CN108836973B - Metformin-glibenclamide capsule and preparation method thereof - Google Patents
Metformin-glibenclamide capsule and preparation method thereof Download PDFInfo
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- CN108836973B CN108836973B CN201810989728.XA CN201810989728A CN108836973B CN 108836973 B CN108836973 B CN 108836973B CN 201810989728 A CN201810989728 A CN 201810989728A CN 108836973 B CN108836973 B CN 108836973B
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- glibenclamide
- metformin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Abstract
The invention discloses a metformin-glibenclamide capsule and a preparation method thereof, wherein the metformin-glibenclamide capsule comprises the following components in parts by weight: 250 parts of metformin hydrochloride; 1.25 parts of glibenclamide per 2.5 parts of glibenclamide; 10 parts of microcrystalline cellulose; 8 parts of cross-linked povidone; 8 parts of polyvidone; 3 parts of magnesium stearate; the preparation method comprises the following steps: (1) mixing metformin hydrochloride, microcrystalline cellulose and crospovidone to obtain mixed powder; (2) dissolving glibenclamide and povidone in an ethanol water solution, then mixing the solution and the mixed powder and preparing into granules; (3) and adding magnesium stearate into the granules, and uniformly mixing to prepare the metformin glibenclamide capsule. According to the invention, by optimizing the formula and the preparation process of the metformin glibenclamide capsule, the problem that glibenclamide is sensitive to damp and heat is solved, the dissolution rate is effectively improved, the content uniformity is improved, and especially the problem that the content of the impurity I in glibenclamide is easy to increase is solved.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a metformin-glibenclamide capsule and a preparation method thereof.
Background
Diabetes is a chronic disease second only to cardiovascular disease, and WHO survey results show that there are billions of diabetic patients worldwide, 90% of which are type II diabetic patients. Because the treatment of diabetes is a long-term process and various medicines have physical tolerance, the longer the use time is, the worse the curative effect is, different types of hypoglycemic medicines are generally advocated to be combined clinically, wherein the most intensive research is the combined use of sulfonylurea and metformin.
Glibenclamide is the representative of the second-generation sulfonylurea oral hypoglycemic drugs, is marketed in Europe in the 60 s of the 20 th century, is listed as a national basic drug, has the advantages of quick absorption, high plasma protein binding rate, low toxicity and the like, and is mainly suitable for light and severe type II diabetes with unsatisfied curative effect by single diet control.
Glibenclamide is white crystalline powder, almost odorless, tasteless, slightly soluble in ethanol, and insoluble in water. Glibenclamide is stable in storage under normal conditions, but is sensitive to humidity and is easily hydrolyzed to generate impurities I: 4- [2 (5-chloro-2-methoxybenzamide) -ethyl ] -benzenesulfonamide, and therefore, its formulation such as a capsule requires raw materials to be specifically protected from high-temperature, high-humidity degradation during the production process.
The glibenclamide in the metformin-glibenclamide capsule is a small-dose medicament and only accounts for 1/100 of the weight of the capsule, and although the preparation method of the metformin-glibenclamide capsule is disclosed in the prior art, the problems of unqualified content uniformity of the glibenclamide, low dissolution rate, poor stability (the content of the impurity I is obviously increased) and the like can be caused due to the limitations of processes, technologies and the like in the production of the existing capsule.
Chinese patent document CN101757002A discloses a metformin-glibenclamide capsule and a preparation method thereof, and the document can provide a metformin-glibenclamide capsule with controllable weight difference, controllable content uniformity, excellent dissolution performance and stable quality. The disadvantages of this document are: on one hand, a special feeding device is needed in the preparation process, and the requirement on equipment is high; on the other hand, the dissolution rate of glibenclamide is improved, but is not ideal, and the maximum dissolution rate is not more than 92%.
Chinese patent document CN105030793A discloses a metformin-glibenclamide capsule and a preparation method thereof, and the document can also provide a metformin-glibenclamide capsule which has the advantages of stable drug release, controllable weight difference, excellent dissolution performance and stable quality. The disadvantages of this document are: on one hand, the dissolution rate of glibenclamide is still not ideal and still does not exceed 92%; on the other hand, quality stability issues are not mentioned, which usually means that it is not ideal.
Disclosure of Invention
The invention aims to solve the problems and provides a metformin-glibenclamide capsule which has good content uniformity of glibenclamide, high dissolution rate and stable quality, and particularly has no obvious increase of the content of impurity I of glibenclamide, and a preparation method thereof.
The technical scheme for realizing the purpose of the invention is as follows: the metformin glibenclamide capsule comprises the following components in parts by weight: 250 parts of metformin hydrochloride; 1.25 parts of glibenclamide per 2.5 parts of glibenclamide; 10 parts of microcrystalline cellulose; 8 parts of crospovidone; 8 parts of polyvidone; and 3 parts of magnesium stearate.
Wherein, when the dosage of the microcrystalline cellulose exceeds 10 parts, and/or the dosage of the crospovidone is less than 8 parts, and/or the dosage of the povidone is less than 8 parts, and/or the dosage of the magnesium stearate is less than 3 parts, based on 250 parts of the metformin hydrochloride, the dissolution rate and the content uniformity of the glibenclamide are influenced.
The metformin hydrochloride, the microcrystalline cellulose, the crospovidone and the magnesium stearate are respectively sieved by a 40-mesh sieve.
The preparation method of the metformin glibenclamide capsule comprises the following steps:
(1) mixing the metformin hydrochloride, the microcrystalline cellulose and the crospovidone in parts by weight to obtain mixed powder;
(2) dissolving the glibenclamide and the povidone in parts by weight in an ethanol water solution, mixing the solution with the mixed powder obtained in the step (1) and preparing into particles;
(3) and (3) adding the magnesium stearate in parts by weight into the granules obtained in the step (2), uniformly mixing, and filling the capsules according to the preset granule weight to obtain the metformin glibenclamide capsules.
And (2) respectively sieving the metformin hydrochloride, the microcrystalline cellulose and the crospovidone in the step (1) by a 40-mesh sieve.
The mixing in the step (1) is to add the metformin hydrochloride, the microcrystalline cellulose and the crospovidone into the fluidized bed, set the air intake at 50 percent and the boiling time at 30min, and mix uniformly.
The ethanol water solution in the step (2) is prepared by ethanol and water according to the weight ratio of 95: 5-80: 20.
The granules prepared in the step (2) are granulated by adopting a fluidized bed, the air inlet amount is set to be 40%, the air inlet temperature is set to be 50 ℃, the boiling time is 5min, the oscillation time is 5s, the liquid spraying speed is 0.2kg/min, the atomization pressure is 1.5bar, and the pressure difference of a filter bag is 200Pa.
And (4) sieving the magnesium stearate in the step (3) by a 40-mesh sieve.
The capsule filled in the step (3) is a No. 1 capsule.
The metformin-glibenclamide capsule prepared in the step (3) is packaged by a PTP blister or a high-density polyethylene plastic bottle.
The invention has the following positive effects: the formula is optimized on one hand, and particularly the weight ratio of each auxiliary material is optimized; on the other hand, the preparation process is optimized, particularly the metformin hydrochloride and the glibenclamide are respectively treated and then mixed for granulation, the problem that the glibenclamide is sensitive to humidity and heat is solved, the dissolution rate of the glibenclamide is effectively improved, the content uniformity of the glibenclamide is improved, and particularly the problem that the content of the glibenclamide impurity I is easily increased in the production and storage processes is solved.
Detailed Description
(example 1)
The specification of the metformin glibenclamide capsule of this example is as follows: each capsule contains 250mg of metformin hydrochloride/1.25 mg of glibenclamide.
The formulation is shown in table 1.
TABLE 1
| Components | Weight (kg) |
| Metformin hydrochloride | 25.0 |
| Glibenclamide | 0.125 |
| Microcrystalline cellulose | 1.0 |
| Cross-linked polyvidone | 0.8 |
| Povidone | 0.8 |
| Magnesium stearate | 0.3 |
| Is made into | 10 ten thousand pills |
The preparation method comprises the following steps:
(1) weighing 25kg of metformin hydrochloride, 1kg of microcrystalline cellulose and 0.8kg of crospovidone, adding into an FLZB-50 fluidized bed, setting the air intake at 50% and the boiling time at 30min, and uniformly mixing to obtain mixed powder.
Wherein, the metformin hydrochloride, the microcrystalline cellulose and the crospovidone are respectively sieved by a 40-mesh sieve.
(2) Weighing 0.125kg of glibenclamide and 0.8kg of povidone, adding 7.2kg of medicinal ethanol (80 wt%) to prepare a solution, mixing the solution with the mixed powder obtained in the step (1), and granulating by adopting a fluidized bed, wherein the air inlet amount is set to be 40%, the air inlet temperature is 50 ℃, the boiling time is 5min, the oscillation time is 5s, the liquid spraying speed is 0.2kg/min, the atomization pressure is 1.5bar, and the pressure difference of a filter bag is 200Pa.
And (5) starting drying after granulation is finished, and stopping drying when the air outlet temperature rises to 8 ℃ to obtain the particles.
(3) And (3) adding 0.3kg of magnesium stearate into the granules obtained in the step (2), setting the air intake to be 50%, boiling and mixing for 5min, and then discharging. And (3) granulating the granules by a quick granulator, wherein the aperture of a screen is 1.5mm, and the granulating power is 30Hz, so as to obtain the final total mixed granules. The capsules are filled by a capsule filling machine. Wherein, the magnesium stearate is sieved by a 40-mesh sieve.
And finally, performing quality detection on the prepared metformin glibenclamide capsule, and packaging the metformin glibenclamide capsule by using a high-density polyethylene plastic bottle after the metformin glibenclamide capsule is detected to be qualified.
(example 2)
The specification of the metformin glibenclamide capsule of this example is as follows: each capsule contains 250mg of metformin hydrochloride/2.5 mg of glibenclamide.
The formulation is shown in Table 2.
TABLE 2
| Components | Weight (kg) |
| Metformin hydrochloride | 25.0 |
| Glibenclamide | 0.25 |
| Microcrystalline cellulose | 1.0 |
| Cross-linked polyvidone | 0.8 |
| Povidone | 0.8 |
| Magnesium stearate | 0.3 |
| Is made into | 10 ten thousand pills |
The preparation method comprises the following steps:
(1) weighing 25kg of metformin hydrochloride, 1kg of microcrystalline cellulose and 0.8kg of crospovidone, adding into an FLZB-50 fluidized bed, setting the air intake at 50% and the boiling time at 30min, and uniformly mixing to obtain mixed powder.
Wherein, the metformin hydrochloride, the microcrystalline cellulose and the crospovidone are respectively sieved by a 40-mesh sieve.
(2) Weighing 0.25kg of glibenclamide and 0.8kg of povidone, adding 7.2kg of medicinal ethanol (95 wt%) to prepare a solution, mixing the solution with the mixed powder obtained in the step (1), and granulating by adopting a fluidized bed, wherein the air inlet amount is set to be 60%, the air inlet temperature is 40 ℃, the boiling time is 5min, the oscillation time is 5s, the liquid spraying speed is 0.25kg/min, the atomization pressure is 1.5bar, and the pressure difference of a filter bag is 200Pa.
And (5) starting drying after granulation is finished, and stopping drying when the air outlet temperature rises to 8 ℃ to obtain the particles.
(3) And (3) adding 0.3kg of magnesium stearate into the granules obtained in the step (2), setting the air intake to be 50%, boiling and mixing for 5min, and then discharging. And (3) granulating the granules by a quick granulator, wherein the aperture of a screen is 1.5mm, and the granulating power is 30Hz, so as to obtain the final total mixed granules. The capsules are filled by a capsule filling machine. Wherein, the magnesium stearate is sieved by a 40-mesh sieve.
And finally, performing quality detection on the prepared metformin glibenclamide capsule, and packaging the metformin glibenclamide capsule by using a PTP bubble cap after the metformin glibenclamide capsule is detected to be qualified.
Comparative example 1
The formulation of this comparative example is the same as example 1, the main difference in the preparation method being: the metformin hydrochloride and the glibenclamide are added into the fluidized bed for granulation at the same time.
(test example 1)
The metformin glibenclamide capsules prepared in examples 1 and 2 and comparative example 1 were tested for dissolution and content uniformity of glibenclamide (the determination method was according to page 17 of the second part of the "chinese pharmacopoeia" 2015), and the results are shown in table 3.
TABLE 3
| Sample (I) | Dissolution rate of glibenclamide (%) | Content uniformity of glibenclamide (A + 2.2S) |
| Example 1 | 97；98；95；97；98；98； | 6.8 |
| Example 2 | 96；95；97；96；98；95； | 5.7 |
| Comparative example 1 | 83；87；80；73；91；80； | 17.5 |
As can be seen from table 3: in the metformin glibenclamide capsule product prepared by the invention, the content uniformity of the small-dose medicament glibenclamide is good, the dissolution rate is high, the data uniformity is good, and the product quality requirement is met.
(test example 2)
The metformin glibenclamide capsules prepared in examples 1 and 2 and comparative example 1 were tested for quality stability (the determination method was according to the "chinese pharmacopoeia" 2015 second part, page 17).
In a stability test box with the temperature of 25 +/-2 ℃ and the relative humidity of 60 +/-5%, long-term test for 36 months is carried out, the content index of the impurity I is inspected, and the result is shown in a table 4.
TABLE 4
As can be seen from table 4: the metformin-glibenclamide capsule prepared by the invention has stable product quality, the content of the impurity I is not obviously increased in 36-month storage period, and the index is superior to the pharmacopeia quality standard (the content of the impurity I is less than or equal to 0.6%).
Claims (10)
1. The metformin-glibenclamide capsule is characterized by comprising the following components in parts by weight: 250 parts of metformin hydrochloride; 1.25 parts/2.5 parts of glibenclamide; 10 parts of microcrystalline cellulose; 8 parts of cross-linked povidone; 8 parts of polyvidone; 3 parts of magnesium stearate;
the preparation method of the metformin-glibenclamide capsule comprises the following steps:
(1) mixing the metformin hydrochloride, the microcrystalline cellulose and the crospovidone in parts by weight to obtain mixed powder;
(2) dissolving the glibenclamide and the povidone in parts by weight in an ethanol water solution, mixing the solution with the mixed powder obtained in the step (1) and preparing into particles;
(3) and (3) adding the magnesium stearate in parts by weight into the granules obtained in the step (2), uniformly mixing, and filling the capsules according to the preset granule weight to obtain the metformin glibenclamide capsules.
2. The metformin glibenclamide capsule according to claim 1, characterized in that: the metformin hydrochloride, the microcrystalline cellulose, the crospovidone and the magnesium stearate are respectively sieved by a 40-mesh sieve.
3. The process for preparing metformin glibenclamide capsules according to claim 1, comprising the steps of:
(1) mixing the metformin hydrochloride, the microcrystalline cellulose and the crospovidone in parts by weight to obtain mixed powder;
(2) dissolving the glibenclamide and the povidone in parts by weight in an ethanol water solution, and then mixing the solution with the mixed powder obtained in the step (1) to prepare particles;
(3) and (3) adding the magnesium stearate in parts by weight into the granules obtained in the step (2), uniformly mixing, and filling capsules according to the preset granule weight to obtain the metformin-glibenclamide capsules.
4. The method for producing a metformin glibenclamide capsule according to claim 3, characterized in that: and (2) respectively sieving the metformin hydrochloride, the microcrystalline cellulose and the crospovidone in the step (1) by a 40-mesh sieve.
5. The method for producing a metformin glibenclamide capsule according to claim 3, characterized in that: the mixing in the step (1) is to add the metformin hydrochloride, the microcrystalline cellulose and the crospovidone into the fluidized bed, set the air intake at 50 percent and the boiling time at 30min, and mix uniformly.
6. The method for producing a metformin glibenclamide capsule according to claim 3, characterized in that: the ethanol water solution in the step (2) is prepared by ethanol and water according to the weight ratio of 95: 5-80: 20.
7. The method for producing a metformin glibenclamide capsule according to claim 3, characterized in that: the granules prepared in the step (2) are granulated by adopting a fluidized bed, the air inlet amount is set to be 40%, the air inlet temperature is set to be 50 ℃, the boiling time is 5min, the oscillation time is 5s, the liquid spraying speed is 0.2kg/min, the atomization pressure is 1.5bar, and the pressure difference of a filter bag is 200Pa.
8. The method for producing a metformin glibenclamide capsule according to claim 3, characterized in that: and (4) sieving the magnesium stearate in the step (3) by a 40-mesh sieve.
9. The method for producing a metformin glibenclamide capsule according to claim 3, characterized in that: the capsule filled in the step (3) is a No. 1 capsule.
10. The method for producing a metformin glibenclamide capsule according to claim 3, characterized in that: the metformin glibenclamide capsule prepared in the step (3) is packaged by a PTP blister or a high-density polyethylene plastic bottle.
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| CN108836973B true CN108836973B (en) | 2022-12-02 |
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| CN112402433B (en) * | 2020-12-07 | 2023-01-24 | 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 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101374523A (en) * | 2005-09-14 | 2009-02-25 | 武田药品工业株式会社 | Dipeptidyl peptidase inhibitors for treating diabetes |
| CN101757002A (en) * | 2010-01-04 | 2010-06-30 | 南昌弘益科技有限公司 | Metformin-glibenclamide capsule and preparation method thereof |
| CN105030793A (en) * | 2015-08-25 | 2015-11-11 | 瑞阳制药有限公司 | Metformin hydrochloride and glibenclamide capsule and preparation method thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101374523A (en) * | 2005-09-14 | 2009-02-25 | 武田药品工业株式会社 | Dipeptidyl peptidase inhibitors for treating diabetes |
| CN101757002A (en) * | 2010-01-04 | 2010-06-30 | 南昌弘益科技有限公司 | Metformin-glibenclamide capsule and preparation method thereof |
| CN105030793A (en) * | 2015-08-25 | 2015-11-11 | 瑞阳制药有限公司 | Metformin hydrochloride and glibenclamide capsule and preparation method thereof |
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