CN101785763B - Metformin hydrochloride enteric-coated sustained release tablet and preparation method thereof - Google Patents
Metformin hydrochloride enteric-coated sustained release tablet and preparation method thereof Download PDFInfo
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- CN101785763B CN101785763B CN2010101052363A CN201010105236A CN101785763B CN 101785763 B CN101785763 B CN 101785763B CN 2010101052363 A CN2010101052363 A CN 2010101052363A CN 201010105236 A CN201010105236 A CN 201010105236A CN 101785763 B CN101785763 B CN 101785763B
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Abstract
The invention discloses a metformin hydrochloride enteric-coated sustained release tablet which is prepared by enteric coating the metformin hydrochloride sustained release tablet. Compared with the prior art, the sustained release tablet integrates with the enteric coating technology to prepare a new form of the metformin hydrochloride enteric-coated sustained release tablet. By using the enteric coating technology, the metformin hydrochloride does not disintegrate in the stomach or stimulate the gastric mucosa, and the adverse reaction of nausea, stomachache and diarrhea caused by medicine taking can be avoided; meanwhile, the metformin hydrochloride is prevented from being damaged by gastric juice, and the bioavailability is improved. The product is a sustained release preparation, the medicine can stably release in vivo, the effective blood concentration can be maintained for a long time, the toxic and side effects caused by over-high blood concentration in a short time are avoided, the medicine taking frequency is decreased, and the patient compliance is improved as well.
Description
Technical field
The present invention relates to the metformin hydrochloride preparation, particularly relate to a kind of metformin hydrochloride enteric-coated sustained release tablet and preparation method thereof.
Background technology
Metformin hydrochloride is the widely used unique oral class hyperglycemia medicine of present world developed country, can improve the tolerance of type 2 diabetes mellitus patient to sugar, reduces the basis and reaches plasma glucose concentration after the meal.This medicine is different with the mechanism of action of sulphanylureas, does not produce hypoglycemic reaction in normal person and type 2 diabetes mellitus patient, does not also produce hyperinsulinemia.The hypoglycemic dominant mechanism of metformin hydrochloride is to improve peripheral tissues and liver to the sensitivity of insulin, reduces insulin resistant, reduces the absorption of gastrointestinal tract to glucose.Because of its blood sugar reducing function affirms that normal person is invalid to blood glucose; Do not stimulate insulin secretion, can keep or lose weight; Over surplus the clinical practice 40 year, obtained good hypoglycemic effect, be subjected to clinician and patient's welcome deeply.
The side effect of metformin hydrochloride mainly is a gastrointestinal reaction, and that symptom mainly contains is nauseating, vomiting, anorexia, diarrhoea etc., and metformin hydrochloride preparation in the market mainly contains metformin hydrochloride tablet, slow releasing tablet, enteric coatel tablets etc.Slow releasing tablet can delay the rate of release of medicine, prolongs effective drug duration, reduces the concentration of medicine in the intestines and stomach, reduces the gastrointestinal side effect.Enteric coatel tablets not disintegrate under one's belt can not cause stimulation to gastric mucosa, untoward reaction such as the feeling sick of causing of can avoiding to a certain extent taking medicine, stomachache, diarrhoea.
Also there is metformin hydrochloride tablet in the prior art with similar functions, for example patent CN1561980A discloses a kind of so-called metformin hydrochloride enteric-coated sustained release tablet, 9 groups of tests are disclosed in its description table 2, its effect is all undesirable, in above-mentioned 9 groups of tests, the 9th group of test that effect is best, the release of metformin hydrochloride is too fast, and the more important thing is and do not carry out the release test of metformin hydrochloride in acid solution in this application, if metformin hydrochloride release in acid solution is improper, its final release test and meaningless.
Summary of the invention
Technical problem to be solved by this invention is how the advantage of diabecron sustained-release tablet and enteric coatel tablets to be merged, and a kind of metformin hydrochloride enteric-coated sustained release tablet and preparation method thereof is provided.
In order to solve the problems of the technologies described above, the present invention adopts following technical scheme:
Metformin hydrochloride enteric-coated sustained release tablet of the present invention is to be prepared from by diabecron sustained-release tablet is enteric coated.
According to listed as parts by weight, the slow releasing tablet for preparing above-mentioned enteric-coated sustained-release tablet is by 50～70 parts of metformin hydrochloride, 3.0～6.5 parts of sodium carboxymethyl cellulose, 18.0～30.0 parts of hypromelloses and polyvinylpyrrolidone K307.7～11.6 part, is that binding agent is prepared from 3.0～6.0 parts of 30% polyacrylic resin IV alcoholic solution.
Polyacrylic resin is often used as enteric, gastric solubleness coating materials in pharmaceutical preparation.We find that it can reach the effect of slow release, and are water-soluble because it is difficult to, and meet water naturally and also can not be clamminess, and do the granule of binding agent preparation with it, combine under pressure, and it also can slowly be disintegrated because of the mosaic texture that enters between making of water; And it is the film property packaging medicine, and drug main will just be released under alkali condition, can stop medicine in the gastric rate of release.As seen, polyacrylic resin both can be used as binding agent in prescription of the present invention, also have slow-release function.
The preparation method of aforementioned metformin hydrochloride enteric-coated sustained release tablet: the diabecron sustained-release tablet for preparing is sprayed the enteric coating liquid coating, promptly.
Further, above-mentioned preparation method is: get metformin hydrochloride, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone K30, with 30% polyacrylic resin IV alcoholic solution is binding agent, press the granulation of tablet common process, oven dry, granulate, tabletting behind the adding lubricant mixing in the dried particles behind granulate, spray enteric coated liquid coating, promptly.
The prescription screening process
Metformin hydrochloride is very easily water-soluble, discharges in order to make drug slow, and effective blood drug concentration can be kept the long period, and to reach therapeutic purposes preferably, we make metformin hydrochloride enteric-coated sustained release tablet, are matrix type.With every hydrochloric metformin 500mg, adopt a kind of in the controlled-release material or several and different size, different amounts prescription, carry out the test of release in vitro degree, find that from a plurality of slow release prescriptions No. 2 prescription slow release effects are better, and the repeatability of particulate compressibility, flowability and prescription is all good, so determine that prescription 2 is this sustained-release tablet recipe.
Prescription screening process such as following table:
| The prescription number | Prescription is formed (1000 amounts) | Criterion | The result |
| 1 | Metformin hydrochloride 500g sodium carboxymethyl cellulose 100g hypromellose 150g polyvinylpyrrolidone (K90) 20g polyacrylic resin II 60～120ml magnesium stearate 1% | Hardness: 9kg angle of repose: 26 ° of outward appearances: but release 2 hours still: 41.9% 6 hours 74.5% 12 hours: 98.5% | Release is slightly fast, and this prescription is infeasible. |
| 2 | Metformin hydrochloride 500g sodium carboxymethyl cellulose 40g hypromellose 200g polyvinylpyrrolidone (K30) 80g polyacrylic resin IV 60～120ml magnesium stearate 1% | Hardness:: 10kg angle of repose: 25 ° of outward appearances: good release 2 hours: 39.7% 6 hours 66.2% 12 hours: 92.1% | Release is approaching with external comparison film, compressibility, flowability, outward appearance etc., and this prescription is feasible. |
| 3 | Metformin hydrochloride 500g ethyl cellulose 200g dextrin 20g polyvinylpyrrolidone (K30) 20g sodium carboxymethyl cellulose 50g polyacrylic resin III 60～120ml magnesium stearate 1% | Hardness:: 10kg angle of repose: 27 ° of outward appearances: good release 2 hours: 74.3% 6 hours 93.5% 12 hours: survey | Release is too fast.This prescription is infeasible. |
2 write out a prescription substantially to write out a prescription, prepare three batch samples for this slow releasing tablet.Again with the phosphate buffer of 0.1mol/l hydrochloric acid solution and pH6.8 release medium as this product, method adopts the basket method (two appendix XC first methods of Chinese Pharmacopoeia version in 2005) of changeing, rotating speed is that per minute 100 changes, sample point is 1 hour, 3 hours and 10 hours, condition has been measured the release of three batch samples in view of the above, and the result is as follows:
| Lot number | Acid solution release % | Phosphate buffer release % |
| 090504 | 2 hours: 1.2 | 1 hour: 31.4 3 hours: 52.4 10 hours: 88.8 |
| 090506 | 2 hours: 1.5 | 1 hour: 32.1 3 hours: 51.6 10 hours: 89.9 |
| 090508 | 2 hours: 1.8 | 1 hour: 30.8 3 hours: 53.5 10 hours: 87.1 |
Comparison with the release curve of listing enteric coatel tablets and import slow releasing tablet
1, the drafting of the release curve of listing Dimethyldiguanide hydrochloride enteric solubility tablet
Get Dimethyldiguanide hydrochloride enteric solubility tablet, according to drug release determination method (two appendix X of Chinese Pharmacopoeia version in 2005 D, the second method method 2), earlier with 0.1mol/L hydrochloric acid solution 900ml as dissolution medium, 100 rev/mins of rotating speeds, operation in accordance with the law is after 2 hours, put in the 900mlpH6.8 phosphate buffered solution, and respectively at 5,10,20,30,45 minutes sampling 5ml (5ml of fluid infusion simultaneously), filter, get subsequent filtrate as need testing solution.
Precision is measured need testing solution 1ml to 100ml volumetric flask, is diluted with water to scale, shakes up, and measures trap at the 233nm place according to spectrophotography (appendix IV A), presses the absorptance (E of metformin hydrochloride
1% 1cm) be 798 to calculate every stripping quantity.Following table as a result:
Listing Dimethyldiguanide hydrochloride enteric solubility tablet release curve (n=6)
As seen, common enteric coatel tablets medicine in 2 and a half hours discharges fully, does not possess slow-release function (accompanying drawing 1).
2, the comparison of the release curve of this product and import diabecron sustained-release tablet
Measured this product (6 every batch) and import diabecron sustained-release tablet with the phosphate buffer of 0.1mol/l hydrochloric acid solution and pH6.8 as release medium, measured the burst size of each point in 0.5,1,2,3,4,6,8,10,12,24 hour at the phosphate buffer of 0.1mol/l hydrochloric acid solution 2 hours and pH6.8, measurement result sees the following form, and draws three batch samples and import reference substance release curve.
This product and reference substance drug release determination result
As seen, (in the acid, that is in the simulation stomach) medicine has begun to discharge in the common slow releasing tablet pro-2 hours, does not possess enteric function (accompanying drawing 2).
3, the release curve of this product
Get this product (6 every batch),, draw release profiles with the phosphate buffer of 0.1mol/l hydrochloric acid solution and pH6.8 release medium as this product.
Above-mentioned data drawing list is as seen: this metformin hydrochloride enteric-coated sustained release tablet has enteric, slow-release function concurrently, simple enteric coatel tablets, slow releasing tablet have superiority (accompanying drawing 3).
Sample (090504) to trial-production has carried out influence factor's test (exposure experiments to light, hot test, high wet test) simultaneously, and method and result are as follows:
(1) exposure experiments to light
At ambient temperature, this product is removed outer package sample is divided in plate, and sampling detects after placing 5,10 days under the 4500lux light intensity.Test data sees the following form:
This product was placed 6 months through accelerated test (40 ℃, RH75%) simulation listing packing, and room temperature keeps sample for a long time to examine or check and checked every investigation index in 6 months, and the result is all up to specification.Illustrate that this product is more stable.
Compared with prior art, the present invention has optimized formulation and technology, and the preparing product processing performance is good, is easy to molding, and sheet is heavy less, is easy to the patient and takes.And slow releasing tablet and enteric coatel tablets merged, prepare this novel form of metformin hydrochloride enteric-coated sustained release tablet, owing to used this dosage form of enteric coatel tablets, institute is so that metformin not disintegrate under one's belt, gastric mucosa is not caused stimulation, untoward reaction such as can avoid takes medicine feeling sick of causing, stomachache, diarrhoea, this product is again a slow releasing preparation simultaneously, can delay the rate of release of medicine, reduce the number of times of taking of medicine.
Description of drawings
Fig. 1 Dimethyldiguanide hydrochloride enteric solubility tablet releasing curve diagram that goes on the market
Fig. 2 this product and import reference substance release curve chart
The release curve chart of Fig. 3 this product
The specific embodiment
Embodiment 1:
1, preparation prescription: metformin hydrochloride 500g, sodium carboxymethyl cellulose 40g, hypromellose 200g, polyvinylpyrrolidone K30 80g, 30% polyacrylic resin (IV alcoholic solution 60～120ml, magnesium stearate 1%, enteric coating powder (off-white color, the enteric coating agents of Huzhou Zhanwang Pharmaceutical Co., Ltd.) and ethanol an amount of, make the enteric-coated sustained-release tablet of 500mg metformin hydrochloride/sheet.
2, preparation technology
(1) preparation of binding agent
Precision take by weighing polyacrylic resin IV number an amount of, being mixed with concentration with 95% ethanol is 30% solution, standby.
(2) preparation of label
Cross 60 mesh sieves after getting principal agent metformin hydrochloride and adjuvant sodium carboxymethyl cellulose, hypromellose, the abundant mixing of polyvinylpyrrolidone K30,60～120ml is a binding agent with 30% polyacrylic resin IV alcoholic solution, the system soft material, 24 mesh sieves are granulated, dry 24 mesh sieve granulate after 30 minutes for 50 ℃, the abundant mixing of magnesium stearate of pellet 1% (weight) is pressed into 1000 behind the adding granulate.
(3) enteric coated
It is an amount of to take by weighing the enteric coating powder, slowly add in 70% the alcoholic solution, be mixed with 6% coating solution, on magnetic stirring apparatus, ceaselessly stir, until dissolving fully, getting label puts in the coating pan, 30～40 rev/mins of pot rotating speeds, kettle temperature is 40～50 ℃, uninterruptedly sprays coating solution to label, until evenly wrapping one deck enteric coating, be drying to obtain.
Embodiment 2:
Preparation prescription: metformin hydrochloride 500g, sodium carboxymethyl cellulose 30g, hypromellose 300g, polyvinylpyrrolidone K30 116g, 20% polyacrylic resin IV number 60～120ml, magnesium stearate 1.0%, enteric coating powder (off-white color, the enteric coating agents of Huzhou Zhanwang Pharmaceutical Co., Ltd.) and ethanol an amount of, make the enteric-coated sustained-release tablet of 500mg metformin hydrochloride/sheet according to the method for embodiment 1.
Embodiment 3:
Preparation prescription: metformin hydrochloride 500g, sodium carboxymethyl cellulose 30g, hypromellose 300g, polyvinylpyrrolidone K30 116g, 20% polyacrylic resin II number 60～120ml, magnesium stearate 1.0%, enteric coating powder (off-white color, the enteric coating agents of Huzhou Zhanwang Pharmaceutical Co., Ltd.) and ethanol an amount of, make the enteric-coated sustained-release tablet of 500mg metformin hydrochloride/sheet according to the method for embodiment 1.
Embodiment 4:
Preparation prescription: metformin hydrochloride 700g, sodium carboxymethyl cellulose 65g, hypromellose 180g, polyvinylpyrrolidone K30 77g, 40% polyacrylic resin III number 60～120ml, magnesium stearate 1.0%, enteric coating powder (off-white color, the enteric coating agents of Huzhou Zhanwang Pharmaceutical Co., Ltd.) and ethanol an amount of, make the enteric-coated sustained-release tablet of 500mg metformin hydrochloride/sheet according to the method for embodiment 1.
Claims (3)
1. metformin hydrochloride enteric-coated sustained release tablet, it is characterized in that described slow releasing tablet is by metformin hydrochloride, sodium carboxymethyl cellulose, hypromellose and polyvinylpyrrolidone, alcoholic solution with polyacrylic resin IV is that binding agent is prepared from, 50～70 parts of wherein said metformin hydrochloride, 3.0～6.5 parts of sodium carboxymethyl cellulose, 30 7.7～11.6 parts of 18.0～30.0 parts of hypromelloses and polyvinylpyrrolidone K, alcoholic solution with polyacrylic resin IV is a binding agent for 3.0～6.0 parts, and according to listed as parts by weight, the concentration of the alcoholic solution of described polyacrylic resin IV is 20%～40%.
2. the preparation method of the described metformin hydrochloride enteric-coated sustained release tablet of claim 1 is characterized in that: the diabecron sustained-release tablet for preparing is sprayed the enteric coating liquid coating, promptly.
3. want the preparation method of 2 described metformin hydrochloride enteric-coated sustained release tablets according to right, it is characterized in that: get metformin hydrochloride, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone K30, with 30% polyacrylic resin IV alcoholic solution is binding agent, press the granulation of tablet common process, oven dry, granulate, tabletting behind the adding lubricant mixing in the dried particles behind granulate, spray enteric coating liquid coating, promptly.
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| CN2010101052363A CN101785763B (en) | 2010-02-04 | 2010-02-04 | Metformin hydrochloride enteric-coated sustained release tablet and preparation method thereof |
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| CN2010101052363A CN101785763B (en) | 2010-02-04 | 2010-02-04 | Metformin hydrochloride enteric-coated sustained release tablet and preparation method thereof |
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| CN101785763B true CN101785763B (en) | 2011-11-23 |
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| SG10201607085WA (en) | 2011-01-07 | 2016-10-28 | Elcelyx Therapeutics Inc | Chemosensory Receptor Ligand-Based Therapies |
| US9572784B2 (en) | 2011-01-07 | 2017-02-21 | Elcelyx Therapeutics, Inc. | Compositions comprising statins, biguanides and further agents for reducing cardiometabolic risk |
| US8796338B2 (en) | 2011-01-07 | 2014-08-05 | Elcelyx Therapeutics, Inc | Biguanide compositions and methods of treating metabolic disorders |
| US11759441B2 (en) | 2011-01-07 | 2023-09-19 | Anji Pharmaceuticals Inc. | Biguanide compositions and methods of treating metabolic disorders |
| US11974971B2 (en) | 2011-01-07 | 2024-05-07 | Anji Pharmaceuticals Inc. | Compositions and methods for treating metabolic disorders |
| US9480663B2 (en) | 2011-01-07 | 2016-11-01 | Elcelyx Therapeutics, Inc. | Biguanide compositions and methods of treating metabolic disorders |
| US9211263B2 (en) | 2012-01-06 | 2015-12-15 | Elcelyx Therapeutics, Inc. | Compositions and methods of treating metabolic disorders |
| CN102357088A (en) * | 2011-10-26 | 2012-02-22 | 河北山姆士药业有限公司 | Metformin hydrochloride enteric-coated tablet |
| BR112014016808B1 (en) | 2012-01-06 | 2022-01-11 | Anji Pharma (Us) Llc | USE OF A BIGUANIDE COMPOUND FOR THE MANUFACTURE OF A DRUG TO LOWER BLOOD GLUCOSE LEVELS AND FOR THE TREATMENT OF A DISORDER OF GLUCOSE METABOLISM |
| JP6175074B2 (en) | 2012-01-06 | 2017-08-02 | エルセリクス セラピューティクス インコーポレイテッド | Compositions and methods for treating metabolic disorders |
| CN103239424A (en) * | 2012-02-09 | 2013-08-14 | 陕西博森生物制药股份集团有限公司 | Metformin hydrochloride sustained-release capsule and its preparation method |
| EP2872127A1 (en) * | 2012-07-11 | 2015-05-20 | Elcelyx Therapeutics, Inc. | Compositions comprising statins, biguanides and further agents for reducing cardiometabolic risk |
| CN104434846A (en) * | 2014-11-17 | 2015-03-25 | 中国药科大学 | Metformin hydrochloride enteric-coated sustained-release pellet and preparation method thereof |
| CN110974792A (en) * | 2019-12-26 | 2020-04-10 | 南京亿华药业有限公司 | Crystalline drug tablet and preparation method thereof |
| CN116421657A (en) * | 2022-12-30 | 2023-07-14 | 陈寿兵 | Pharmaceutical composition for treating diabetes insulin resistance |
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