CN1742730A - Method for preparing high stripping-degree hautriwaic glipizide capsule - Google Patents
Method for preparing high stripping-degree hautriwaic glipizide capsule Download PDFInfo
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- CN1742730A CN1742730A CN 200510105796 CN200510105796A CN1742730A CN 1742730 A CN1742730 A CN 1742730A CN 200510105796 CN200510105796 CN 200510105796 CN 200510105796 A CN200510105796 A CN 200510105796A CN 1742730 A CN1742730 A CN 1742730A
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- metformin hydrochloride
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Abstract
The preparation method of metformin hydrochloride glipizide capsule includes the following steps: using 250-500 weight portions of metformin hydrochloride, sieving it by using sieve with 100 meshes, using 2.5 weight portions of glipizide, sieving it by using sieve with 200 meshes or pulverizing it to make its fineness greater than 200 meshes, then uniformly mixing the above-mentioned materials, using dilute ethyl alcohol solution of polyvidone as adhesive, making soft material, granulating by using sieve with 24 meshes, drying at 50-60deg.C, finishing granules by using sieve with 20 meshes, adding 1% of magnesium stearate and capsulizing so as to obtain the invented finished product.
Description
Technical field
The present invention relates to a kind of preparation method of metformin hydrochloride glipizide capsule of high-dissolution, belong to field of pharmaceutical preparations.
Background technology
Diabetes (diabetes mellitus) are the commonly encountered diseases that influences human health and life, it is a kind of clinical syndrome that causes by the h and E factor interaction, induction reduces to insulin for absolute or relative deficiency and target tissue cell because of insulin secretion, cause a series of metabolism disorders such as sugar, albumen, power and water Xie Zhi, clinical is main common sign with the hyperglycemia.Prolonged illness can cause a plurality of systems grievous injury and threat to life.The eighties, there were 1.35 hundred million patients in the whole world, and wherein China has more than 1,000 ten thousand, and Epidemiological study discovery diabetes prevalence in recent years present ascendant trend year by year, estimate that whole world patient in 2025 will exceed 300,000,000.Diabetes are divided into insulin dependent diabetes mellitus (IDDM) (I type) and non-insulin-dependent diabetes mellitus (II type), and about in China's diabetics is the II type more than 90%.
The target for the treatment of diabetes is the control hyperglycemia, corrects metabolism disorder, prevents and delays complication.Main treatment means is for using insulin and orally-taken blood sugar reducing medicine.Be usually used in clinical diabetes oral drugs and mainly contain three major types, be i.e. biguanides, sulfonylurea and Alpha-glucosidase inhibitor three major types.
The metformin hydrochloride mechanism of action mainly is by promoting insulin and receptors bind to improve the sensitivity of diabetics to insulin, increase surrounding tissue promotes sugar to the anerobic glycolysis of sugar utilization, suppress steatolysis, reduce the blood plasma free fatty acid level, weaken insulin resistant, improve the utilization of glucose and bring into play blood sugar lowering, blood fat reducing, the arteriosclerotic effect of inhibition.Because the metformin hypoglycemic activity is obvious, advantage is many than other blood sugar lowering class medicine, and side effect and incompatibility are less, thereby are used widely clinically as type ii diabetes patient's choice drug, are subjected to doctor and patient's welcome deeply.
Glipizide is a second filial generation sulphonyl class oral antidiabetic drug, and be applied to clinical the beginning of the eighties, has now become one of the most widely used oral antidiabetic drug, and its main mechanism is for promoting the endogenous insulin secretion.
Compatibility uses above-mentioned two kinds of medicines clinically at present, to treat patient dissatisfied with sulphanylureas control merely or that secondary lost efficacy, share to strengthen curative effect.
Chinese patent CN1451385A discloses a kind of " oral compound hypoglycemic medicine ", it uses metformin and glipizide compatibility, make oral compound hypoglycemic medicine, its technical problem that will solve is to reduce the untoward reaction of biguanides and sulfonylurea drugs.
Chinese patent CN1617728A discloses a kind of " diabetes pharmaceutical preparation and method ", it discloses metformin and glipizide amount ratio between 1000: 1～100: 1, its technical problem that will solve is the problem of glipizide uniform content, for this reason, it adopts the method for bilayer tablet to be prepared, or the method that gradation is injected in the capsule is carried out; Therefore, its complex process, cost height.
Chinese patent CN1562034A discloses a kind of " assay method of metformin hydrochloride enteric-coated preparation of glipizide and drug release rate thereof ", it uses glipizide and metformin hydrochloride compatibility, glipizide and metformin hydrochloride amount ratio are: 1.0-5.0: 100-500, its technical problem that will solve is to reduce the metformin hydrochloride enteric-coated preparation untoward reaction of glipizide.
Chinese patent CN1602873A discloses a kind of " glipizide diabecron sustained-release preparation and preparation method thereof ", and the purpose of this slow releasing preparation is under the prerequisite of treatment, and the protective effect to stomach is provided.
The disclosed content of above patent application does not all provide the dissolution index of preparation, and practical test result does not reach 75% yet, thereby, be necessary to provide a kind of drug dose homogeneous, the metformin hydrochloride glipizide preparation that dissolution is high.
Summary of the invention
The object of the present invention is to provide a kind of preparation method of metformin hydrochloride glipizide capsule of high-dissolution.
The metformin hydrochloride glipizide capsule of high-dissolution of the present invention contains following components by weight percent:
Metformin hydrochloride 250-500
Glipizide 2.5
The preparation method of metformin hydrochloride glipizide capsule of the present invention is: get metformin hydrochloride and cross 100 mesh sieves, glipizide is crossed 200 mesh sieves or is carried out micronization processes and makes its fineness less than 200 orders, and mixing is made binding agent with the Diluted Alcohol solution of polyvidone then, the system soft material, 24 mesh sieves are granulated, and put 50～60 ℃ of oven dryings, 20 mesh sieve granulate, add 1% magnesium stearate, after the assay was approved is irritated No. 0 capsule, promptly.
Above-mentioned mixing carries out mixing according to the equivalent incremental method.
The Diluted Alcohol solution of above-mentioned polyvidone is 15% 30 POVIDONE K 30 BP/USP
30Alcoholic solution.
Above-mentioned capsule can be three kinds of specifications: glipizide 2.5mg/ metformin hydrochloride 250mg; Glipizide 2.5mg/ metformin hydrochloride 500mg; Glipizide 5.0mg/ metformin hydrochloride 500mg; Be preferably glipizide 2.5mg/ metformin hydrochloride 250mg.
In product of the present invention, glipizide and metformin hydrochloride consumption differ greatly, and wherein glipizide only accounts for 1.0% of metformin hydrochloride weight, so the uniformity of glipizide content is a key issue.
The inventor at first adopts the powder fill, since mobile poor, cause a method of double differences different big.Further, the inventor is dissolved in glipizide in the binding agent, solve the inhomogeneity problem of content with wet granulation, because glipizide is slightly soluble in ethanol, so the glipizide of recipe quantity is insoluble in the binding agent of recipe quantity, so, inventor's glipizide and metformin hydrochloride equivalent the most at last increases progressively mixing, carries out fill after adopting wet granulation, makes the medicine uniformity of dosage units good, therefore, the inventive method preferably adopts the equivalent incremental method to carry out the mixing operation.
Capsule of the present invention is because the principal agent amount is big, so the inventor do not add filler in when prescription design, adopts the direct fill of powder or the method for the back fill of granulating is screened.
In the prescription screening process, the inventor screens binding agent emphatically; The binding agent of selecting has the dilute alcohol solution of Diluted Alcohol, hypromellose solution, polyvidone, and investigates with indexs such as particle appearance, flowability and dissolutions.
Whether investigate particle appearance and be the wet feed that will make and be put on the palm porpoising three times, observing granule has the pulverizing situation.
The mobile investigation with α＜35 ℃ angle of repose, flowability is " good "; α＞35 ℃, flowability is " generally "; Mobilely carry out for the standard of " poor " α 〉=45 ℃.
Dissolution is weighed with quality standard (draft) by clinical research, promptly 45 minutes sampling and measuring, dissolution 〉=80%.
The selection result sees Table 1.
Table 1; Unit: mg
| Prescription | Prescription 1 | Prescription 2 | Prescription 3 | Prescription 4 | Prescription 5 | Prescription 6 | |
| Component | Metformin hydrochloride | 250 | 250 | 250 | 250 | 250 | 250 |
| Glipizide | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 | |
| 80% ethanol | / | In right amount | / | / | / | / | |
| 3% hypromellose solution | / | / | In right amount | / | / | / | |
| 15% polyvidone alcoholic solution | / | / | / | In right amount | In right amount | In right amount | |
| Magnesium stearate | / | / | / | 1％ | 1％ | 1％ | |
| Investigate index | Outward appearance | / | Pine, fine powder is many | Pine is frangible | Granule is neat | Granule is neat | Granule is neat |
| Angle of repose (℃) | 60 | / | / | 30 | 32 | 31 | |
| 45 minutes dissolutions (%) | / | / | / | 77.4 | 95.4 | 94.3 |
By last table result as can be known, prescription 1 be the powder fill, its mobile poor (α=60 ℃), so that a method of double differences is different greatly; Prescription 2 and 3 fine powders are many, and the granule pine, and during fill, because the vibrations of machinery, too much fine powder and granule easily produce lamination, so that grain is heavy wayward, is unfavorable for the big production of enterprise; Glipizide in the prescription 4 is crossed 100 mesh sieves, and dissolution is less than normal; The glipizide of prescription in 5 crossed 200 mesh sieves, and dissolution is more than 90%, and granule is neat, mobile might as well (α=30 ℃); Glipizide in the prescription 6 is through micronization processes, and dissolution is more than 90%.
Based on The above results, the inventor selects the alcoholic solution of polyvidone to make binding agent; On the other hand, because glipizide is water insoluble, the inventor passes through 200 mesh sieves with glipizide, or after the micronization processes, reduced drug particle size, increased specific surface area, thereby improved the dissolubility and the dissolution velocity of glipizide, reached the purpose that improves dissolution.
Simultaneously, glipizide is passed through 200 mesh sieves, or after the micronization processes, the drug dissolution basically identical; According to last table as can be known, the glipizide fineness is less than 200 orders, and then drug dissolution can't reach 90%; Therefore, determine that glipizide should sieve or micronization processes before adding.
Description of drawings
Fig. 1 is the inventive method process chart
The specific embodiment
Embodiment 1
Get metformin hydrochloride 250g and cross 100 mesh sieves, glipizide 2.5g crosses 250 mesh sieves, carries out mixing according to the equivalent incremental method then, with 15% 30 POVIDONE K 30 BP/USP
30Alcoholic solution is made binding agent, the system soft material, and 24 mesh sieves are granulated, and put 50～60 ℃ of oven dryings, and 20 mesh sieve granulate add 1% magnesium stearate, and after the assay was approved is irritated No. 0 capsule, promptly gets product.
Embodiment 2
Get metformin hydrochloride 250g and cross 100 mesh sieves, glipizide 2.5g carries out micronization processes, makes its fineness less than 200 orders, carries out mixing according to the equivalent incremental method then, with 15% 30 POVIDONE K 30 BP/USP
30Alcoholic solution is made binding agent, the system soft material, and 24 mesh sieves are granulated, and put 50～60 ℃ of oven dryings, and 20 mesh sieve granulate add 1% magnesium stearate, and after the assay was approved is irritated No. 0 capsule, promptly gets product.
Embodiment 3
Get metformin hydrochloride 350g and cross 100 mesh sieves, glipizide 2.5g carries out micronization processes, makes its fineness less than 200 orders, carries out mixing according to the equivalent incremental method then, with 15% 30 POVIDONE K 30 BP/USP
30Alcoholic solution is made binding agent, the system soft material, and 24 mesh sieves are granulated, and put 50～60 ℃ of oven dryings, and 20 mesh sieve granulate add 1% magnesium stearate, and after the assay was approved is irritated No. 0 capsule, promptly gets product.
Embodiment 4
Get metformin hydrochloride 500g and cross 100 mesh sieves, glipizide 2.5g crosses 200 mesh sieves, carries out mixing according to the equivalent incremental method then, with 15% 30 POVIDONE K 30 BP/USP
30Alcoholic solution is made binding agent, the system soft material, and 24 mesh sieves are granulated, and put 50～60 ℃ of oven dryings, and 20 mesh sieve granulate add 1% magnesium stearate, and after the assay was approved is irritated No. 0 capsule, promptly gets product.
Experimental example
In the double blinding clinical trial of 24 all initial treatments by a definite date that the product of use embodiment of the invention 1-4 carries out and the double blinding clinical trial of 18 all two wires treatments by a definite date, except that hypoglycemic activity, some other common side effect, for example, the ratio of upper respiratory tract infection, diarrhoea, dizziness/headache, hypertension, nausea, skeletal muscle pain and urinary tract infection symptom is than METAGLIP (U.S. Bristol-Myers Squibb company, the compound recipe that glipizide and metformin are formed, glipizide 5mg/ metformin 500mg) product on average reduces 40-70%.
Adopt the UV method to measure the dissolution and the content of the product of embodiment of the invention 1-4, adopt the HPLC method to measure the dissolution and the content of glipizide, catabolite is all measured with the HPLC method, dissolution, content and catabolite are all up to specification as a result, the glipizide dissolution is respectively 98.36%, 97.63%, 99.36%, 99.30%, and the metformin hydrochloride dissolution is respectively 99.79%, 97.95%, 101.6%, 103.1%.
Glipizide is carried out the uniformity of dosage units inspection, and the result is up to specification.
Through the preliminarily stabilised investigation, the result shows, product of the present invention under each influence factor's condition, place 10 days, accelerated test 6 months, room temperature place 6 months all investigate index with 0 day than having no significant change, illustrate that this product has good stability.
Claims (6)
1, a kind of metformin hydrochloride glipizide capsule of high-dissolution is characterized in that, described metformin hydrochloride glipizide capsule contains following component: metformin hydrochloride 250-500 weight portion, glipizide 2.5 weight portions; Get metformin hydrochloride and cross 100 mesh sieves, glipizide is crossed 200 mesh sieves or is carried out micronization processes and makes its fineness less than 200 orders, and mixing is made binding agent with the Diluted Alcohol solution of polyvidone then, the system soft material, 24 mesh sieves are granulated, and put 50～60 ℃ of oven dryings, 20 mesh sieve granulate, add 1% magnesium stearate, after the assay was approved is irritated No. 0 capsule, promptly.
2, capsule according to claim 1 is characterized in that, described blending manner is to carry out mixing according to the equivalent incremental method.
3, capsule according to claim 1 is characterized in that, the Diluted Alcohol solution of described polyvidone is 15% 30 POVIDONE K 30 BP/USP
30Alcoholic solution.
4, a kind of metformin hydrochloride glipizide capsule preparation method of high-dissolution is characterized in that, described metformin hydrochloride glipizide capsule contains following component: metformin hydrochloride 250-500 weight portion, glipizide 2.5 weight portions; Get metformin hydrochloride and cross 100 mesh sieves, glipizide is crossed 200 mesh sieves or is carried out micronization processes and makes its fineness less than 200 orders, and mixing is made binding agent with the Diluted Alcohol solution of polyvidone then, the system soft material, 24 mesh sieves are granulated, and put 50～60 ℃ of oven dryings, 20 mesh sieve granulate, add 1% magnesium stearate, after the assay was approved is irritated No. 0 capsule, promptly.
5, preparation method according to claim 4 is characterized in that, described blending manner is to carry out mixing according to the equivalent incremental method.
6, preparation method according to claim 4 is characterized in that, the Diluted Alcohol solution of described polyvidone is 15% 30 POVIDONE K 30 BP/USP
30Alcoholic solution.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005101057968A CN1331470C (en) | 2005-09-29 | 2005-09-29 | Method for preparing high stripping-degree hautriwaic glipizide capsule |
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|---|---|---|---|
| CNB2005101057968A CN1331470C (en) | 2005-09-29 | 2005-09-29 | Method for preparing high stripping-degree hautriwaic glipizide capsule |
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| CN1742730A true CN1742730A (en) | 2006-03-08 |
| CN1331470C CN1331470C (en) | 2007-08-15 |
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| CNB2005101057968A Expired - Fee Related CN1331470C (en) | 2005-09-29 | 2005-09-29 | Method for preparing high stripping-degree hautriwaic glipizide capsule |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102416007A (en) * | 2011-12-12 | 2012-04-18 | 珠海润都制药股份有限公司 | Metformin hydrochloride enteric-coated capsules |
| CN105213335A (en) * | 2015-09-28 | 2016-01-06 | 宁夏康亚药业有限公司 | Glipizide tablet and preparation method thereof and application |
| CN107714666A (en) * | 2016-08-11 | 2018-02-23 | 迪沙药业集团有限公司 | A kind of Glipizide composition |
| CN108451923A (en) * | 2018-05-31 | 2018-08-28 | 常州兰陵制药有限公司 | Metformin hydrochloride quick-release capsules and preparation method thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1602873A (en) * | 2004-07-23 | 2005-04-06 | 海南国栋药物研究所有限公司 | Sustained release preparation of glipizide/metformin hydrochloride and its preparation method |
-
2005
- 2005-09-29 CN CNB2005101057968A patent/CN1331470C/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102416007A (en) * | 2011-12-12 | 2012-04-18 | 珠海润都制药股份有限公司 | Metformin hydrochloride enteric-coated capsules |
| CN102416007B (en) * | 2011-12-12 | 2014-08-20 | 珠海润都制药股份有限公司 | Metformin hydrochloride enteric-coated capsules |
| CN105213335A (en) * | 2015-09-28 | 2016-01-06 | 宁夏康亚药业有限公司 | Glipizide tablet and preparation method thereof and application |
| CN107714666A (en) * | 2016-08-11 | 2018-02-23 | 迪沙药业集团有限公司 | A kind of Glipizide composition |
| CN108451923A (en) * | 2018-05-31 | 2018-08-28 | 常州兰陵制药有限公司 | Metformin hydrochloride quick-release capsules and preparation method thereof |
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| Publication number | Publication date |
|---|---|
| CN1331470C (en) | 2007-08-15 |
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Assignee: Guangdong Aimin Pharmaceutical Co., Ltd. Assignor: Zhou Zhuohe Contract fulfillment period: 2008.10.20 to 2014.10.20 contract change Contract record no.: 2009440001747 Denomination of invention: Method for preparing high stripping-degree hautriwaic glipizide capsule Granted publication date: 20070815 License type: Exclusive license Record date: 20091026 |
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Free format text: EXCLUSIVE LICENSE; TIME LIMIT OF IMPLEMENTING CONTACT: 2008.10.20 TO 2014.10.20; CHANGE OF CONTRACT Name of requester: GUANGDONG AIMIN MEDICINE CO., LTD. Effective date: 20091026 |
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Assignee: Guangdong Aimin Pharmaceutical Co., Ltd. Assignor: Zhou Zhuohe Contract record no.: 2009440001747 Date of cancellation: 20100416 |
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