CN109010298B - Metformin and glipizide compound composition and preparation method thereof - Google Patents
Metformin and glipizide compound composition and preparation method thereof Download PDFInfo
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- CN109010298B CN109010298B CN201811009420.0A CN201811009420A CN109010298B CN 109010298 B CN109010298 B CN 109010298B CN 201811009420 A CN201811009420 A CN 201811009420A CN 109010298 B CN109010298 B CN 109010298B
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- glipizide
- metformin hydrochloride
- magnesium stearate
- coating layer
- tablet core
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
-
- 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
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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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 relates to a metformin glipizide compound tablet for treating diabetes and a preparation method thereof, belonging to the technical field of medicines. The technical scheme of the invention is as follows: the metformin hydrochloride and glipizide compound tablet composition consists of a tablet core and a coating layer, wherein the tablet core contains metformin hydrochloride and magnesium stearate added in the tablet core, and the coating layer contains glipizide. The invention improves the stability of drug release, improves the compressibility of the product and the content uniformity of glipizide, and provides a good medicine for clinic.
Description
Technical Field
The invention relates to a metformin glipizide compound tablet for treating diabetes and a preparation method thereof, belonging to the technical field of medicines.
Background
Diabetes mellitus is a metabolic disease characterized by hyperglycemia, resulting from defective insulin secretion or impaired biological action, or both factors. Chronic hyperglycemia easily causes chronic damage to body tissues, particularly kidney, heart, blood vessels and the like, and is considered as a third major killer which is harmful to human health after tumors and cardiovascular and cerebrovascular diseases.
The metformin hydrochloride and glipizide compound preparation is a medicine for improving the blood sugar of a type 2 diabetes patient on the market in recent years, the action mechanisms of the two medicines are complementary, and the medication compliance of the patient is greatly improved while the convenience is improved.
Metformin hydrochloride is white needle-shaped crystals, tablets containing metformin hydrochloride components are prone to reduction of compressibility of the tablets due to the needle-shaped crystals, and the phenomenon of 'top crack' of tabletting is prone to occurring, conventional solutions include universal pulverization treatment, control of particle moisture at a high level, improvement of environmental humidity, reduction of speed of a tabletting machine and the like, but the conventional solutions are prone to reduction of particle fluidity due to improvement of moisture, high energy consumption due to improvement of environmental humidity, reduction of speed of the tabletting machine and low production efficiency, and the measures are often poor in effect. Meanwhile, the hardness is increased and the drug release speed is reduced due to recrystallization polymerization of the metformin hydrochloride component in the product, so that the product quality is reduced, the specific surface area of the pulverized metformin hydrochloride is increased, and the recrystallization polymerization is accelerated. The average hardness of a tablet core of a American same-variety reference preparation (glipizide and metformin hydrochloride tablet, TEVA PHARMACEUTICAL USA) is about 130 newtons, the storage condition of the preparation is required to be 20-25 ℃, the research finds that the preparation has a slow release rate under the condition of acceleration (40 ℃/75% RH), and in China with a large area, the storage temperature range required by the original preparation is difficult to maintain all the time in the storage or transportation process, so that the risk of unstable release of the preparation is caused.
Technical scheme
The purpose of the invention is as follows: overcomes the defects of the prior art, takes the average hardness of a reference preparation of 130 newtons as the minimum hardness requirement, solves the problems of top crack in the prior tabletting process and instability in the storage process on the premise of ensuring the dissolution rate of the product, and provides the metformin hydrochloride and glipizide compound preparation which has stable drug release performance and is suitable for industrial production.
The technical scheme is as follows:
the applicant unexpectedly finds that the unconventional use of magnesium stearate, namely, the range of 0.25-0.5% (W/W) of the conventional use amount of magnesium stearate as a lubricant is broken through, and the drug release stability and the product compressibility of the metformin hydrochloride and glipizide compound tablet are well improved. The rationale is that a modest increase in magnesium stearate can block agglomeration between metformin hydrochloride particles and prevent further recrystallization processes. The use of the traditional Chinese medicine composition within a certain range does not cause the problem of reduction of compressibility, but has superior blocking effect, and the compressibility of the product is improved unexpectedly. Meanwhile, the glipizide component in the prescription is homogenized by adopting a premixing agent with a film coating and then is added by spraying, so that the content uniformity of the glipizide is ensured, and finally, a qualified product with stable release, good compressibility and good content uniformity is obtained.
The technical scheme of the invention is as follows: the metformin hydrochloride and glipizide compound tablet composition consists of a tablet core and a coating layer, wherein the tablet core contains metformin hydrochloride and magnesium stearate added in the tablet core, and the coating layer contains glipizide.
In the metformin hydrochloride and glipizide compound tablet composition, in the composition with unit dose, a tablet core contains 500mg of metformin hydrochloride, 25-40mg of magnesium stearate (internal addition), 65-80mg of microcrystalline cellulose, 53mg of corn starch, 22.7mg of croscarmellose sodium, 12.3mg of povidone and 7mg of magnesium stearate (external addition); the coating layer contains 2.5mg of glipizide and 21mg of film coating premix with the model number of 85F 18422.
Preferably, the metformin hydrochloride and glipizide compound tablet composition disclosed by the invention comprises a tablet core and a coating layer in a unit dose composition, wherein the tablet core in the unit dose composition contains 500mg of metformin hydrochloride, 27-33mg of magnesium stearate (internal addition), 75-78mg of microcrystalline cellulose, 53mg of corn starch, 22.7mg of croscarmellose sodium, 12.3mg of povidone and 7mg of magnesium stearate (external addition); the coating layer contains 2.5mg of glipizide and 21mg of film coating premix with the model number of 85F 18422.
The film coated premix of the invention, model 85F18422, was purchased from Shanghai Kalekang coating technology, Inc.
The preparation method of the metformin hydrochloride and glipizide compound tablet comprises the following steps:
step 1: uniformly mixing metformin hydrochloride with an internal addition amount of magnesium stearate in a wet mixing granulator;
step 2: uniformly mixing the mixture obtained in the step 1 and the microcrystalline cellulose, the corn starch and the croscarmellose sodium in the formula amount of the tablet core in a wet mixing granulator;
and step 3: preparing a formula amount of povidone into a 7.5% aqueous solution, adding the aqueous solution into the mixture obtained in the step 2, performing wet granulation, drying the mixture by a fluidized bed until the moisture of the granules is 2.5-4.5%, granulating the granules by a rapid granulator, adding a formula amount of magnesium stearate (additionally), uniformly mixing, and tabletting at the machine speed of 25 ten thousand tablets/hour, wherein the target hardness is not lower than 130N;
and 4, step 4: preparing a film coating premix solution (the film coating premix of the prescription amount is uniformly mixed with purified water and has the concentration of 12% (W/W)), slowly adding glipizide of the prescription amount into the film coating premix solution, stirring and uniformly dispersing the glipizide by a colloid mill to obtain a film coating premix solution containing active ingredients, and coating an outer coating layer containing a medicine.
According to the preparation method of the metformin hydrochloride and glipizide compound tablet, the coating of the outer coating layer containing medicine is completed in an atomization spraying mode.
Has the advantages that:
according to the implementation of the technical scheme, the preparation of the mixture of the metformin hydrochloride and the magnesium stearate improves the stability of drug release, improves the compressibility of the product and provides a good medicine for clinic.
Because the main drug glipizide is small in specification, the prescription accounts for only 0.36%, and the internal addition is not easy to mix uniformly, the glipizide injection solution is added in a mode of atomizing and spraying coating powder, so that the content uniformity of glipizide is ensured.
Examples
1000 tablets of the products of examples 1-5 and comparative examples 1-2 were prepared according to the recipe given in Table 1 and the preparation method described in the technical scheme.
TABLE 1 formulation composition of examples and comparative examples
Note 1 is the solvent for the binder, which is removed during the granulation drying process.
Note 2 is the coating solvent, which is removed during the coating process.
The recipe of comparative example 4 and reference example 3 is as follows:
tablet core: 500g of metformin hydrochloride, 2.5g of glipizide, 32.5g of magnesium stearate, 72.5g of microcrystalline cellulose, 53g of corn starch, 22.7g of croscarmellose sodium, 12.3g of povidone and 7.0g of additional magnesium stearate; film coating premix 85F 1842221 g, and 1000 tablets were prepared as follows
Step 1: uniformly mixing metformin hydrochloride with an internal addition amount of magnesium stearate in a wet mixing granulator;
step 2: uniformly mixing the mixture obtained in the step 1 and glipizide, microcrystalline cellulose, corn starch and croscarmellose sodium in a wet mixing granulator according to the formula amount of the tablet core;
and step 3: preparing a formula amount of povidone into a 7.5% aqueous solution, adding the aqueous solution into the mixture obtained in the step 2, performing wet granulation, drying the mixture by a fluidized bed until the moisture of the granules is 2.5-4.5%, granulating the granules by a rapid granulator, adding a formula amount of magnesium stearate (additionally), uniformly mixing, and tabletting at the machine speed of 25 ten thousand tablets/hour, wherein the target hardness is not lower than 130N;
and 4, step 4: preparing a film coating premix solution (the film coating premix of the prescription amount is uniformly mixed with purified water, the concentration is 12% (W/W)), uniformly stirring and dispersing by a colloid mill to obtain a film coating premix solution containing active ingredients, and atomizing and spraying the film coating premix solution into a coating.
Test example 1. dissolution test of tablets prepared in examples 1 to 5 and comparative examples 1 to 3:
dissolution conditions: the dissolution rates of samples at the end of 3 months and at the end of 6 months in 0 day and accelerated tests (40 ℃ +/-2 ℃/RH75 +/-5%) are respectively tested by a PH6.8 medium and a paddle method of 50 revolutions (a second method of 0931 on the version of Chinese pharmacopoeia 2015), and the cumulative dissolution rates of metformin hydrochloride and glipizide at 45min are counted by referring to the standard of USP40-NF35 in the United states pharmacopoeia, wherein the data are shown in Table 2.
TABLE 2 dissolution under accelerated test conditions of examples and comparative examples
Test example 2
Evaluation of content, content uniformity and plain film hardness in examples 1 to 5 and comparative examples 1 to 4
The determination method comprises the following steps: and (3) determining and evaluating the content and content uniformity of glipizide and the content of metformin hydrochloride by referring to the standard of United states pharmacopoeia USP40-NF35, and monitoring and evaluating the hardness of the tablet.
TABLE 3 evaluation of content, content uniformity and tablet hardness
The data in tables 2 and 3 show that the release stability of the metformin hydrochloride and the glipizide is better than that of the control examples 1 to 2 and the reference preparation when the weight ratio of the metformin hydrochloride to the magnesium stearate is 100:5.0 to 100:8.0 in the examples 1 to 5 compared with that of the control examples 1 to 4, and the release stability of the metformin hydrochloride and the glipizide is optimal when the weight ratio is 100:5.6 to 100: 7.4.
Compared with compressibility, when the weight ratio of the metformin hydrochloride to the magnesium stearate is 100: 5.0-100: 8.0, the compressibility problem of the product can be solved, the hardness is consistent with or better than that of a reference preparation, the dosage of the magnesium stearate is continuously increased, and the compressibility shows a descending trend.
The data in table 3 show that the preparation method of the invention solves the problem of overproof content uniformity by adding glipizide along with a coating mode.
In conclusion, the weight ratio of the metformin hydrochloride to the magnesium stearate is 100: 5.0-100: 8.0, and the high-quality product with stable release and good compressibility is obtained in the comparative examples and comparative examples, thereby achieving the purpose of the invention.
The friability of the tablet is an index reflecting the shock resistance and wear resistance of the tablet, and the smaller the friability value is, the better the wear resistance of the tablet is. The data in Table 3 show that the friability of the tablets prepared in inventive examples 1-5 is significantly better than the values of comparative examples 1, 2, 4. Namely, under the condition of ensuring the dissolution rate, the wear resistance of the product of the embodiment of the invention is better than that of the comparative example, which is beneficial to keeping the product still firm in the transportation process.
Claims (3)
1. The metformin hydrochloride and glipizide compound tablet composition is characterized by comprising a tablet core and a coating layer, wherein the tablet core contains metformin hydrochloride and added magnesium stearate, the coating layer contains glipizide, and in the composition with unit dose, the tablet core contains 500mg of metformin hydrochloride, 25-40mg of added magnesium stearate, 65-80mg of microcrystalline cellulose, 53mg of corn starch, 22.7mg of croscarmellose sodium, 12.3mg of povidone and 7mg of additional magnesium stearate; the coating layer contains 2.5mg of glipizide and 21mg of film coating premix with the model number of 85F 18422.
2. The metformin hydrochloride and glipizide compound tablet composition according to claim 1, wherein the unit dose composition comprises a tablet core and a coating layer, and the tablet core comprises 500mg of metformin hydrochloride, 27-33mg of magnesium stearate added internally, 75-78mg of microcrystalline cellulose, 53mg of corn starch, 22.7mg of croscarmellose sodium, 12.3mg of povidone and 7mg of magnesium stearate added externally; the coating layer contains 2.5mg of glipizide and 21mg of film coating premix with the model number of 85F 18422.
3. The preparation method of the metformin hydrochloride and glipizide compound tablet composition as claimed in claim 1, which is characterized by comprising the following steps:
step 1: uniformly mixing metformin hydrochloride with an internal addition amount of magnesium stearate in a wet mixing granulator;
step 2: uniformly mixing the mixture obtained in the step 1 and the microcrystalline cellulose, the corn starch and the croscarmellose sodium in the formula amount of the tablet core in a wet mixing granulator;
and step 3: preparing a formula amount of povidone into a 7.5% aqueous solution, adding the aqueous solution into the mixture obtained in the step 2, performing wet granulation, drying the granules by a fluidized bed until the moisture of the granules is 2.5-4.5%, granulating by a rapid granulator, adding an additional amount of magnesium stearate, uniformly mixing, and tabletting;
and 4, step 4: the film coating premix with the prescription amount is evenly mixed with purified water to prepare coating liquid with the concentration of 12 percent, glipizide with the prescription amount is slowly added into the coating liquid, the mixture is stirred and evenly dispersed by a colloid mill to obtain film coating premix solution containing active ingredients, and the coating of the outer coating layer containing the medicine is finished in an atomization spraying mode.
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| CN110215437B (en) * | 2019-07-18 | 2021-10-08 | 北京中惠药业有限公司 | Metformin hydrochloride tablet and preparation method thereof |
| CN113616613A (en) * | 2021-08-30 | 2021-11-09 | 河南合智医药科技有限公司 | Metformin-glipizide compound tablet for treating diabetes and preparation method thereof |
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| DK1377276T3 (en) * | 2001-04-10 | 2012-01-02 | Sun Pharma Advanced Res Co Ltd | Calculation of pulse-release composition |
| US7183321B2 (en) * | 2001-12-17 | 2007-02-27 | Bristol-Myers Squibb Company | Antidiabetic formulation and method |
| CN101810628B (en) * | 2010-04-13 | 2012-05-23 | 北京四环科宝制药有限公司 | Melbine glipizide tablet and preparation method thereof |
| CN103494816B (en) * | 2013-09-29 | 2019-06-14 | 威海迪素制药有限公司 | A kind of pharmaceutical composition for treating diabetes |
| WO2015071889A1 (en) * | 2013-11-18 | 2015-05-21 | Ranbaxy Laboratories Limited | Oral compositions of saxagliptin |
| CN104473894A (en) * | 2014-12-18 | 2015-04-01 | 浙江华海药业股份有限公司 | Pioglitazone hydrochloride medicine-loading coating preparation and preparation method thereof |
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Effective date of registration: 20200902 Address after: 264205 No. 1 South Qingdao Road, Weihai economic and Technological Development Zone, Shandong, China Applicant after: DISHA PHARMACEUTICAL GROUP Co.,Ltd. Applicant after: Dijia Pharmaceutical Group Co.,Ltd. Address before: 264205 South Qingdao Road-1-4, Weihai Economic and Technological Development Zone, Weihai City, Shandong Province Applicant before: DISHA PHARMACEUTICAL GROUP Co.,Ltd. Applicant before: WEIHAI DISU PHARMACEUTICAL Co.,Ltd. |
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Effective date of registration: 20210622 Address after: No.1 Qingdao South Road, Weihai Economic and Technological Development Zone, Shandong Province Patentee after: DISHA PHARMACEUTICAL GROUP Co.,Ltd. Address before: No.1 Qingdao South Road, Weihai Economic and Technological Development Zone, Shandong Province Patentee before: DISHA PHARMACEUTICAL GROUP Co.,Ltd. Patentee before: Dijia Pharmaceutical Group Co.,Ltd. |
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Denomination of invention: Metformin glipizide compound composition and preparation method thereof Effective date of registration: 20211025 Granted publication date: 20201027 Pledgee: Bank of China Limited Weihai Branch Pledgor: DISHA PHARMACEUTICAL GROUP Co.,Ltd. Registration number: Y2021980010533 |