CN103432092B - A kind of slow releasing preparation of repaglinide - Google Patents
A kind of slow releasing preparation of repaglinide Download PDFInfo
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- CN103432092B CN103432092B CN201310340837.6A CN201310340837A CN103432092B CN 103432092 B CN103432092 B CN 103432092B CN 201310340837 A CN201310340837 A CN 201310340837A CN 103432092 B CN103432092 B CN 103432092B
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Abstract
The present invention relates to slow releasing preparation of a kind of repaglinide and preparation method thereof and analytical method, component is that hydroxypropyl emthylcellulose, ethyl cellulose, acrylic resin, poloxamer, sodium carboxymethyl cellulose, Polyethylene Glycol etc. are as slow-release material.
Description
Technical field
The invention belongs to medical art, be specifically related to slow releasing preparation of a kind of repaglinide and preparation method thereof, analytical method.
Background technology
Repaglinide is a kind of insulin secretion stimulant, in white or yellow-white powder under room temperature, is a kind of antidiabetic drug with the novel fugitive oral insulin secretion accelerating of the non-sulphanylureas of amino acid structure.English name: repaglinide, its chemical name is: 2-ethyoxyl-4-{2-{ [(1S)-3-methyl isophthalic acid-[2-(piperidin-1-yl) phenyl] butyl] is amino]-2-oxoethyl] benzoic acid, molecular formula: C27H36N204, molecular weight: 452.6, structural formula is as follows:
Repaglinide is methyl benzene methanamine benzoic acid (CBMA) the class oral antidiabetic drug by Novo Nordi sk and Boehr inger Ingelheim cooperative research and development, and in April, 1998 in U.S.'s Initial Public Offering, October in the same year goes on the market in Britain.Clinical being mainly used in treats type 2 diabetes mellitus.
The insulin secretion of normal person is pulsed, a secretion peak is there will be after dining, with the alignment processing blood glucose that brings of abundance of food after the meal, and type 2 diabetes mellitus patient insulin summit after the meal postpones, low subtracting even disappears, cause postprandial hyperglycemia, postprandial hyperglycemia has been proved to be comparatively hyperglycemia and has more easily brought out heart, vascular lesion, the diabetic complication of initiation potential.Utilize short, onset repaglinide action time rapidly, remove fast feature, administration before the meal, stimulate insulin releasing during meal, form an insulin secretion peak after the meal, and between two meal, then can not stimulate insulin secretion, reach the object of imitating physiological insulin secretion.This reduces complication occur the full-time average blood glucose levels of control, and in protection islets of langerhans, normal β cell is significant.
Repaglinide stimulating pancreas uelralante makes blood sugar level reduce rapidly, this effect depends on beta Cell of islet, it is as different in glimepiride (glimepiride) etc. with sulfonylurea drugs from the binding site of β cell, repaglinide by from different receptors bind to close ATP mono-dependent potassium channel in B cell film, it makes β cell depolarization, open calcium channel, the inflow of calcium is increased, the secretion of insulin in this process inducing beta cell, because it absorbs fast, to take medicine onset in latter 15 minutes, reaching blood medicine rush hour is 1 hour, metabolism is rapid, half-life is 1 hour, at once take before each dinner, physiological insulin secretion can be simulated, reach blood sugar reducing function, there is the title of " blood sugar regulator used during user having meals ", repaglinide absorbs rapidly, rapid-action, removing speed is in vivo also relatively very fast, half-life is short, there is the action character of " open soon-speed close ".
Repaglinide no matter on an empty stomach or feed time take and all absorb good, reach plasma peaks after 30 ~ 60 minutes, and be nonactive thing by CYP3A4 enzyme system tachymetabolism in liver, major part is removed with bile, plasma half life 1 hour.Liver function injury person plasma drug level is higher.Plasma insulin concentrations raises with drug in blood serum concentration and increases, and generally before upper once dining, is returned to foundation level again.
Repaglinide both can be used as independent application, also can with other antidiabetic drugs as the use in conjunction such as rosiglitazone (rosiglitazone), metformin (metformin) increase curative effect.But repaglinide is almost insoluble in water, and the dissolubility in water is only 0.005mg/mL, and vitro Drug dissolution is poor, cause its bioavailability low.At present, commercial dosage forms only has repaglinide, takes 3 every day, thus brings inconvenience to the patient of patient especially long-term prescription, and easily causes the drug level defect that undulatory property is large in vivo.Therefore, the novel formulation developing repaglinide has realistic meaning and market prospect.
Summary of the invention
The present invention is the slow releasing preparation developing a kind of repaglinide, mainly solves the problem of insoluble drug repaglinide slow release, thus reaches the object improving curative effect further.
A slow releasing preparation for repaglinide, component is that hydroxypropyl emthylcellulose, ethyl cellulose, acrylic resin, poloxamer, sodium carboxymethyl cellulose, Polyethylene Glycol etc. are as slow-release material.
A slow releasing preparation for repaglinide, is preparing the application on hypoglycemic drug.
A slow releasing preparation for repaglinide, component comprises:
A slow releasing preparation for repaglinide, component comprises:
A slow releasing preparation for repaglinide, component is:
A slow releasing preparation for repaglinide, component is:
A slow releasing preparation for repaglinide, component is:
A slow releasing preparation for repaglinide, component is:
Accompanying drawing explanation
Fig. 1 Chinese Pharmacopoeia condition determination
Fig. 2 American Pharmacopeia 32 editions raw material determination of related substances conditions
Fig. 3 American Pharmacopeia 32 editions tablet determination of related substances conditions
Fig. 4 European Pharmacopoeia 7.0 determination of related substances condition
Fig. 5 embodiment of the present invention 7 condition determination
Detailed description of the invention:
The preparation (1000 amounts) of embodiment 1 repaglinide slow releasing tablet
Binding agent: 5%PVP80% alcoholic solution
Preparation technology:
Repaglinide, hydroxypropyl emthylcellulose, microcrystalline Cellulose, polyvinyl alcohol, Macrogol 2000, hydroxyproline are pressed the mixing of equal increments method, adds suitable amount of adhesive and prepare soft material, cross 18 mesh sieves and granulate.60 DEG C of dryings, granulate, adds magnesium stearate, mix homogeneously, tabletting.
The preparation (1000 amounts) of embodiment 3 repaglinide slow releasing tablet
Binding agent: 5%PVP80% alcoholic solution
Preparation technology:
Repaglinide, acrylic resin, microcrystalline Cellulose, polyvinyl alcohol, Macrogol 2000, hydroxyproline are pressed the mixing of equal increments method, adds suitable amount of adhesive and prepare soft material, cross 18 mesh sieves and granulate.60 DEG C of dryings, granulate, adds magnesium stearate, mix homogeneously, tabletting.
The preparation (1000 amounts) of embodiment 4 repaglinide controlled release tablet
Binding agent: dehydrated alcohol
Preparation technology:
Repaglinide, poloxamer, microcrystalline Cellulose, polyvinyl alcohol, Macrogol 2000, hydroxyproline are pressed the mixing of equal increments method, adds suitable amount of adhesive and prepare soft material, cross 18 mesh sieves and granulate.60 DEG C of dryings, granulate, adds magnesium stearate, mix homogeneously, tabletting.
Embodiment 5 repaglinide slow releasing tablet
Preparation technology:
Solvent method is adopted to prepare solid dispersion repaglinide, polyvinylpyrrolidone, pulverized 100 mesh sieves, repaglinide solid dispersion, Cellulose ethyl hydroxypropyl ether, microcrystalline Cellulose, CMC-Na, polyvinyl alcohol, Macrogol 2000, hydroxyproline are pressed the mixing of equal increments method, add magnesium stearate mix homogeneously, direct powder compression.
Embodiment 6 product of the present invention is on the impact of alloxan diabetes mouse blood sugar
1. experiment material
1.1 animals: cleaning grade male ICR mouse, 18-22g,
2 medicines and reagent:
Alloxan, sigma company of the U.S., Lot37H1381;
Glucose estimation kit, Shanghai Rongsheng Bioisystech Co., Ltd;
Repaglinide, 1.0mg/ sheet;
Embodiment 1-5,1.0mg/ sheet.
2. experimental technique
Random taking-up mice 10 is only as normal group, after all the other mice fasting 14-16h, tail vein injection alloxan 60mg/kg, after injection, 72h retroorbital venous clump gets blood, separation of serum, prediction blood glucose, select the mice of fasting glucose > 12mmol/L, random packet, repaglinide 0.5mg/kg, embodiment 1-5 sheet 0.5mg/kg is given respectively by 10ml/kg body weight per os), normal group and model group per os give isopyknic 0.2% sodium carboxymethyl cellulose (CMC-Na).Every day gastric infusion once, successive administration 6 days.Fasting 3.5h before each group of administration, fasting 1.5h again after administration, namely after all mice fasting 5h, retroorbital venous clump is taken a blood sample, and separation of serum, with determination of glucose oxidase blood glucose.
3. add up: experimental data with
± SE represents, and represents group difference with t inspection statistics.
4. result
4.1 compound recipes are on the impact of alloxan diabetes mouse blood sugar
Blood sugar level before and after treatment of respectively organizing table 1 compares (mmol/L,
± SE)
As shown in table 1, compared with normal group, the fasting glucose of alloxan diabetes mice extremely obviously raises (P < 0.01*).Compared with model group, after administration 6 days, repaglinide group, embodiment 1-5 group all extremely significantly (P < 0.01*) reduced the fasting glucose of diabetic mice; Embodiment 1-5 group reduces the fasting glucose of diabetic mice than repaglinide group more remarkable (P < 0.05 ▲).
The analytical method of embodiment 7 product of the present invention
Product of the present invention (comprise and be not restricted to the product of embodiment 1-5), should be 95.0% ~ 105.0% of labelled amount containing repaglinide.
Character
This product is white or off-white color sheet.
Differentiate
(1) this product fine powder appropriate (being equivalent to repaglinide 0.5mg) is got, put in 25ml measuring bottle, add 0.1mol/L hydrochloric acid solution appropriate, jolting makes repaglinide dissolve, and is diluted to scale, shakes up with 0.1mol/L hydrochloric acid solution, filter, get subsequent filtrate, measure according to ultraviolet visible spectrophotometry (annex IV A), have absorption maximum at the wavelength place of 243nm and 298nm.
(2), in the chromatogram recorded under assay item, the retention time of need testing solution main peak should be consistent with the retention time of reference substance solution main peak.
Check
Uniformity of dosage units
Get this product 1, put in 20ml measuring bottle, according to the method under assay item, from " adding 0.1mol/L hydrochloric acid solution appropriate ", measure in accordance with the law, calculate content, should conform with the regulations (annex X E).
Dissolution
Get this product, according to dissolution method (annex X C second method), be dissolution medium with pH5.0 phosphate buffer (10.2g citric acid monohydrate and 36.51g disodium hydrogen phosphate, the 1000ml that adds water makes dissolving) 900ml, rotating speed is 75 turns per minute, operate in accordance with the law, through 30 minutes time, get solution and filter in right amount, according to the chromatographic condition under assay item, precision measures subsequent filtrate 100 μ l injection liquid chromatography, record chromatogram; Separately get repaglinide reference substance appropriate, accurately weighed, add methanol and make dissolving in right amount, quantitatively dilute the solution made containing 0.56 μ g in every 1ml with dissolution medium, be measured in the same method, calculate the stripping quantity of every sheet, limit is 80% of labelled amount, should conform with the regulations.
Related substance gets this product fine powder appropriate (being equivalent to repaglinide 25mg), put in 25ml measuring bottle, solubilizer mobile phase A-acetonitrile (20: 80) (volume: volume), the ultrasonic 10min of jolting makes repaglinide dissolve and dilutes the solution made containing 1mg in every 1ml, filter, get subsequent filtrate as need testing solution; Precision measures 1ml, puts in 100ml measuring bottle, for solvent dilution is to scale, shakes up, solution in contrast with mobile phase A-acetonitrile (20: 80) (volume: volume).Separately get Magnesium Stearate proper quantity, accurately weighed, the ultrasonic 10min of solubilizer mobile phase A-acetonitrile (20: 80) (volume: volume) jolting, quantitatively concentration is made in dilution is the solution containing 1.6mg in every 1ml, filter, get subsequent filtrate and locate contrast solution as adjuvant.Test according to high performance liquid chromatography (annex V D), be filler with octyl silane group silica gel, (potassium dihydrogen phosphate 4.0g is got with phosphate buffer, after the 1000ml that adds water dissolves, by phosphoric acid adjust ph to 3.2) be mobile phase A, take acetonitrile as Mobile phase B, according to the form below program carries out gradient elution; Flow velocity is 1.0ml per minute, and determined wavelength is 240nm; Column temperature is 45 DEG C.Get need testing solution, put 90 DEG C of heating in water bath 24 hours, let cool, get 20 μ l injection liquid chromatographies, record chromatogram, repaglinide peak retention time is 23 minutes, number of theoretical plate calculates by repaglinide peak and is not less than 2000, and the separating degree at repaglinide peak and other impurities peak should meet the requirements.Get contrast solution 20 μ l injection liquid chromatography, regulate detection sensitivity, make the peak height of repaglinide chromatographic peak be 20 ~ 25% of full scale, then precision measures need testing solution, contrast solution and adjuvant and locates each 20 μ l of contrast solution, injection liquid chromatography respectively, record chromatogram.Deduct chromatographic peak corresponding in the adjuvant peak before 0.10 times of main peak retention time and adjuvant location contrast solution, if any impurity peaks in need testing solution chromatogram, single impurity peak area must not be greater than 0.5 times (0.5%) of contrast solution main peak, each impurity peak area and 1.5 times (1.5%) of contrast solution main peak area must not be greater than.The impurity that in need testing solution chromatogram, peak area is less than 0.05 times, repaglinide peak in contrast solution can be ignored.
The gradient elution program of related substance
Laevoisomer gets this product fine powder appropriate (being equivalent to repaglinide 25mg), puts in 50ml measuring bottle, adds methanol 15ml and repaglinide is dissolved, be diluted with water to scale, shake up, and filters, gets subsequent filtrate as need testing solution; Precision measures 1ml, puts in 100ml measuring bottle, is diluted with water to scale, shake up, in contrast solution; Repaglinide reference substance 5mg is revolved in another cancellation, puts in 50ml measuring bottle, adds methanol 15ml and makes dissolving, be diluted with water to scale, shake up, and makes the solution containing 0.1mg in every 1ml, as racemization reference substance solution.Test according to high performance liquid chromatography (annex V D), (filler is α 1-acidoglycoprotein to adopt chiral chromatographic column, 100mm × 4.0mm × 5 μm), with phosphate buffer, (get potassium dihydrogen phosphate 2.72g, the 800ml that adds water makes dissolving, by sodium hydroxide test solution adjust ph to 6.3, be diluted with water to 1000ml, shake up) be mobile phase A, acetonitrile is Mobile phase B, and determined wavelength is 240nm.According to the form below program carries out gradient elution.Cancel and revolve reference substance solution 20 μ l, injection liquid chromatography, record chromatogram, peak sequence is followed successively by repaglinide peak and laevoisomer peak, and its separating degree should meet the requirements, and number of theoretical plate calculates by repaglinide peak and is not less than 2000.Get contrast solution 20 μ l injection liquid chromatography, regulate detection sensitivity, make the peak height of repaglinide chromatographic peak be 25% of full scale, then precision measures need testing solution and each 20 μ l of contrast solution injection liquid chromatography respectively, record chromatogram.If any laevoisomer peak in the chromatogram of need testing solution, its peak area must not be greater than 0.5 times (0.5%) of contrast solution main peak area.
The gradient elution program of laevoisomer
Microbial limit according to microbial limit test (Chinese Pharmacopoeia version in 2010 second annex XIJ) get this product routinely method make the test liquid of 1: 10, Bacteria fungi and yeasts count adopts Plating, Control bacteria examination carries out with conventional method, in every 1g test sample, bacterial population must not cross 1000cfu, yeast and mold number must not cross 100cfu, must not detect escherichia coli.
Annex is Chinese Pharmacopoeia version in 2010 second annex
Other should meet the relevant every regulation (Chinese Pharmacopoeia version in 2010 second annex I A) under tablet item
Assay measures according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 second annex V D).
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are filler; Be mobile phase with ammonium acetate buffer (get ammonium acetate 3.85g, the 1000ml that adds water makes dissolving, with glacial acetic acid adjust pH to 4.0)-methanol (20: 80) (volume: volume), determined wavelength is 243nm.Number of theoretical plate calculates by repaglinide peak and is not less than 2000.Place 24 hours and the solution 20 μ l let cool in 90 DEG C of water-baths under getting related substance item, injection liquid chromatography, record chromatogram, peak sequence is followed successively by ester degradants peak and repaglinide peak, and its separating degree should meet the requirements.
Algoscopy gets this product 20, accurately weighed, porphyrize, and precision takes in right amount (being equivalent to repaglinide 1.25mg), put in 50ml measuring bottle, add 0.1mol/L hydrochloric acid solution appropriate, jolting makes repaglinide dissolve, be diluted to scale with 0.1mol/L hydrochloric acid solution, shake up, filter; Precision measures subsequent filtrate 20 μ l injection liquid chromatography, record chromatogram; Separately get repaglinide reference substance, accurately weighed, add 0.1mol/L dissolve with hydrochloric acid solution and quantitatively dilute the solution made containing 25 μ g in every 1ml, being measured in the same method.By external standard method with calculated by peak area, to obtain final product.
Classification blood sugar lowering.
Specification 0.5mg
Storage shading, sealing, less than 25 DEG C preservations.
Packaging aluminium-plastic bubble plate packing.
Tentative 24 months of effect duration
The determination of related substances conditional filtering process of embodiment 8 product of the present invention
One, each impurity reference substance structural formula
Get the known impurities preparation mixed solution that may exist, investigate the peak-to-peak separating degree of each impurity and impurity peaks and lead peak-to-peak separating degree, each impurity is as follows:
European Pharmacopoeia impurity A: 4-(carboxymethyl)-2-ethoxybenzoic acid
European Pharmacopoeia impurity B: [3-ethyoxyl-4-(carbethoxyl group) phenyl] acetic acid
European Pharmacopoeia impurity C:(1S)-3-methyl isophthalic acid-[2-(piperidin-1-yl) phenyl] butane-1-amine
European Pharmacopoeia impurity D:2-ethyoxyl-4-[2-[[(1S)-3-methyl isophthalic acid-[2-(piperidin-1-yl) phenyl] butyl] is amino]-2-oxoethyl] benzoic acid
American Pharmacopeia impurity C:
(S)-2-ethyoxyl-4-[2-[[2-phenyl-1-[2-(piperidino) phenyl] ethyl] is amino]-2-oxoethyl] benzoic acid
Two, related substance detects alternative mobile phase condition
Claims (1)
1. a Related substance method for repaglinide, is characterized in that:
Get this product fine powder appropriate, be equivalent to repaglinide 25mg, put in 25ml measuring bottle, solubilizer mobile phase A-acetonitrile, 20:80, volume: volume, the ultrasonic 10min of jolting makes repaglinide dissolve and dilutes the solution made containing 1 mg in every 1ml, filters, gets subsequent filtrate as need testing solution;
Precision measures 1ml, puts in 100ml measuring bottle, with mobile phase A-acetonitrile, and 20:80, volume: volume, for solvent dilution is to scale, shakes up, in contrast solution,
Separately get Magnesium Stearate proper quantity, accurately weighed, solubilizer mobile phase A-acetonitrile, 20:80, volume: volume, the ultrasonic 10min of jolting, quantitatively concentration is made in dilution is the solution containing 1.6mg in every 1ml, filters, gets subsequent filtrate and locate contrast solution as adjuvant,
According to high performance liquid chromatography, test, being filler with octyl silane group silica gel, take phosphate buffer as mobile phase A,
Phosphate buffer: get potassium dihydrogen phosphate 4.0g, after the 1000ml that adds water dissolves, by phosphoric acid adjust ph to 3.2,
Take acetonitrile as Mobile phase B, the program of pressing carries out gradient elution;
Flow velocity is 1.0ml per minute, and determined wavelength is 240nm, column temperature is 45 DEG C, get need testing solution, put 90 DEG C of heating in water bath 24 hours, let cool, get 20 μ l injection liquid chromatographies, record chromatogram, repaglinide peak retention time is 23 minutes, number of theoretical plate calculates by repaglinide peak and is not less than 2000, the separating degree at repaglinide peak and other impurities peak should meet the requirements, get contrast solution 20 μ l injection liquid chromatography, regulate detection sensitivity, the peak height of repaglinide chromatographic peak is made to be 20 ~ 25% of full scale, precision measures need testing solution again, the each 20 μ l of contrast solution located by contrast solution and adjuvant, injection liquid chromatography respectively, record chromatogram, deduct chromatographic peak corresponding in the adjuvant peak before 0.10 times of main peak retention time and adjuvant location contrast solution, if any impurity peaks in need testing solution chromatogram, single impurity peak area must not be greater than 0.5% of contrast solution main peak, each impurity peak area and 1.5% of contrast solution main peak area must not be greater than, the impurity that in need testing solution chromatogram, peak area is less than 0.05 times, repaglinide peak in contrast solution can be ignored,
Time minute mobile phase A % Mobile phase B %
0 70 30
15 60 40
20 60 40
50 20 80
60 20 80
60.01 70 30
70 stop;
The preparation method of this product is the preparation method of any one repaglinide slow releasing tablet following
The preparation method of repaglinide slow releasing tablet, 1000 amounts,
Repaglinide 6g
Hydroxypropyl emthylcellulose 40g
Polyvinyl alcohol 15g
Macrogol 2000 15g
Hydroxyproline 10g
Microcrystalline Cellulose 20g
Magnesium stearate 1g
Binding agent: 5%PVP80% alcoholic solution
Preparation technology:
Repaglinide, hydroxypropyl emthylcellulose, microcrystalline Cellulose, polyvinyl alcohol, Macrogol 2000, hydroxyproline are pressed the mixing of equal increments method, adds suitable amount of adhesive and prepare soft material, cross 18 mesh sieves and granulate, 60 DEG C of dryings, granulate, adds magnesium stearate, mix homogeneously, tabletting;
The preparation of repaglinide slow releasing tablet, 1000 amounts,
Repaglinide 6g
Acrylic resin 50g
Polyvinyl alcohol 15g
Macrogol 2000 15g
Hydroxyproline 10g
Microcrystalline Cellulose 50g
Magnesium stearate 1g
Binding agent: 5%PVP80% alcoholic solution
Preparation technology:
Repaglinide, acrylic resin, microcrystalline Cellulose, polyvinyl alcohol, Macrogol 2000, hydroxyproline are pressed the mixing of equal increments method, adds suitable amount of adhesive and prepare soft material, cross 18 mesh sieves and granulate, 60 DEG C of dryings, granulate, adds magnesium stearate, mix homogeneously, tabletting;
The preparation of repaglinide slow releasing tablet, 1000 amounts,
Repaglinide 6g
Poloxamer 50g
Polyvinyl alcohol 15g
Macrogol 2000 15g
Hydroxyproline 10g
Microcrystalline Cellulose 100g
Magnesium stearate 2g
Binding agent: dehydrated alcohol
Preparation technology:
Repaglinide, poloxamer, microcrystalline Cellulose, polyvinyl alcohol, Macrogol 2000, hydroxyproline are pressed the mixing of equal increments method, adds suitable amount of adhesive and prepare soft material, cross 18 mesh sieves and granulate, 60 DEG C of dryings, granulate, adds magnesium stearate, mix homogeneously, tabletting.
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| US6830759B2 (en) * | 2002-06-28 | 2004-12-14 | Ajinomoto Co., Inc. | Antidiabetic preparation for oral administration |
| CN102247370B (en) * | 2011-05-19 | 2013-04-17 | 中国药科大学 | Compound repaglinide-metformin hydrochloride controlled release preparation |
| CN103027900B (en) * | 2012-09-27 | 2014-12-03 | 江苏豪森药业股份有限公司 | Repaglinide tablet and preparation method thereof |
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