CN101167731A - Dispersible tablet containing metformin and glibenclamide and preparation method thereof - Google Patents
Dispersible tablet containing metformin and glibenclamide and preparation method thereof Download PDFInfo
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- CN101167731A CN101167731A CNA2007101131927A CN200710113192A CN101167731A CN 101167731 A CN101167731 A CN 101167731A CN A2007101131927 A CNA2007101131927 A CN A2007101131927A CN 200710113192 A CN200710113192 A CN 200710113192A CN 101167731 A CN101167731 A CN 101167731A
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Abstract
The invention relates to dispersible tablets containing diabetosan and glibenclamide. The dissolving rate of glibenclamide is improved by making colloidal powder or solid dispersion powder of glibenclamide before making tablets. The dispersible tablets can disintegrate quickly, and the dissolving rates of diabetosan and glibenclamide of the dispersible tablets are significantly faster than that of common preparation.
Description
Technical field:
The present invention relates to a kind of pharmaceutical composition that contains metformin hydrochloride and glibenclamide, is the improvement technology about a kind of oral solid formulation of metformin-glibenclamide compound preparation.
Background technology:
Now in the world, along with improving constantly of people's living standard, the change of dietary structure, the improvement of labor intensity, the increasing of stress state, the sickness rate of world's diabetes increases just with surprising rapidity.According to internal authority diabetes epidemiology scholarly forecast, will increase to 2.39 hundred million to global diabetics in 2010, will reach 300,000,000 in 2025, wherein all type 2 diabetes mellitus more than 90%.The situation of China is no exception, show according to nearest Epidemiological study, the onset diabetes rate of China by 0.67% before 15 years rise in recent years 3.21%, and annual speed with 0.1% increases sharply, wherein the type ii diabetes patient accounts for more than 95% of sum.As seen, diabetes have become the great public health problem that countries in the world are paid close attention to as a kind of serious non-infectious chronic disease, and antidiabetic medicine has become the task of top priority so research and develop safely and effectively.
At present, for treatment of diabetes, except that diet control and exercise therapy, mainly be Drug therapy.The medicine of common clinically treatment diabetes has: 1. sulfonylurea: as tolbutamide, glibenclamide, glimepiride, gliclazide, glipizide and gliquidone etc.; 2. biguanides: example hydrochloric acid metformin and phenformin; 3. alpha-glucosidase inhibitor: as acarbose, voglibose etc.; 4. benzoic acid derivative: as Nateglinide and repaglinide etc.; 5. thiazolidinediones: as rosiglitazone, pioglitazone etc.; And 6. insulin etc.
Show that according to Britain perspective diabetes study (UKPDS) when the patient was diagnosed as type 2 diabetes mellitus, the β cell function had descended 50%, insulin sensitivity also is normal 50%.Because single antidiabetic drug can only correct wherein, so to give single medicine be not ideal scheme the starting stage.For making patient's glycemic control in desirable level, better way is promptly to adopt sulphanylureas/biguanides mixing treatment in early days, so not only can stimulate insulin secretion but also can reduce insulin resistant.
At present, the compound oral solid preparation mainly formed of common clinically such preparation by glibenclamide and metformin hydrochloride.Its common dosage form is tablet and capsule, and specification is: 500mg/5mg, 500mg/2.5mg, 250mg/1.25mg, 250mg/2.5mg.
The dissolution rate of oral administration solid medicine can reflect the situation that absorbs of medicine to a certain extent.Glibenclamide is insoluble in water, absorbs intravital rate-limiting step so its process in leaching is it, reduces the glibenclamide particle grain size and can improve its dissolution rate and dissolution, makes glibenclamide energy fast Absorption, and can improve its bioavailability.
In disclosed patented technology, thereby the concentration that causes entering blood because of the too little meeting of granule of considering glibenclamide increases and causes hypoglycemia, so the granularity to its glibenclamide limits: 10% granule is less than 2 μ m at the most, and 10% greater than 60 μ m at the most; Preferred limits is that 10% granule is less than 3 μ m at the most, and 10% greater than 40 μ m at the most; The glibenclamide of this limit can be by sieving and aerojet mill obtains.
Summary of the invention:
The object of the present invention is to provide a kind of taking convenience, absorb the metformin-glibenclamide compound oral dispersible tablet formulation fast, that bioavailability is high.
Glibenclamide is water insoluble, and the present invention adopts micropowder technology, solid dispersion technology that the glibenclamide raw material is handled, and increases the particulate specific surface area of glibenclamide, improves its dissolution rate and dissolution; And by optimizing the disintegration time that the adjuvant prescription shortens preparation, improving its glibenclamide and metformin dissolution rate, thereby improve the absorption rate and the bioavailability of glibenclamide and metformin.
The metformin-glibenclamide compound preparation of public technology is close with the independent pharmacokinetic parameter of glibenclamide sheet and metformin hydrochloride tablet that uses.Behind the oral folk prescription metformin hydrochloride, peak reaching time of blood concentration is for taking medicine back 2.4 ± 0.8 hours; Behind the oral folk prescription glibenclamide, peak reaching time of blood concentration is 3.2 ± 0.6 hours, at the liver intracellular metabolite, main metabolites be 4-anti--hydroxy derivatives, metabolite does not almost have hypoglycemic activity.The patient who had taken other antidiabetic drug before being used for, recommending starting dose is 2 times on the 1st, 1 2.5mg/500mg or 2 times on the 1st, 1 5mg/1000mg, with meal with clothes.For single with sulphanylureas or metformin hydrochloride can not fine blood sugar control patient, recommending starting dose is 2 times on the 1st, 1 2.5mg/500mg or 2 times on the 1st, 14 5mg/1000mg, maximum daily dose is no more than 10mg/2000mg.
Be later than the peak time of metformin in view of the peak time of glibenclamide in the common compound preparation, adopt micropowder technology and solid dispersions technique that the grain diameter of glibenclamide is further reduced among the present invention, and the disintegration time of shortening preparation, make glibenclamide enter blood fast after taking, peak time in advance.
The usage of the dispersible tablet that the present invention is prepared is: add after the aqueous dispersion orally or tablet is contained in suckes clothes in the mouth or swallow, take when having dinner.Because blood sugar concentration reaches peak value in patient's blood in 2～3 hours that use after the meal, be difficult for hypoglycemia takes place, metformin and glibenclamide can during this period of time reach the highest blood drug level, play the effect of blood sugar lowering; Blood sugar concentration can reduce gradually before patient's blood sugar concentration was extremely had meal after reaching the peak next time, and when the intravital blood sugar concentration of patient reduced, the blood drug level of metformin and glibenclamide also began to reduce after reaching the peak.Therefore, the present invention is intended to make the peak time of metformin and glibenclamide to disclose the metformin-glibenclamide compound preparation more in advance, in the higher time range of post-prandial glycemia concentration, make metformin and glibenclamide blood drug level reach peak value, the blood drug level of metformin and glibenclamide reduces gradually in the time range that blood sugar concentration reduces, and can improve curative effect and reduce hypoglycemic danger.
The present invention is limited to the ratio of metformin and glibenclamide 100: 1～200: 1, for example, can be made into 2.5mg glibenclamide and 250mg metformin, or specifications such as 1.25mg glibenclamide and 250mg metformin, determine first dosage and adjust daily dose according to the course of disease and the blood glucose situation of individual patients.
Glibenclamide micropowder preparing process of the present invention is:
Glibenclamide is added an amount of sodium lauryl sulphate make dispersant, place micronization equipment mixed grinding, the particle diameter that makes the glibenclamide fine powder does not more add dispersant obviously to be reduced.In this preparation process, the sodium lauryl sulphate of adding can reduce the intergranular electrostatic interaction of glibenclamide, stops glibenclamide aggregation of particles in the mechanical milling process.The adding method can directly be mixed with sodium lauryl sulphate with glibenclamide, also sodium lauryl sulphate can be mixed with solution and add in the glibenclamide raw material, the drying mixed material that gets of mix homogeneously after bake.The sodium lauryl sulphate consumption is 0.2～1.0%, and optimum amount is 0.6%, can make the particle diameter minimum of glibenclamide micropowder, and the glibenclamide grain size of micropowder scope that makes is 1～10 μ m, and the distribution of particles more than 90% is at 1～3 μ m.
The consumption of table 1 sodium lauryl sulphate and glibenclamide particle diameter
| Sodium lauryl sulphate concentration (%) | 0 | 0.2 | 0.4 | 0.6 | 0.8 | 1.0 | 1.2 |
| Particle diameter more than 90% (μ m) | 10～20 | 8～10 | 4～7 | 1～3 | 4～7 | 8～10 | 10～15 |
The preparation method of glibenclamide solid dispersion of the present invention is:
Earlier glibenclamide is dissolved in the ethanol, add Macrogol 4000 again, the ratio of Macrogol 4000 and glibenclamide is 1: 1～8: 1 a ratio mixing, rotary evaporation, drying is pulverized, and obtains the solid dispersion powder of glibenclamide, investigate the dissolution of preparation, all significantly improve than the glibenclamide ordinary preparation.Wherein, the optimum amount of Macrogol 4000 and glibenclamide ratio is 4: 1.
Metformin-glibenclamide dispersible tablet of the present invention is made up of components such as metformin hydrochloride, glibenclamide micropowder or glibenclamide solid dispersion, disintegrating agent carboxymethyl base Starch Sodium, dry adhesive microcrystalline Cellulose, magnesium stearate lubricant and adhesive polyvinylpyrrolidones.Its constituent content, be by weight percentage: the metformin hydrochloride of 50.0～70.0wt%, 0.25 the glibenclamide of～0.7wt%, 4.0 the carboxymethyl starch sodium of～13.0wt%, 18.0 the microcrystalline Cellulose of～25.0wt%, 0.1 the magnesium stearate of～1.0wt%, the polyvinylpyrrolidone of 5.0～10.0wt%, the sodium lauryl sulphate of 0.5～1.0wt%.
The present invention is a disintegrating agent with carboxymethyl starch sodium and microcrystalline Cellulose.Its degree of exchange of the carboxymethyl starch sodium of selecting for use is generally about 0.3～0.5, and swellbility is 5ml/g, all can use as commercial goods Primojel, Explotab or DST etc.The microcrystalline Cellulose of selecting for use is the straight-chain polysaccharide that is made of pyranoid ring D-glucose, and its degree of polymerization is 200, and swellbility is 3.4ml/g, all can use as commercial goods Avicel, PH-101, PH-102, PH103 etc.Microcrystalline Cellulose has good flowability and disintegration, and chance water disintegrate rapidly forms uniform viscosity suspension, has the effect of disintegrating agent, suspensoid and filler.
The molecular weight of the polyvinylpyrrolidone of selecting for use is 25000～40000, as PVPK
25Or PVPK
30All can use Deng the commercial goods.Polyvinylpyrrolidone is the amorphous macromolecule polymer, and fusing point is higher, to thermally-stabilised (150 ℃ of variable colors), soluble in water and multiple organic solvent, and hydrophilic is strong, uses this binding agent that disintegration of tablet is accelerated, and helps the stripping of medicine.
The surfactant sodium lauryl sulphate has and disperses and solubilization, can promote the stripping of medicine.
Because the amount of metformin is bigger among the present invention, considers the compliance that the patient takes medicine, reduce sheet heavily thereby reduce supplementary product consumption as far as possible, the micromeritis characteristic of metformin is the principal element that influences granule and tablet physical quality.Metformin ratio in tablet is excessive to cause the pellet hardness for preparing bad, looser, and fine powder is many, is unfavorable for industrial-scale production; Adjust the adhesive consumption, along with the increase of adhesive consumption, though particulate hardness increases gradually, the time of disintegration of tablet prolongs gradually.For solving this technological problems, be that branch two parts add with disintegrating agent carboxymethyl base Starch Sodium, a part is to be added among the disintegrate granule, adds in the title; Another part then adds when tabletting, is included in outside the disintegrate granule, is distributed between these microgranules, claims to add.Adjusting the carboxymethyl starch sodium consumption is 4.0～13.0wt%, and tablet can be uniformly dispersed in 3min in disintegrate, and optimum amount is 8%; In add with the ratio that adds carboxymethyl starch sodium be 1～3, preferred relative scale is 2: 1.Adjust adhesive polyvinylpyrrolidone K
30Concentration be that the pellet hardness for preparing when being 18.0～25.0wt% of 5.0～10.0wt%, microcrystalline Cellulose consumption is better, dispersing uniformity meets the prescription of dispersible tablet; Adhesive polyvinylpyrrolidone K
30Optimum amount be 7.5%, the optimum amount of microcrystalline Cellulose is 22%.
The preparation method of dispersible tablet of the present invention is a wet granulation, promptly at first metformin hydrochloride, carboxymethyl starch sodium, microcrystalline Cellulose, magnesium stearate etc. is crossed 100 mesh sieves respectively; Polyvinylpyrrolidone is water-soluble, be mixed with 25～30% polyvinylpyrrolidone aqueous solution, add sodium lauryl sulphate again, make that its concentration is 1～3%, make both mixed solutions, preserve standby; Then with glibenclamide micropowder or solid dispersion powder successively with carboxymethyl starch sodium (in add), microcrystalline Cellulose, metformin hydrochloride adds the mixed aqueous solution of a certain amount of polyvinylpyrrolidone and sodium lauryl sulphate again with the equivalent method mixing that progressively increases, and makes soft material; With 20 mesh sieves with wet granulation, 60 ℃ of oven dry, reuse 20 mesh sieve granulate; The magnesium stearate of additional proportion amount and remaining carboxymethyl starch sodium (adding) mix homogeneously again, tabletting makes metformin-glibenclamide dispersible tablet of the present invention.
Before an important feature of the present invention is film-making, make glibenclamide micropowder or solid dispersion powder, increase the particulate specific surface area of glibenclamide, improve its dissolution rate and dissolution.The key technology of glibenclamide micropowder preparation is that the sodium lauryl sulphate of adding 0.2～1.0% is made dispersant, places micronization equipment mixed grinding, and optimum amount is 0.6%; The key technology of the preparation of glibenclamide solid dispersion is that the ratio of Macrogol 4000 and glibenclamide is 1: 1～8: 1 a ratio, and the optimum amount ratio is 4: 1.
Another important feature of the present invention is the disintegration rate that has improved tablet, and the present invention is improved than the dissolution rate of metformin in the public technology metformin-glibenclamide compound preparation.For this reason, disintegrating agent carboxymethyl base Starch Sodium is that branch two parts add, and adds in the part, and another part adds, and Nei Jia is 1: 1～3: 1 with the ratio that adds carboxymethyl starch sodium, and preferred relative scale is 2: 1.The metformin-glibenclamide dispersible tablet of so making, after taking, the very fast disintegrate of tablet becomes granule, then these granules again secondary disintegrate promptly be tiny microgranule; And because the solubilization of surfactant sodium lauryl sulphate in the disintegrate granule, improved the dissolution rate of principal agent.
For comparing the dissolution of metformin-glibenclamide dispersible tablet and ordinary tablet, the present invention has done the dissolution curve of three batches of dispersible tablet samples and ordinary tablet respectively, by measurement result as can be known, three batch sample dissolution homogeneity are good, individual variation is little in batch, repeatability is good between batch, and all more commercially available ordinary tablet of the dissolution rate of three batches of dispersible tablets is accelerated, and test data sees Table 2, table 3.
Metformin hydrochloride stripping curve contrast in table 2 metformin-glibenclamide dispersible tablet and the ordinary tablet
| Lot number | Time (minute) | 1 | 2 | 3 | 4 | 5 | 6 | On average ± SD (%) |
| The metformin-glibenclamide dispersible tablet | 5 10 20 30 45 | 71.7 95.7 97.9 98.8 100.6 | 77.9 96.8 97.0 98.7 98.7 | 74.2 93.4 96.4 98.6 98.8 | 76.0 92.0 96.9 96.8 99.3 | 75.7 92.5 96.4 96.8 100.3 | 70.2 92.9 97.1 97.6 100.0 | 74.3±2.88 93.9±1.92 97.0±0.55 97.9±0.94 99.6±0.80 |
| The metformin-glibenclamide dispersible tablet | 5 10 20 30 45 | 75.4 95.5 96.7 96.9 96.8 | 70. 92.2 93.1 98.2 101.2 | 76.2 96.8 98.7 98.7 99.2 | 71.7 97.0 97.4 98.3 99.3 | 75.4 95.5 96.7 97.1 97.6 | 78.7 96.3 97.4 98.7 100.4 | 74.6±3.11 95.6±1.76 96.7±1.89 98.0±0.79 99.1±1.65 |
| The metformin-glibenclamide dispersible tablet | 5 10 20 30 45 | 75.7 96.5 97.4 100.4 101.1 | 71.7 82.4 97.0 98.7 100.0 | 78.7 95.8 96.4 96.9 98.7 | 74.2 93.4 96.4 96.7 97.1 | 71.7 82.4 96.7 98.7 100.4 | 77.7 95.5 96.9 97.7 97.8 | 75.0±2.96 91.0±6.74 96.8±0.38 98.2±1.38 99.0±1.36 |
| Metformin hydrochloride tablet | 5 10 20 30 45 | 45.4 62.4 92.1 95.5 96.6 | 45.6 62.4 74.3 98.0 98.0 | 45.4 77.4 87.7 99.6 100.1 | 45.6 62.4 74.3 92.5 98.9 | 48.9 77.4 87.8 99.6 99.8 | 44.1 62.4 92.6 95.5 96.4 | 45.8±1.61 67.4±7.75 84.8±8.39 96.8±2.79 98.3±1.58 |
Glibenclamide stripping curve contrast in table 3 metformin-glibenclamide dispersible tablet and the ordinary tablet
| Lot number | Time (minute) | 1 | 2 | 3 | 4 | 5 | 6 | On average ± SD (%) |
| The metformin-glibenclamide dispersible tablet | 5 10 20 30 45 | 69.4 83.5 94.9 97.2 96.3 | 67.5 86.0 92.1 99.6 97.1 | 65.1 80.9 87.4 88.9 97.7 | 68.8 84.1 93.0 96.3 96.8 | 66.8 86.6 95.7 99.1 97.5 | 67.0 83.4 90.1 91.6 97.5 | 67.4±1.53 84.1±2.05 92.2±3.09 95.4±4.29 97.2±0.55 |
| The metformin-glibenclamide dispersible tablet | 5 10 20 30 45 | 61.6 78.5 95.3 87.8 95.8 | 71.5 87.8 86.1 98.7 96.8 | 63.2 80.9 88.3 90.6 96.3 | 69.4 85.1 92.7 95.9 96.4 | 65.6 78.8 84.3 90.5 96.9 | 67.5 81.2 86.8 91.7 97.1 | 66.5±3.74 82.0±3.68 88.9±4.22 92.5±4.01 96.6±0.46 |
| The metformin-glibenclamide dispersible tablet | 5 10 20 30 45 | 67.6 81.9 92.7 99.8 97.9 | 62.1 75.5 82.5 92.4 96.7 | 66.4 83.6 90.1 91.6 95.5 | 65.5 84.5 95.4 96.9 97.7 | 64.4 80.9 87.3 89.0 96.7 | 63.8 77.8 85.0 89.9 97.7 | 65.0±1.96 80.7±3.46 88.8±4.83 93.3±4.22 97.0±0.92 |
| The glibenclamide sheet | 5 10 20 30 45 | 38.2 58.6 75.0 79.9 86.6 | 37.2 57.0 77.1 82.1 89.2 | 39.7 59.2 77.7 85.1 86.5 | 40.7 60.9 80.0 87.6 88.9 | 41.8 64.3 81.6 92.9 96.1 | 40.7 62.3 79.4 90.4 93.4 | 39.7±1.73 60.4±2.66 78.5±2.35 86.3±4.94 90.1±3.86 |
From table 2 and table 3 as can be known, the sample of the present invention's preparation and the single preparations of ephedrine of listing total stripping quantity difference with insignificance in 45min, but the prepared sample of the present invention is significantly higher than the listing preparation at the dissolution rate of 5～10min, metformin and glibenclamide that prompting the present invention prepares in the dispersible tablet can enter blood system fast, more openly metformin in the metformin-glibenclamide compound preparation and glibenclamide peak time are in advance, make metformin and glibenclamide blood drug level in the higher time range of post-prandial glycemia concentration reach the peak, the blood drug level of metformin and glibenclamide reduces in the time range that blood sugar concentration reduces, and can improve curative effect and reduce hypoglycemic danger.
The specific embodiment:
The invention will be further described with by way of example more below, provides implementation detail of the present invention, but be not to be intended to limit protection scope of the present invention.
Embodiment 1
The preparation of glibenclamide micropowder: glibenclamide is added sodium lauryl sulphate powder (weight ratio of sodium lauryl sulphate and glibenclamide is 0.6%) mixing, place micropowder equipment, grind, the little micropowder of glibenclamide is examined under a microscope, and the distribution of particles more than 90% is at 2～3 μ m.
Prescription:
Metformin hydrochloride 250g
The little micropowder 2.5g of glibenclamide
Carboxymethyl starch sodium (in add) 15g
Carboxymethyl starch sodium (adding) 15g
Microcrystalline Cellulose PH101 95g
Magnesium stearate 3.0g
30% 30 POVIDONE K 30 BP/USP
30Aqueous solution 102ml
3% lauryl sodium sulfate aqueous solution 102ml
Make 1000
The dispersible tablet preparation method: metformin hydrochloride, carboxymethyl starch sodium, microcrystalline Cellulose, magnesium stearate are crossed 100 mesh sieves respectively; Prepare 30% polyvinylpyrrolidone K
30Aqueous solution adds sodium lauryl sulphate and makes it into 3% aqueous solution, and is as adhesive, standby; Take by weighing the little micropowder 2.5g of glibenclamide respectively, metformin hydrochloride 250g, two parts of each 15g of carboxymethyl starch sodium, microcrystalline Cellulose PH101 95g, magnesium stearate 3.0g, with the glibenclamide micropowder successively with carboxymethyl starch sodium (in add), microcrystalline Cellulose PH101 and metformin hydrochloride with the equivalent method mix homogeneously that progressively increases, add adhesive system soft material, 20 mesh sieves are granulated, 60 ℃ of dryings, 20 mesh sieve granulate, add carboxymethyl starch sodium (adding) and magnesium stearate mix homogeneously, heavy and the pressure of adjustment sheet, tabletting, promptly.
Be 138 seconds dispersible tablet disintegration that makes, and friability is 0.60%, meets two prescriptions about dispersible tablet of Chinese Pharmacopoeia version in 2005; The dissolution of 45 minutes metformin hydrochloride is 99.2%, glibenclamide be that the uniformity of dosage units A+1.8S of 97.6% glibenclamide is 11.35; The content of metformin hydrochloride is 99.7%, and the content of glibenclamide is 99.4%.Sample of the present invention is carried out influence factor's test, the results are shown in Table 4.
Table 4 metformin-glibenclamide dispersible tablet influence factor result of the test
| Experimental condition | Time (my god) | Appearance character | Dissolution () | Dispersing uniformity (second) | Related substance (%) | Content (%) | ||||||
| Glibenclamide | Metformin | |||||||||||
| Metformin hydrochloride | Glibenclamide | Impurity A | Impurity B | Other impurity (%) | Dicyandiamide | Other impurity (%) | Metformin hydrochloride | Glibenclamide | ||||
| 0 | White tablets | 99.2 | 97.6 | 149 | 0.139 | 0.192 | 0.069 | Do not detect | 0.0103 | 99.7 | 99.4 | |
| Illumination | 5 | White tablets | 99.0 | 97.8 | 152 | 0.087 | 0.199 | 0.061 | Do not detect | 0.0101 | 99.7 | 99.3 |
| 10 | White tablets | 99.6 | 97.5 | 155 | 0.082 | 0.187 | 0.062 | Do not detect | 0.0103 | 99.5 | 99.4 | |
| 60 ℃ of high temperature | 5 | White tablets | 99.6 | 97.3 | 154 | 0.084 | 0.191 | 0.058 | Do not detect | 0.0103 | 99.8 | 99.5 |
| 10 | White tablets | 99.2 | 96.8 | 159 | 0.084 | 0.192 | 0.059 | Do not detect | 0.0102 | 99.7 | 99.4 | |
| High humidity | 5 | White tablets, the moisture absorption fluffs | 99.4 | 96.8 | 146 | 0.089 | 0.205 | 0.064 | Do not detect | 0.0098 | 99.8 | 99.4 |
| 10 | White tablets, the moisture absorption fluffs | 98.9 | 97.0 | 144 | 0.084 | 0.194 | 0.063 | Do not detect | 0.0100 | 99.7 | 99.4 | |
*Annotate: impurity A: 4-(2-(5-chloro-2-methoxy benzamide)-ethyl)-benzsulfamide;
Impurity B: 4-(2-(5-chloro-2-methoxy benzamide)-ethyl)-benzenesulfonamido--Ethyl formate.
Result of the test shows: (placed 10 days under the condition of 4500LX ± 500LX), high temperature (60 ℃), high humidity (RH92.5%), only under the super-humid conditions, the tablet moisture absorption fluffs the sample of the present invention preparation, shows it to high moist lability, needs moistureproof in illumination; Other every quality index and relatively having no significant change in 0 day.
Embodiment 2
The preparation of glibenclamide micropowder:
Sodium lauryl sulphate is done (with the weight ratio of glibenclamide be 0.6%) aqueous solution of making soluble in water, add glibenclamide, stir, 40 ℃ of dryings, place grinding in ball grinder, the little micropowder of glibenclamide is examined under a microscope, the distribution of particles more than 90% is at 2～3 μ m.
Prescription:
Metformin hydrochloride 500g
Glibenclamide micropowder 5g
Carboxymethyl starch sodium (in add) 25.9g
Carboxymethyl starch sodium (adding) 17.3g
Microcrystalline Cellulose PH102 215.9g
Magnesium stearate 4.3g
30% 30 POVIDONE K 30 BP/USP
30Aqueous solution 288ml
3% lauryl sodium sulfate aqueous solution 288ml
Make 1000
The dispersible tablet preparation method: metformin hydrochloride, carboxymethyl starch sodium, microcrystalline Cellulose, magnesium stearate are crossed 100 mesh sieves respectively; Prepare 30% polyvinylpyrrolidone K
30Aqueous solution adds sodium lauryl sulphate and makes it into 3% aqueous solution, and is as adhesive, standby; Take by weighing glibenclamide micropowder 5.03g respectively, metformin hydrochloride 500g, two parts of carboxymethyl starch sodium are respectively 25.9g (in add), 17.3g (adding), microcrystalline Cellulose PH102 215.9g, magnesium stearate 4.3g; With the glibenclamide powder compounds successively with carboxymethyl starch sodium (in add), microcrystalline Cellulose PH102 and metformin hydrochloride with the equivalent method mix homogeneously that progressively increases, add adhesive system soft material, 20 mesh sieves are granulated, 60 ℃ of dryings, 20 mesh sieve granulate add carboxymethyl starch sodium (adding) and magnesium stearate mix homogeneously, the heavy and pressure of adjustment sheet, tabletting, promptly.
Be 160 seconds dispersible tablet disintegration that makes, and friability is 0.71%, meets two prescriptions about dispersible tablet of Chinese Pharmacopoeia version in 2005; The dissolution of 45 minutes metformin hydrochloride is 99.9%, glibenclamide be 96.3%; The uniformity of dosage units A+1.8S of glibenclamide is 12.05; The content of metformin hydrochloride is 99.9%, and the content of glibenclamide is 99.6%.
Embodiment 3
The preparation of glibenclamide solid dispersion:
Earlier glibenclamide is dissolved in the ethanol, adds Macrogol 4000 again, the ratio of Macrogol 4000 and glibenclamide is 4: 1 a ratio mixing, rotary evaporation, and drying is pulverized, and obtains the solid dispersion powder of glibenclamide.
Prescription:
Metformin hydrochloride 250g
Glibenclamide solid dispersion powder 6.25g (containing glibenclamide 1.25g)
Carboxymethyl starch sodium (in add) 29.5g
Carboxymethyl starch sodium (adding) 10.0g
Microcrystalline Cellulose PH102 71.5g
Magnesium stearate 2.4g
25% 30 POVIDONE K 30 BP/USP
30Aqueous solution 94.8ml
2.5% lauryl sodium sulfate aqueous solution 94.8ml
Make 1000
The dispersible tablet preparation method: metformin hydrochloride, carboxymethyl starch sodium, microcrystalline Cellulose, magnesium stearate are crossed 100 mesh sieves respectively; Prepare 25% polyvinylpyrrolidone K
30Aqueous solution adds sodium lauryl sulphate and makes it into 2.5% aqueous solution, and is as adhesive, standby; Take by weighing glibenclamide solid dispersion powder 6.25g respectively, metformin hydrochloride 250g, two parts of carboxymethyl starch sodium, respectively be 29.5g (in add), (10.0g adding), microcrystalline Cellulose PH102 71.5g, magnesium stearate 2.4g, with the glibenclamide solid dispersion successively with carboxymethyl starch sodium (in add), microcrystalline Cellulose PH102 and metformin hydrochloride add adhesive system soft material with the equivalent method mix homogeneously that progressively increases, the granulation of 20 mesh sieves, 60 ℃ of dryings, 20 mesh sieve granulate add carboxymethyl starch sodium (adding) and magnesium stearate mix homogeneously, the heavy and pressure of adjustment sheet, tabletting, promptly.
Be 156 seconds dispersible tablet disintegration that makes, and friability is 0.70%, meets two prescriptions about dispersible tablet of Chinese Pharmacopoeia version in 2005; The dissolution of 45 minutes metformin hydrochloride is 99.0%, glibenclamide be 95.7%; The uniformity of dosage units A+1.8S of glibenclamide is 11.58; The content of metformin hydrochloride is 99.7%, and the content of glibenclamide is 98.8%.
Subordinate list 1 each embodiment constituent content synopsis
| Component | Embodiment | ||
| 1 | 2 | 3 | |
| Metformin hydrochloride (%) glibenclamide (%) Macrogol 4000 carboxymethyl starch sodium (%) microcrystalline Cellulose (%) magnesium stearate (%) polyvinylpyrrolidone (%) sodium lauryl sulphate (%) | 60.36 0.60 - 7.24 22.94 0.72 7.39 0.74 | 57.90 0.58 - 5.00 25.00 0.50 10.00 1.00 | 63.18 0.32 1.26 9.98 18.07 0.61 6.00 0.60 |
The present invention presses the plastic bottle packing with three batches of test samples, puts into 40 ± 2 ℃, carries out accelerated test 6 months in the climatic chamber of relative humidity 75% ± 5%, sampling and measuring; Three batches of test samples are pressed the plastic bottle packing,, place under the condition of relative humidity 60% ± 10%, carry out long term test, regularly investigate every index, the results are shown in subordinate list 2 25 ℃ ± 2 ℃ of temperature.
Subordinate list 2 metformin-glibenclamide dispersible tablet accelerated test and long-term test results
| Lot number | Time (moon) | Appearance character | Dissolution (%) | Dispersing uniformity second | Related substance (%) | Content (%) | ||||||
| Glibenclamide | Metformin | |||||||||||
| Metformin hydrochloride | Glibenclamide | Impurity A | Impurity B | Other impurity (%) | Dicyandiamide | Other impurity (%) | Metformin hydrochloride | Glibenclamide | ||||
| Embodiment 1 | 0 | White tablets | 99.2 | 97.6 | 136 | 0.139 | 0.192 | 0.068 | Do not detect | 0.0089 | 99.7 | 99.4 |
| Quicken 6 | White tablets | 98.9 | 97.3 | 140 | 0.129 | 0.188 | 0.069 | Do not detect | 0.0086 | 99.8 | 99.0 | |
| Long-term by 6 | White tablets | 98.3 | 97.5 | 138 | 0.125 | 0.180 | 0.074 | Do not detect | 0.0086 | 99.5 | 99.2 | |
| Embodiment 2 | 0 | White tablets | 99.9 | 96.3 | 145 | 0.135 | 0.185 | 0.068 | Do not detect | 0.0088 | 99.9 | 99.6 |
| Quicken 6 | White tablets | 98.5 | 95.7 | 142 | 0.126 | 0.183 | 0.069 | Do not detect | 0.0089 | 100.2 | 99.5 | |
| Long-term by 6 | White tablets | 99.2 | 96.7 | 142 | 0.136 | 0.173 | 0.065 | Do not detect | 0.0092 | 100.0 | 99.8 | |
| Embodiment 3 | 0 | White tablets | 99.0 | 95.7 | 149 | 0.139 | 0.192 | 0.069 | Do not detect | 0.0103 | 99.7 | 98.8 |
| Quicken 6 | White tablets | 98.5 | 95.0 | 147 | 0.129 | 0.184 | 0.074 | Do not detect | 0.0107 | 100.1 | 99.6 | |
| Long-term by 6 | White tablets | 98.6 | 96.4 | 141 | 0.133 | 0.165 | 0.065 | Do not detect | 0.0106 | 99.7 | 99.4 | |
*Annotate: impurity A: 4-(2-(5-chloro-2-methoxy benzamide)-ethyl)-benzsulfamide;
Impurity B: 4-(2-(5-chloro-2-methoxy benzamide)-ethyl)-benzenesulfonamido--Ethyl formate.
Result of the test shows: the sample of the present invention's preparation is in accelerated test and long term test research, its appearance character, dissolution, related substance, dispersing uniformity and content, every investigation index and comparison in 0 month have no significant change, and illustrate that the steady quality of the sample that the present invention prepares is reliable.
Claims (5)
1. the dispersible tablet that contains metformin and glibenclamide, by metformin hydrochloride, glibenclamide micropowder or glibenclamide solid dispersion, disintegrating agent carboxymethyl base Starch Sodium, the filler microcrystalline Cellulose, components such as magnesium stearate lubricant and adhesive polyvinylpyrrolidone are formed, its constituent content is by weight percentage: the metformin hydrochloride of 50.0～70.0wt%, 0.25 the glibenclamide of～0.7wt%, 4.0 the carboxymethyl starch sodium of～13.0wt%, 18.0 the microcrystalline Cellulose of～25.0wt%, 0.1 the magnesium stearate of～1.0wt%, 5.0 the polyvinylpyrrolidone of～10.0wt%, the sodium lauryl sulphate of 0.5～1.0wt%.
2. according to the described dispersible tablet of claim 1, it is characterized in that making glibenclamide micropowder or solid dispersion powder before the film-making, improve its dissolution rate and dissolution.The key technology of glibenclamide micropowder preparation is that the sodium lauryl sulphate of adding 0.2～1.0% is made dispersant, places micronization equipment mixed grinding, and the glibenclamide micropowder particle size range that makes is 1～10 μ m; The sodium lauryl sulphate optimum amount is 0.6%, and the distribution of particles of glibenclamide micropowder more than 90% that makes is at 1～3 μ m.The key technology of the preparation of glibenclamide solid dispersion is that the ratio of Macrogol 4000 and glibenclamide is 1: 1～8: 1 a ratio, and the optimum amount ratio is 4: 1.
3. according to the compound method of the described dispersible tablet of claim 1, it is characterized in that comprising following main preparation steps:
(1) preparation glibenclamide micropowder or solid dispersion powder: glibenclamide is added the sodium lauryl sulphate mixing, place micropowder equipment to grind, making particle size range is the glibenclamide micropowder of 1～10 μ m; Or glibenclamide is dissolved in the ethanol, adding Macrogol 4000 again, the ratio of Macrogol 4000 and glibenclamide is 1: 1～8: 1 a ratio mixing, rotary evaporation, drying is pulverized, and obtains the solid dispersion powder of glibenclamide.
(2) preparation granule:
A) metformin hydrochloride, carboxymethyl starch sodium, microcrystalline Cellulose, magnesium stearate are crossed 100 mesh sieves respectively;
B) preparation 30% polyvinylpyrrolidone K
30Aqueous solution adds sodium lauryl sulphate and makes it into 3% aqueous solution, and is as adhesive, standby;
C) with glibenclamide micropowder or solid dispersion powder successively with carboxymethyl starch sodium (in add), microcrystalline Cellulose and metformin hydrochloride with the equivalent method mix homogeneously that progressively increases, add adhesive system soft material, the granulation of 20 mesh sieves, 60 ℃ of dryings, 20 mesh sieve granulate.
(3) preparation dispersible tablet: with the carboxymethyl starch sodium and the dried granules mix homogeneously of magnesium stearate and outer dosage, the heavy and pressure of adjustment sheet, tabletting is made dispersible tablet of the present invention.
4. according to claim 1 or 3 described dispersible tablets, it is characterized in that carboxymethyl starch sodium adds at preparation granule and dispersible tablet time-division two parts respectively, Nei Jia is 1: 1～3: 1 with the ratio that adds carboxymethyl starch sodium, and preferred relative scale is 2: 1.
5. according to claim 1 or 3 described dispersible tablets, its feature is 100: 1～200: 1 at the ratio of metformin and glibenclamide.
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| CNA2007101131927A CN101167731A (en) | 2007-10-22 | 2007-10-22 | Dispersible tablet containing metformin and glibenclamide and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CNA2007101131927A CN101167731A (en) | 2007-10-22 | 2007-10-22 | Dispersible tablet containing metformin and glibenclamide and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101829175A (en) * | 2010-06-03 | 2010-09-15 | 浙江得恩德制药有限公司 | Rapidly disintegrable Zhenju antihypertensive tablets and preparation method thereof |
| CN104415345A (en) * | 2013-08-30 | 2015-03-18 | 天津药物研究院 | Multi-element compound and preparation method thereof |
| CN110731948A (en) * | 2019-12-06 | 2020-01-31 | 仁和堂药业有限公司 | Metformin hydrochloride fast-release agent tablet and application thereof |
| CN110876728A (en) * | 2019-12-06 | 2020-03-13 | 仁和堂药业有限公司 | Preparation method of metformin hydrochloride quick-release preparation |
| CN112402433A (en) * | 2020-12-07 | 2021-02-26 | 成都恒瑞制药有限公司 | Metformin-glibenclamide composition and preparation method thereof |
| CN113143940A (en) * | 2020-12-30 | 2021-07-23 | 成都恒瑞制药有限公司 | Preparation method of antidiabetic pharmaceutical composition |
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2007
- 2007-10-22 CN CNA2007101131927A patent/CN101167731A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101829175A (en) * | 2010-06-03 | 2010-09-15 | 浙江得恩德制药有限公司 | Rapidly disintegrable Zhenju antihypertensive tablets and preparation method thereof |
| CN101829175B (en) * | 2010-06-03 | 2011-11-30 | 浙江得恩德制药有限公司 | Rapidly disintegrable Zhenju antihypertensive tablets and preparation method thereof |
| CN104415345A (en) * | 2013-08-30 | 2015-03-18 | 天津药物研究院 | Multi-element compound and preparation method thereof |
| CN110731948A (en) * | 2019-12-06 | 2020-01-31 | 仁和堂药业有限公司 | Metformin hydrochloride fast-release agent tablet and application thereof |
| CN110876728A (en) * | 2019-12-06 | 2020-03-13 | 仁和堂药业有限公司 | Preparation method of metformin hydrochloride quick-release preparation |
| CN112402433A (en) * | 2020-12-07 | 2021-02-26 | 成都恒瑞制药有限公司 | Metformin-glibenclamide composition and preparation method thereof |
| CN113143940A (en) * | 2020-12-30 | 2021-07-23 | 成都恒瑞制药有限公司 | Preparation method of antidiabetic pharmaceutical composition |
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