alpha-emitting X-ray powder diffraction of Cu-K, represents, at 5.8 ± 0.2 ° with angle of reflection 2 θ, 7.8 ± 0.2 °, 10.7 ± 0.2 °, 12.6 ± 0.2 °, 16.4 ± 0.2 °, 18.3 ± 0.2 °, 19.8 ± 0.2 °, 22.5 ± 0.2 °, 24.9 ± 0.2 °, there is characteristic peak at 28.9 ± 0.2,39.1 ± 0.2 ° of places.
Above-mentioned Repaglinide tablet, the maximum endothermic peak of described repaglinide compound differential thermal spectrogram is 118 ± 2 DEG C.
Above-mentioned Repaglinide tablet, the preparation method of described repaglinide compound, comprises the steps:
Be the repaglinide of 1:1 by mol ratio, meglumine adds in isoamyl acetate-chloroform mixed solvent, the mass volume ratio of described repaglinide and isoamyl acetate-chloroform mixed solvent is 1g:30ml ~ 40ml; In described isoamyl acetate-chloroform mixed solvent, the volume fraction of chloroform is 55-65%; Be heated to 60 ~ 70 DEG C; Stir or ultrasonicly make dissolving; Slow cooling; Stirring and crystallizing, controls speed of agitator at 20 ~ 40 revs/min; Leave standstill after 4 ~ 6 hours and filter; ) drying under reduced pressure, dry temperature is 30 ~ 40 DEG C, and drying time is 4-6 hour, obtains repaglinide compound.
Preferably, above-mentioned Repaglinide tablet, the mass volume ratio of described repaglinide and isoamyl acetate-chloroform mixed solvent is 1g:35ml; In described isoamyl acetate-chloroform mixed solvent, the volume fraction of chloroform is 60%; Described heating, is heated to 65 DEG C; Described slow cooling, controls to be cooled to 10 DEG C at 6 hours; Described stirring and crystallizing, controls speed of agitator at 30 revs/min; Leave standstill after 5 hours and filter; Described drying under reduced pressure, dry temperature is 35 DEG C, and drying time is 5 hours.
A preparation method for above-mentioned Repaglinide tablet, comprises the steps:
(1) pretreatment: diluent, disintegrating agent, binding agent, lubricant are crossed 80 mesh sieves respectively, for subsequent use;
(2) prepare burden: take supplementary material according to recipe quantity;
(3) premix: adopt high-speed mixing granulating machine, stirring at low speed 300rpm, low speed cutting 1500rpm, carry out premix to repaglinide compound, diluent, disintegrating agent, binding agent, does time as 10min in advance;
(4) granulate: purified water is joined in step (3) gained material mixed in advance and carry out wet granulation, grain made parameter is stirring at low speed 300rpm, low speed cutting 1500rpm, 150 seconds time, soft material processed terminates, the soft material oscillating granulator made is granulated, sieve number 24 order;
(5) dry: use multifunctional fluidized bed granulating coated machine to carry out drying, inlet temperature is 60 DEG C, and blower fan frequency setting is 30 ~ 40Hz, whole granule is stirred, and measure moisture with fast tester for water content, moisture Control is 9.9 ~ 10.9%, dry end, rewinding;
(6) granulate: by dried dry granule oscillating granulator granulate, sieve number 20 order;
(7) always mix: the dry granule after granulate, lubricant are mixed 10min in V-Mixer;
(8) tabletting: tablet weight variation controls ± 6.0%, and pressure limit 2.0 ~ 4.0kg, tabletting obtains Repaglinide tablet.
Repaglinide tablet provided by the invention, its active substance repaglinide compound used has structure shown in formula (I).Shown in formula (I), the repaglinide compound of structure maintains the drug effect of repaglinide itself, and dissolubility, stability and bioavailability have obvious change, and its preparation method technique is simple, easy and simple to handle.Experiment shows, repaglinide compound provided by the invention reduces angle of repose compared with repaglinide commercially available product, and mobility is better, and every pharmacokinetic parameter AUC0-t, Cmax, Tmax are more excellent, bioavailability is significantly improved, and is more conducive to the production of pharmaceutical preparation.In addition, the Repaglinide tablet this product prepared by the present invention, temperature 40 DEG C ± 2 DEG C, is placed 6 months under the condition of relative humidity 75% ± 5%, in 1,2,3,6 sampling at the end of month, investigates character, dissolution, related substance, content, laevoisomer.Compared with 0 day, except related substance slightly increases (much smaller than limit regulation), every quality index has no significant change, and illustrates that Repaglinide tablet of the present invention has good stability.
Accompanying drawing explanation
The XRPD figure of Fig. 1 repaglinide compound of the present invention.
The DSC figure of Fig. 2 repaglinide compound of the present invention.
Detailed description of the invention
Below by detailed description of the invention, the present invention is described in further detail, but just understands the present invention for helping, professional and technical personnel in the field realized or uses the present invention, any restriction not formed to the present invention.
The preparation of embodiment 1 repaglinide compound of the present invention
Take repaglinide 45.3g and meglumine 19.6g, add 634.2ml isoamyl acetate, 915.3ml chloroform, be heated to 65 DEG C, stirring and dissolving, obtain settled solution.Slow cooling 6 hours, is down to 10 DEG C, carries out stirring crystallization with the rotating speed of 30 revs/min, and leave standstill after 5 hours and filter, 35 DEG C of drying under reduced pressure 5 hours, obtain repaglinide compound 61.8g, yield 95.2%.
The crystal formation parameter of gained repaglinide compound is shown in Fig. 1, Fig. 2.
The preparation of embodiment 2 repaglinide compound of the present invention
Take repaglinide 45.3g and meglumine 19.6g, add 611.6ml isoamyl acetate, 747.5ml chloroform, be heated to 60 DEG C, ultrasonicly make dissolving, obtain settled solution.Slow cooling 6 hours, is down to 10 DEG C, carries out stirring crystallization with the rotating speed of 20 revs/min, and leave standstill after 4 hours and filter, 30 DEG C of drying under reduced pressure 4 hours, obtain repaglinide compound 59.8g, yield 92.1%.
The crystal formation parameter of gained Repaglinide tablet is as embodiment 1.
The preparation of embodiment 3 repaglinide compound of the present invention
Take repaglinide 45.3g and meglumine 19.6g, add 6342ml isoamyl acetate, 11778ml chloroform, be heated to 70 DEG C, ultrasonicly make dissolving, obtain settled solution.Slow cooling 6 hours, is down to 10 DEG C, carries out stirring crystallization with the rotating speed of 40 revs/min, and leave standstill after 6 hours and filter, 40 DEG C of drying under reduced pressure 6 hours, obtain repaglinide compound 58.5g, yield 90.1%.
The crystal formation parameter of gained repaglinide compound is as embodiment 1.
Test example 1 fluidity determining
Injection method (fixed funnel method) is adopted to measure the angle of repose of repaglinide compound of the present invention and commercially available repaglinide.Pour testing sample into funnel, make it fall into disc centre lightly, equably, form a cone, when material is reinforced along stopping when freely falling disk border from powder body hypotenuse, measures angle of repose with protractor, the results are shown in Table 1.
Table 1 measurement result angle of repose
| Sample | Outward appearance | Angle of repose |
| Embodiment 1 | White crystalline powder | 28.1 |
| Embodiment 2 | White crystalline powder | 28.9 |
| Embodiment 3 | White crystalline powder | 29.2 |
| Commercially available product | White crystalline powder | 34.9 |
Angle of repose is the easiest method checking powder fluidity quality, and angle of repose is less, illustrates that frictional force is less, and mobility is better.The result of the test of upper table 1 can be found out: the angle of repose of obvious reduction compared with commercially available product of repaglinide compound provided by the invention, shows that its mobility is more superior, be more conducive to meet need of production.
Test example 2 pharmacokinetic trial
Test objective: the bioavailability being investigated repaglinide compound of the present invention by pharmacokinetic trial.
Trial drug: the repaglinide compound that the embodiment of the present invention 1 provides is as investigational agent; Repaglinide commercially available product medicine in contrast.
Experimental animal: Wistar rat, body weight 150-200g, male and female are also used.
Dosage and mode: Rat Fast spends the night, oral administration gavage administration 100mg/kg.
Blood sampling time: before administration and after administration 0.25,0.50,1.00,1.50,2.00,3.00,4.00,6.00,12.00h.
Test method: after blood specimen collection, is collected in vitro, goes out serum through centrifugalize, and-12 degree ice chests save backup, and get blood serum sample 0.5ml respectively and measure serum drug level with HPLC method, calculate main pharmacokinetic parameter.
Result of the test: in table 2
Table 2 pharmacokinetic trial result
Upper table 2 data show, AUC0-t, Cmax of repaglinide compound provided by the invention are apparently higher than commercially available repaglinide, and Tmax also obviously accelerates, show that repaglinide compound bioavailability provided by the invention is significantly improved, be better than commercially available repaglinide.
The stability test of test example 3 repaglinide compound of the present invention
Stability test is carried out to repaglinide compound prepared by the embodiment of the present invention 1, the results are shown in Table 3.
The stability result of table 3 embodiment 1 repaglinide compound
Upper table 3 data show, repaglinide compound provided by the invention is in harshness test, long term test, accelerated test, and related substance, shape, content have no significant change, and has good quality stability.
The preparation (specification 0.5mg/ sheet) of embodiment 4 Repaglinide tablet of the present invention
Table 4
Preparation method:
(1) pretreatment: calcium hydrogen phosphate, microcrystalline Cellulose, starch, carboxymethylstach sodium, PVP K30, magnesium stearate are crossed 80 mesh sieves respectively, for subsequent use;
(2) prepare burden: take supplementary material according to recipe quantity;
(3) premix: adopt high-speed mixing granulating machine, stirring at low speed 300rpm, low speed cutting 1500rpm, carry out premix to repaglinide compound, calcium hydrogen phosphate, microcrystalline Cellulose, starch, carboxymethylstach sodium, PVP K30, does time as 10min in advance;
(4) granulate: purified water is joined in step (3) gained material mixed in advance and carry out wet granulation, grain made parameter is stirring at low speed 300rpm, low speed cutting 1500rpm, 150 seconds time, soft material processed terminates, the soft material oscillating granulator made is granulated, sieve number 24 order;
(5) dry: use multifunctional fluidized bed granulating coated machine to carry out drying, inlet temperature is 60 DEG C, and blower fan frequency setting is 30 ~ 40Hz, whole granule is stirred, and measure moisture with fast tester for water content, moisture Control is 9.9 ~ 10.9%, dry end, rewinding;
(6) granulate: by dried dry granule oscillating granulator granulate, sieve number 20 order;
(7) always mix: the dry granule after granulate, magnesium stearate are mixed 10min in V-Mixer;
(8) tabletting: tablet weight variation controls ± 6.0%, and pressure limit 2.0 ~ 4.0kg, tabletting obtains Repaglinide tablet.
The preparation (specification 1.0mg/ sheet) of embodiment 5 Repaglinide tablet of the present invention
Table 5
Preparation method:
(1) pretreatment: calcium hydrogen phosphate, microcrystalline Cellulose, starch, carboxymethylstach sodium, PVP K30, magnesium stearate are crossed 80 mesh sieves respectively, for subsequent use;
(2) prepare burden: take supplementary material according to recipe quantity;
(3) premix: adopt high-speed mixing granulating machine, stirring at low speed 300rpm, low speed cutting 1500rpm, carry out premix to repaglinide compound, calcium hydrogen phosphate, microcrystalline Cellulose, starch, carboxymethylstach sodium, PVP K30, does time as 10min in advance;
(4) granulate: purified water is joined in step (3) gained material mixed in advance and carry out wet granulation, grain made parameter is stirring at low speed 300rpm, low speed cutting 1500rpm, 150 seconds time, soft material processed terminates, the soft material oscillating granulator made is granulated, sieve number 24 order;
(5) dry: use multifunctional fluidized bed granulating coated machine to carry out drying, inlet temperature is 60 DEG C, and blower fan frequency setting is 30 ~ 40Hz, whole granule is stirred, and measure moisture with fast tester for water content, moisture Control is 9.9 ~ 10.9%, dry end, rewinding;
(6) granulate: by dried dry granule oscillating granulator granulate, sieve number 20 order;
(7) always mix: the dry granule after granulate, magnesium stearate are mixed 10min in V-Mixer;
(8) tabletting: tablet weight variation controls ± 6.0%, and pressure limit 2.0 ~ 4.0kg, tabletting obtains Repaglinide tablet.
The preparation (specification 1.0mg/ sheet) of embodiment 6 Repaglinide tablet of the present invention
Table 6
Preparation method:
(1) pretreatment: calcium hydrogen phosphate, microcrystalline Cellulose, starch, carboxymethylstach sodium, PVP K30, magnesium stearate are crossed 80 mesh sieves respectively, for subsequent use;
(2) prepare burden: take supplementary material according to recipe quantity;
(3) premix: adopt high-speed mixing granulating machine, stirring at low speed 300rpm, low speed cutting 1500rpm, carry out premix to repaglinide compound, calcium hydrogen phosphate, microcrystalline Cellulose, starch, carboxymethylstach sodium, PVP K30, does time as 10min in advance;
(4) granulate: purified water is joined in step (3) gained material mixed in advance and carry out wet granulation, grain made parameter is stirring at low speed 300rpm, low speed cutting 1500rpm, 150 seconds time, soft material processed terminates, the soft material oscillating granulator made is granulated, sieve number 24 order;
(5) dry: use multifunctional fluidized bed granulating coated machine to carry out drying, inlet temperature is 60 DEG C, and blower fan frequency setting is 30 ~ 40Hz, whole granule is stirred, and measure moisture with fast tester for water content, moisture Control is 9.9 ~ 10.9%, dry end, rewinding;
(6) granulate: by dried dry granule oscillating granulator granulate, sieve number 20 order;
(7) always mix: the dry granule after granulate, magnesium stearate are mixed 10min in V-Mixer;
(8) tabletting: tablet weight variation controls ± 6.0%, and pressure limit 2.0 ~ 4.0kg, tabletting obtains Repaglinide tablet.
The stability test of test example 4 Repaglinide tablet of the present invention
Repaglinide tablet prepared by test specimen embodiment 4,5,6, investigates condition: 40 ± 2 DEG C, RH75% ± 5%, the results are shown in Table 7,8,9.
Repaglinide tablet stability prepared by table 7 embodiment 4
Repaglinide tablet stability prepared by table 8 embodiment 5
Repaglinide tablet stability prepared by table 9 embodiment 6
Repaglinide tablet this product prepared by the embodiment of the present invention 4,5,6 is temperature 40 DEG C ± 2 DEG C, place 6 months under the condition of relative humidity 75% ± 5%, in 1,2,3,6 sampling at the end of month, investigate character, dissolution, related substance, content, laevoisomer.Compared with 0 day, except related substance slightly increases (much smaller than limit regulation), every quality index has no significant change, and illustrates that Repaglinide tablet of the present invention has good stability.
Below be only the preferred embodiment of the present invention; not in order to limit the present invention, to those skilled in the art, under the premise without departing from the principles of the invention; the some improvement that can also make, retouching, equivalent replacement, all should be included within protection scope of the present invention.
Claims (7)
1. a Repaglinide tablet, is characterized in that, it is prepared from by following parts by weight of component: repaglinide compound is in repaglinide 0.5 ~ 2, diluent 80 ~ 90, disintegrating agent 8 ~ 10, lubricant 1 ~ 2, purified water 22 ~ 23; Wherein, described repaglinide compound, it has such as formula structure (I) Suo Shi, this repaglinide compound take repaglinide as active component, take meglumine as the pharmaceutical co-crystals of eutectic formation, a repaglinide molecule and a meglumine molecular composition basic structural unit
Wherein A is meglumine, has formula (II) structure
2. Repaglinide tablet according to claim 1, is characterized in that, described diluent is the mixture of calcium hydrogen phosphate, microcrystalline Cellulose, starch; Described disintegrating agent is carboxymethylstach sodium; Described binding agent is PVP K30; Described lubricant is magnesium stearate.
3. Repaglinide tablet according to claim 2, is characterized in that, described repaglinide compound uses the alpha-emitting X-ray powder diffraction of Cu-K, represent with angle of reflection 2 θ, at 5.8 ± 0.2 °, 7.8 ± 0.2 °, 10.7 ± 0.2 °, 12.6 ± 0.2 °, 16.4 ± 0.2 °, 18.3 ± 0.2 °, 19.8 ± 0.2 °, 22.5 ± 0.2 °, 24.9 ± 0.2 °, there is characteristic peak at 28.9 ± 0.2,39.1 ± 0.2 ° of places.
4. Repaglinide tablet according to claim 3, is characterized in that, the maximum endothermic peak of described repaglinide compound differential thermal spectrogram is 118 ± 2 DEG C.
5. Repaglinide tablet according to claim 4, is characterized in that, the preparation method of described repaglinide compound, comprises the steps:
Be the repaglinide of 1:1 by mol ratio, meglumine adds in isoamyl acetate-chloroform mixed solvent, the mass volume ratio of described repaglinide and isoamyl acetate-chloroform mixed solvent is 1g:30ml ~ 40ml; In described isoamyl acetate-chloroform mixed solvent, the volume fraction of chloroform is 55-65%; Be heated to 60 ~ 70 DEG C; Stir or ultrasonicly make dissolving; Slow cooling; Stirring and crystallizing, controls speed of agitator at 20 ~ 40 revs/min; Leave standstill after 4 ~ 6 hours and filter; ) drying under reduced pressure, dry temperature is 30 ~ 40 DEG C, and drying time is 4-6 hour, obtains repaglinide compound.
6. Repaglinide tablet according to claim 5, is characterized in that, the mass volume ratio of described repaglinide and isoamyl acetate-chloroform mixed solvent is 1g:35ml; In described isoamyl acetate-chloroform mixed solvent, the volume fraction of chloroform is 60%; Described heating, is heated to 65 DEG C; Described slow cooling, controls to be cooled to 10 DEG C at 6 hours; Described stirring and crystallizing, controls speed of agitator at 30 revs/min; Leave standstill after 5 hours and filter; Described drying under reduced pressure, dry temperature is 35 DEG C, and drying time is 5 hours.
7. a preparation method for Repaglinide tablet described in claim 1, is characterized in that, comprises the steps:
(1) pretreatment: diluent, disintegrating agent, binding agent, lubricant are crossed 80 mesh sieves respectively, for subsequent use;
(2) prepare burden: take supplementary material according to recipe quantity;
(3) premix: adopt high-speed mixing granulating machine, stirring at low speed 300rpm, low speed cutting 1500rpm, carry out premix to repaglinide compound, diluent, disintegrating agent, binding agent, does time as 10min in advance;
(4) granulate: purified water is joined in step (3) gained material mixed in advance and carry out wet granulation, grain made parameter is stirring at low speed 300rpm, low speed cutting 1500rpm, 150 seconds time, soft material processed terminates, the soft material oscillating granulator made is granulated, sieve number 24 order;
(5) dry: use multifunctional fluidized bed granulating coated machine to carry out drying, inlet temperature is 60 DEG C, and blower fan frequency setting is 30 ~ 40Hz, whole granule is stirred, and measure moisture with fast tester for water content, moisture Control is 9.9 ~ 10.9%, dry end, rewinding;
(6) granulate: by dried dry granule oscillating granulator granulate, sieve number 20 order;
(7) always mix: the dry granule after granulate, lubricant are mixed 10min in V-Mixer;
(8) tabletting: tablet weight variation controls ± 6.0%, and pressure limit 2.0 ~ 4.0kg, tabletting obtains Repaglinide tablet.
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| CN1268121A (en) * | 1997-08-14 | 2000-09-27 | 杜邦药品公司 | Crystalline 10,10-bis ((2-fluoro-4-pyridinyl) methyl)-9 (10H)-anthraclnone and an improved process for preparing the same |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1268121A (en) * | 1997-08-14 | 2000-09-27 | 杜邦药品公司 | Crystalline 10,10-bis ((2-fluoro-4-pyridinyl) methyl)-9 (10H)-anthraclnone and an improved process for preparing the same |
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