CN1209101C - Metformin hydrochloride sustained-release tablet and method for preparing the same - Google Patents
Metformin hydrochloride sustained-release tablet and method for preparing the same Download PDFInfo
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- CN1209101C CN1209101C CN 200310112200 CN200310112200A CN1209101C CN 1209101 C CN1209101 C CN 1209101C CN 200310112200 CN200310112200 CN 200310112200 CN 200310112200 A CN200310112200 A CN 200310112200A CN 1209101 C CN1209101 C CN 1209101C
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- ethyl cellulose
- metformin hydrochloride
- release tablet
- hydroxypropyl methylcellulose
- micropowder
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- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin hydrochloride Natural products CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 title claims abstract description 38
- OETHQSJEHLVLGH-UHFFFAOYSA-N metformin hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N OETHQSJEHLVLGH-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 229960004329 metformin hydrochloride Drugs 0.000 title claims abstract description 24
- 239000007939 sustained release tablet Substances 0.000 title claims abstract description 22
- 238000000034 method Methods 0.000 title claims abstract description 12
- 239000001856 Ethyl cellulose Substances 0.000 claims abstract description 42
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims abstract description 42
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Abstract
The present invention provides a metformin hydrochloride sustained release tablet and a preparing method thereof. The metformin hydrochloride sustained release tablet is composed of 46.5% to 70% of metformin hydrochloride, 13.5% to 33.0% of hydroxypropyl methylcellulose, 10.0% to 14.0% of miropowder ethyl cellulose, 1.3% to 9.4% of filling agent and 1.2% to 1.5% of lubricant. The preparing method comprises the steps that the metformin hydrochloride, the hydroxypropyl methylcellulose and the filling agent of the raw material prescription quantity are granulated, baked and perfected according to conventional technology of the tablet; subsequently, the miropowder ethyl cellulose and the lubricant are added into perfected dry granules, and the perfected dry granules are uniformly mixed and then pressed into the tablets.
Description
Technical field
The present invention relates to a kind of slow releasing agent for the treatment of the hyperglycemia medicine and preparation method thereof, specifically diabecron sustained-release tablet and preparation method thereof.
Background technology
Metformin hydrochloride is mainly used in type ii diabetes people glucose level control as one of common drug for the treatment of diabetes.It is mainly by strengthening picked-up and the utilization of surrounding tissue to glucose, the anaerobic glycolysis of muscular tissue is increased, aerobic metabolism is constant, it concentrates on intestinal wall, suppress the absorption of glucose at intestinal, suppress glyconeogenesis, suppress the release of glucagon or the effect of inhibition insulin antagonist, and increase the sensitivity of insulin.Metformin hydrochloride to islet function normally or the diabetes of having lost hypoglycemic activity is arranged per capita, the normal person is not had hypoglycemic activity.This product both can be used for unsatisfied light, the moderate patient of simple diet control separately.It does not stimulate the beta cell excreting insulin, and insulin concentration does not have significant change in the medication bleeding from anus.Simultaneously, it can also share with insulin or sulfonylurea hypoglycemic agent, heightens the effect of a treatment.Can reduce insulin dosage.
The metformin hydrochloride common dose is bigger, reaches 500mg/ time, because the interior half-life of metformin hydrochloride body is shorter, for keeping effective blood drug concentration, clinical oral administration ordinary tablet every day 2-3 time, each 1～2, this has just brought many inconvenience to the patient, and the incidence rate of adverse reaction height.Be necessary to develop its slow releasing preparation for this reason, make to reduce and take number of times, reduce Cmax to reduce the untoward reaction of medicine.
Because metformin hydrochloride is the very big medicine of a kind of water solublity, and dosage is bigger, therefore, this medicine is made slow releasing tablet very big difficulty.For example utilizing preparation slow releasing tablet technology commonly used, all be difficult to reach ideal slow release effect as single gel type slow releasing tablet or rigid backbone sheet etc., particularly need to control in 24 hours and steadily discharge, keep and treat blood drug level stably and make that to reach in the body excellent curative difficult with certain speed.
Said diabecron sustained-release tablet is the macromolecular material pharmaceutically commonly used that adopts hydroxypropyl methylcellulose, ethyl cellulose, sodium carboxymethyl cellulose etc. common among the patent CN1391890A, to form the slow releasing agent of gel-type, and adopt organic carboxyl acid or alcohol under 50～60 ℃ of molten conditions, to granulate, technological operation is extremely inconvenient, and said preparation still is difficult to reach the purpose that the control medicine steadily discharges with certain speed.
The diabecron sustained-release tablet of the product commodity of U.S. BMS company " Glucophage XR " by name, it is that what to make with hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, microcrystalline Cellulose, magnesium stearate etc. also is a kind of gel barrier type hydrophilic skeleton slow releasing agent, after oral tablets is met water, hydroxypropyl methylcellulose, these macromolecular materials that form skeleton of sodium carboxymethyl cellulose form the layer of gel barrier layer rapidly on the surface of tablet, and the release of medicine is controlled by two kinds of mechanism of diffusion of gel layer by the corrosion and the medicine of gel layer.Adopt the prepared slow releasing tablet of this mechanism, the amount of the skeleton macromolecular material that it is used is bigger, corresponding sheet is heavy and the sheet type is also just big, the sheet of the product of " Glucophage XR " heavily is 1g, wherein active drug is 0.5g, promptly the excipient scope of " GlucophageXR " account for sheet heavy about 50%.Because the effective dose of diabecron sustained-release tablet is each every 500mg, need granulate to swallow when taking, can not bite into pieces, the heavy too big tablet of the sheet of must swallowing like this is very inconvenient, such especially concerning Chinese, and be to take medicine for a long time to some patient, the tablet of the very big grain of swallowing for a long time, it is very painful that patient can feel.Be necessary that for this reason the molded tablet type only takes the diabecron sustained-release tablet an of a slice less every day.
Goal of the invention
The purpose of this invention is to provide a kind of type and only take one time a slice diabecron sustained-release tablet less every day;
Another object of the present invention has provided a kind of method for preparing diabecron sustained-release tablet.
Summary of the invention
For implementing the technical scheme that purpose of the present invention adopts be: diabecron sustained-release tablet is to be become by following raw materials by weight percent: metformin hydrochloride 46.5～70.0%, hydroxypropyl methylcellulose 13.5～33.0%, micropowder ethyl cellulose 10.0～14.0%, filler 1.3～9.4%, lubricant 1.2～1.5%.
The ethyl cellulose that the present invention adopts is the ethyl cellulose of micro powder grade.The particle diameter that is ethyl cellulose must be below 100 μ m, and it is that the content of 6.0～11.0 centipoises, substituent group ethyoxyl is 48.0～49.5%, average particle size is the micropowder ethyl cellulose of 3～15 μ m that the present invention preferably adopts viscosity.
The ethyl cellulose particle diameter of regular grade is generally 150-500 μ m, if directly with ethyl cellulose and the hydroxypropyl methylcellulose and the medicament mixed of the regular grade of reasonable amount, pelletizing press sheet, then institute's tabletting is loose or rate of release is too fast, can't play slow releasing function, as reaching an amount of drug releasing rate, then the consumption of ethyl cellulose is too big, and sheet is great to irrational level.
If with common ethyl cellulose organic solvent wiring solution-forming, make adhesive and granulate, then need very a large amount of organic liquids, do not meet environmental protection and want ball.Adopt the made granule of this technology too hard, the sheet that is pressed into is unilateral coarse, and is undesirable.
It needs to be noted that slow releasing agent of the present invention has adopted the micropowder ethyl cellulose.The micropowder ethyl cellulose is the special adjuvant of a class, and it can also directly add dry powder mixes the back tabletting in the granule, and technology is simple, and is easy to operate.With the micropowder ethyl cellulose can reduce hydroxypropyl methylcellulose and ethyl cellulose consumption, its total consumption reduces, and just can reach the control medicine with the steady purpose of release of given pace.
The preparation method of the said diabecron sustained-release tablet of the present invention, be with the metformin hydrochloride of recipe quantity, hydroxypropyl methylcellulose, the filler dried particles after by the common process granulation of tablet, oven dry, granulate, granulate, add micropowder ethyl cellulose, lubricant mixing after tabletting promptly.
It is as follows to carry out the test determination of release in vitro degree with diabecron sustained-release tablet provided by the present invention: drug release determination employing method:
Experimental technique: sample thief, according to drug release determination method (two appendix XD of Chinese Pharmacopoeia version in 2000), adopt dissolution method (two appendix XC of Chinese Pharmacopoeia version in 2000) first timid (basket method) device, be solvent with water 1000ml, rotating speed is that per minute 100 changes, operation in accordance with the law is 1,3,8, got molten axil 5ml in 15 hours, filter, as testing sample.
The mensuration of trap: (1) draws 1 hour solution example 2ml, puts in the 50ml volumetric flask, is diluted with water to scale, shakes up standby: (2) draw solution example 2ml after 3 hours, put in the 100ml volumetric flask, are diluted with water to scale, shake up standby.Above sample solution is that blank records trap A at 233nm wavelength place with water, with the standard absorption coefficient
Calculate the release of each time point.
It the results are shown in accompanying drawing 1.The result shows that diabecron sustained-release tablet provided by the present invention can be with the steady slow release release of speed of design.
Carry out the test of human body pharmacokinetics with diabecron sustained-release tablet provided by the present invention.
Test method:
1, study subject: 20 of healthy male volunteers, accept each 10 of single-dose and multiple dosing tests respectively.Test preceding 2 all interior duration of test that reach and do not take other drug.
2, medication
Single-dose: once take 2 (1000mg) this product, use warm water delivery service, water was prohibited 2 hours in the back of taking medicine, and fasting is taken food after 4 hours to seek unity of standard and eaten.
With intersecting self-controlled method at random, 20 experimenters are divided into two groups at random, once take A, each 1000mg of B preparation respectively for every group, use the 250ml warm water delivery service, take the back and prohibited water 2 hours, the fasting unified standard of taking food after 4 hours, twice dosing interval phase is a week.Duration of test ban on opium-smoking and the opium trade wine, prohibit the beverage that contains caffeine, avoid strenuous exercise.
Multiple dosing: 10 experimenters, 2 (1000mg) this product of taking medicine, the every day-inferior, each 2, took medicine continuous 5 days 24 hours at interval.Fasting in the auf nuechternen Magen einnehmen in early morning, was used the 250ml warm water delivery service after 12 hours, the back fasting 2 hours of taking medicine in the 1st～4 day, and water was prohibited 2 hours, fasting 4 hours in the back of taking medicine in the 5th day.
3, EXPERIMENTAL DESIGN and blood specimen collection
Single-dose: got blood from veins of upper extremity in 0.5,1,1.5,2,3,4,5,6,8,10,12,24 hour in the back of taking medicine preceding 0 hour and took medicine, each 3.5ml.
Multiple dosing: blood was got from veins of upper extremity in 0.5,1,1.5,2,3,4,5,6,8,10,12,24 hour in (3 days paddy concentration of METHOD FOR CONTINUOUS DETERMINATION) and the back of taking medicine in the 5th day before taking medicine in the 1st, 3,4,5 day, each 3.6ml.
Centrifugalize goes out blood plasma, puts-20 ℃ of cryopreservation to measuring.
4, metformin determination of plasma concentration
Adopt the HPLC method to detect metformin concentration in the blood plasma, undertaken quantitatively by external standard method.Chromatographic condition: chromatographic column is Hypersil BDS C
18(150 * ID4.6mm), mobile phase is methanol: 5molL to (5 μ particle diameter) stainless steel column
-1Potassium dihydrogen phosphate: acetonitrile (43: 57: 5), every 1000ml add 100mg SDS (with sodium hydroxide pH to 7.95), flow velocity 1.2ml/min.25 ℃ of room temperatures; Wavelength 233nm, AUFS0.01.18 ℃ of auto injection actuator temperatures.
5, result of the test
(1) chromatographic behavior
Metformin standard and blood sample are analyzed by aforementioned chromatographic condition sample introduction, and metformin separates well with the blood plasma impurity peaks, and retention time is about 4.0min.
(2) linear relationship and detectability
0.02-4.0 μ gml
-1The sample introduction analysis after extraction is handled of the standard blood plasma of series concentration, the border directrix curve regression equation between its concentration (X) peak area (Y) is: Y=21.818X-242.287 (r=0.9995, n=9).By signal to noise ratio is that the minimal detectable concentration of 3 estimations in blood plasma is about 0.02 μ gml
-1
(3) yield, repeatability and plasma sample estimation of stability
To 0.08,0.4 and 2.0 μ gml
-1Three concentration in the totally 5 batches of metformin blood plasma standards are carried out day, day between variation measure and response rate result: the RSD of variation is 1.2～5.5% in day, and the RSD of variation is 0.3～6.6% between day.Average extraction absolute recovery is 92.2～96.7%, and relative recovery is 90.7～104.9%.Show that this assay method can satisfy the requirement of metformin bioavailability study.
Plasma sample extract (being the HPLC sample) stability test result: three concentration metformin plasma samples are-0.4～9.7% through three its irrelevances of freeze thawing; Its irrelevance was-8.3～0.7% in freezing 73 days; It is 4.5～10.1% that the plasma sample room temperature is placed 4 hours basic irrelevances.The result shows that metformin is comparatively stable in blood plasma.It is-0.2～16.0% that three concentration metformin blood plasma extract room temperatures are placed 4 hours its irrelevances.
(4) determination of plasma concentration and pharmacokinetic parameters research
A) single-dose
Pharmacokinetic parameters: be subjected to test preparation peak concentration C
MaxBe 1893.3 ± 533.8 μ gL
-1Peak time T
MaxBe 3.6 ± 0.7h; Eliminating the phase half-life is 6.2 ± 1.7h; AUC
0-24Be 12582.8 ± 4030.2 μ gL
-1H; AUC
0-∞Be 13230.2 ± 4174.7 and μ gL
-1H.20 the average blood of health volunteer's single oral print of the present invention medicine-time curves (accompanying drawing 2).
B) multiple dosing
Pharmacokinetic parameters result is as seen: be subjected to test preparation C
MaxBe 1536.3 ± 385.0 μ gL
-1Peak time T
MaxBe 3.3 ± 0.8h; The paddy concentration C
MinBe 72.8 ± 29.2 μ gL
-1The average blood drug level C of stable state
wBe 412.7 ± 91.6 μ gL
-1Eliminate phase half-life t
1/2Be 7.7 ± 2.1h; AUC
SsBe 9904.3 ± 2199.2 μ gL
-1H; Fluctuation degree DF is 327.4 ± 67.5%.
Above blood drug level data declaration, after oral diabecron sustained-release tablet provided by the present invention reached stable state, blood drug level met the treatment requirement once-a-day of type ii diabetes.
Advantage of the present invention is that it can directly add granule mixing doctor sheet by dry powder owing to adopt a kind of special adjuvant of micropowder ethyl cellulose, and technology is simple, and is easy to operate, is suitable for suitability for industrialized production; Adopted the micropowder ethyl cellulose, and the slow releasing function of the hydrophilic matrix tablet of some rigid backbone is played in hydroxypropyl methylcellulose (HPMC K series) combination, and can reduce hydroxypropyl methylcellulose and ethyl cellulose consumption, make sheet heavy and light, sheet type little, make things convenient for patient to swallow, because supplementary product consumption is few, cost of material and production cost have been reduced relatively simultaneously; And total consumption of hydroxypropyl methylcellulose and ethyl cellulose only need sheet heavy below 30%, just can reach the purpose that the control medicine steadily discharges with given pace, slow releasing tablet provided by the present invention only needs take in 24 hours a slice, every 500mg.
Description of drawings
Accompanying drawing 1 is the diabecron sustained-release tablet release in vitro provided by the present invention line chart of writing music, and wherein abscissa is hour, and the vertical border of sitting is an accumulation stripping percentage rate;
Accompanying drawing 2 is the average blood drug-time curve figure behind 20 health volunteer's single oral diabecron sustained-release tablets provided by the invention, and wherein horizontal seat border is hour, and vertical to sit the border be blood drug level (micrograms per litre).
Specific embodiments
Embodiment 1
Take by weighing metformin hydrochloride 500g, hydroxypropyl methylcellulose (model 15KM) 105g; Micropowder ethyl cellulose 110g (model: 10FP, specification: viscosity is 9.0～11.0 centipoises, ethyoxyl content is 48.0～49.5%, average particle size is 3～15), ethyl cellulose (model: 10CP) 7g, Pulvis Talci 5g, magnesium stearate 2g.
Preparation: with metformin hydrochloride (powder essence is crossed 100 orders in advance) 500g, hydroxypropyl methylcellulose (HPMCK15M).The machinery mixing, the ethyl cellulose (85% ethanol) of adding 10% is granulated in the stirring, oven dry, granulate.With the dried particles behind the above-mentioned granulate, add micropowder ethyl cellulose dry powder, Pulvis Talci and magnesium stearate place and mix grain machine, mix homogeneously.Tabletting gets 1000.Every hydrochloric metformin 500mg, the heavy 729mg of sheet.
Embodiment 2
Take by weighing metformin hydrochloride 500g, hydroxypropyl methylcellulose (model 100KM) 150g; Micropowder ethyl cellulose 110g (model: 7FP, specification: viscosity is 6.0～8.0 centipoises, ethyoxyl content is 48.0～49.5%, average particle size is 5～15), ethyl cellulose (model: 10CP) 5g, lactose 30g, Pulvis Talci 1g, magnesium stearate 4g.
Operational approach: with metformin hydrochloride, lactose powder essence, 100 orders, hydroxypropyl methylcellulose are crossed 80 orders excessively, mechanical mixing, and the ethyl cellulose (70% ethanol) of adding 8% is granulated in the stirring, oven dry, granulate.With the dried particles behind the above-mentioned granulate, add micropowder ethyl cellulose dry powder, Pulvis Talci and magnesium stearate place and mix grain machine, mix homogeneously.Tabletting gets 1000.Every hydrochloric metformin 500mg, the heavy 811mg of sheet.
Take by weighing metformin hydrochloride 500g, hydroxypropyl methylcellulose (model: 4KM) 350g; Micropowder ethyl cellulose 125g (model: 7FP), lactose 25g, Pulvis Talci 4g, magnesium stearate 5g.
Operational approach: with metformin hydrochloride, lactose powder essence, 100 orders, hydroxypropyl methylcellulose are crossed 100 orders excessively.The machinery mixing adds 65% alcohol granulation, oven dry, granulate in the stirring.With the dried particles behind the above-mentioned granulate, add micropowder ethyl cellulose dry powder, Pulvis Talci and magnesium stearate place and mix grain machine, mix homogeneously.Tabletting gets 1000.Every hydrochloric metformin 500mg, the heavy 1000mg of sheet.
Embodiment 4
Take by weighing metformin hydrochloride 500g, hydroxypropyl methylcellulose (model: 15KM) 250g; Micropowder ethyl cellulose 90g (model: 10FP), ethyl cellulose (model: 10CP) 12g, lactose 20g, Pulvis Talci 4g, magnesium stearate 4g.
Operational approach:
With metformin hydrochloride, lactose powder essence, 100 orders, hydroxypropyl methylcellulose are crossed 100 orders excessively.The machinery mixing, the ethyl cellulose (85% ethanol) of adding 10% is granulated in the stirring, oven dry, granulate.With the dried particles behind the above-mentioned granulate, add micropowder ethyl cellulose dry powder, Pulvis Talci and magnesium stearate place and mix grain machine, mix homogeneously.Tabletting gets 1000.Every hydrochloric metformin 500mg, the heavy 868mg of sheet.
Take by weighing metformin hydrochloride 500g, and hydroxypropyl methylcellulose (model: 100KM) 300g, micropowder ethyl cellulose 80g (model: 10FP), ethyl cellulose (model: 10CP) 10g, lactose 30g, Pulvis Talci 3g, magnesium stearate 3g.
Operational approach:
With metformin hydrochloride, lactose powder essence, 100 orders, hydroxypropyl methylcellulose are crossed 100 orders excessively.The machinery mixing, the ethyl cellulose (85% ethanol) of adding 10% is granulated in the stirring, oven dry, granulate.With the dried particles behind the above-mentioned granulate, add micropowder ethyl cellulose dry powder, Pulvis Talci and magnesium stearate place and mix grain machine, mix homogeneously.Tabletting gets 1000.Every hydrochloric metformin 500mg, the heavy 926mg of sheet.
Claims (3)
1, a kind of diabecron sustained-release tablet is characterized in that being made up of following raw materials by weight percent:
Metformin hydrochloride 46.0～70.0%
Hydroxypropyl methylcellulose 13.5～33.0%
Micropowder ethyl dimension plain 10.0～14.0%
Filler 1.3～9.4%
Lubricant 1.2～1.5%.
2, diabecron sustained-release tablet according to claim 1 is characterized in that the micropowder ethyl cellulose is that to adopt viscosity be that 6.0～11.0 centipoises, ethyoxyl content are 48.0～49.5%, mean diameter is the ethyl cellulose of 3～15 μ m.
3, the preparation method of diabecron sustained-release tablet according to claim 1, it is characterized in that the metformin hydrochloride of raw material recipe quantity, hydroxypropyl methylcellulose, the filler dried particles after by the common process granulation of tablet, oven dry, granulate, granulate, add micropowder ethyl cellulose, lubricant mixing after tabletting promptly.
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| Application Number | Priority Date | Filing Date | Title |
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| CN 200310112200 CN1209101C (en) | 2003-11-19 | 2003-11-19 | Metformin hydrochloride sustained-release tablet and method for preparing the same |
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| CN 200310112200 CN1209101C (en) | 2003-11-19 | 2003-11-19 | Metformin hydrochloride sustained-release tablet and method for preparing the same |
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| CN1209101C true CN1209101C (en) | 2005-07-06 |
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| CN101843617B (en) * | 2010-03-05 | 2012-07-18 | 中国药科大学 | Slow release preparation of compound Repaglinide-metformin hydrochloride |
| CN101912374B (en) * | 2010-08-08 | 2016-01-20 | 浙江华海药业股份有限公司 | Quetiapine sustained release tablet and preparation method thereof |
| CN102525983A (en) * | 2010-12-31 | 2012-07-04 | 北京万全阳光医药科技有限公司 | Guanfacine sustained-release tablet and preparation method thereof |
| CN103479592B (en) * | 2013-09-06 | 2015-07-22 | 浙江新光药业股份有限公司 | Metformin hydrochloride sustained release tablets and preparation method thereof |
| CN112645845A (en) * | 2021-01-05 | 2021-04-13 | 海南海力制药有限公司 | Purification method of metformin hydrochloride, metformin hydrochloride sustained-release tablet and preparation method thereof |
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