CN106138059A - A kind of stable Li Gelieting pharmaceutical composition - Google Patents
A kind of stable Li Gelieting pharmaceutical composition Download PDFInfo
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- CN106138059A CN106138059A CN201510137463.7A CN201510137463A CN106138059A CN 106138059 A CN106138059 A CN 106138059A CN 201510137463 A CN201510137463 A CN 201510137463A CN 106138059 A CN106138059 A CN 106138059A
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- gelieting
- pharmaceutical composition
- diluent
- mannitol
- disintegrating agent
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Abstract
The invention discloses a kind of stable Li Gelieting pharmaceutical composition and preparation method thereof.The ratio of each component, in addition to containing active component, by choosing diluent and the disintegrating agent of specific components, and is controlled, makes Li Gelieting have good stability and bioavailability by the prescription that the present invention provides.
Description
Technical field
The present invention relates to a kind of stable Li Gelieting pharmaceutical composition and preparation method thereof.
Background technology
Li Gelieting (Linagliptin) is a kind of selectivity DPP IV (DPP-IV) inhibitor, can significantly control blood glucose, only needing every day oral once, the risk occurring hypoglycemia, cardiovascular event and body weight to increase is relatively low, good market prospect.Li Gelieting is a kind of purine derivative, containing substituted quinazoline group and 3-aminopiperidine group in its compound structure, shown in its structure such as following formula (1):
(1)
Chemical name: 8-[(3R)-3-amino-piperidino]-7-(2-butynyl)-3,7-dihydro-3-methyl isophthalic acid-[(4-methyl-2-quinazolyl) methyl]-1H-purine-2,6-diketone
Molecular formula: C25H28N8O2
Molecular weight: 472.54
By the research to prior art, the stability problem of Li Gelieting preparation is still puzzlement people's urgent problem.It addition, suitably preparation method and process conditions, the kind of diluent and consumption are most important to the result of extraction of preparation.Conventional diluent lactose, microcrystalline Cellulose, starch etc., conventional disintegrating agent has microcrystalline Cellulose, carboxymethyl starch sodium etc..But, how to obtain more excellent dissolution rate by dissolution adjustment formula and the technique adjustment of described Li Gelieting, how to select suitable process conditions to avoid problem, the prior aries such as the degraded of Li Gelieting the most not to provide further prompting, in view of this, this invention of special proposition.
Summary of the invention
It is contemplated that obtain stable Li Gelieting pharmaceutical composition, improve its curative effect simultaneously.According to existing adjuvant and working condition, ensureing that there is relatively low production cost and simple preparation technology, on the premise of having been adapted for large-scale industrial production, it is necessary to work out a kind of suitable prescription composition and preparation technology, makes Li Gelieting have good stability and bioavailability.
Therefore, it is an object of the invention to provide a kind of stable Li Gelieting pharmaceutical composition, said composition is containing favourable Ge Lieting, diluent and disintegrating agent, and Li Gelieting: diluent: the weight ratio of disintegrating agent is 1:25-35:3-5, preferably weight ratio is 1:28-32:3-4, most preferably 1:28:4.
In addition, said composition is possibly together with binding agent and lubricant, wherein one or more in copolyvidone, hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (polyvidone) and low substituted hydroxypropyl cellulose (L-HPC) of binding agent, preferably copolyvidone；Wherein one or more in Pulvis Talci, calcium stearate, sodium stearyl fumarate or magnesium stearate of lubricant, preferably magnesium stearate.
One or more in microcrystalline Cellulose, calcium hydrogen phosphate (specially calcium phosphate dibasic anhydrous or dicalcium phosphate dihydrate), low substituted hydroxypropyl cellulose, mannitol, starch, pregelatinized Starch and xylitol of diluent in this pharmaceutical composition, preferred diluent is mannitol and pregelatinized Starch, the ratio of two kinds of diluent is regulated and controled simultaneously, mannitol is 6-9 with the weight ratio of pregelatinized Starch, preferably 6.7.
Disintegrating agent in this pharmaceutical composition is selected from crospovidone, low substituted hydroxypropyl cellulose and starch, preferably corn starch.
Specifically, the formula composition making 1000 tablet medicament compositions is as follows:
Li Gelieting 5g
Mannitol
108-157g
Pregelatinized Starch 18g
Disintegrating agent
15-25g
Binding agent 5g
Lubricant 1g
Film coating agent 5g
Preferably formula consists of:
Li Gelieting
5g
Mannitol
122g
Pregelatinized Starch 18g
Disintegrating agent
20g
Binding agent
5g
Lubricant
1g
Film coating agent 5g
It is a further object to provide the preparation method of a kind of Li Gelieting pharmaceutical composition, comprise the steps:
1) Li Gelieting, diluent and disintegrating agent are dried, pulverize, sieve, and taking adhesive is dissolved in solvent, produce granulation liquid；
2) adjuvant taking recipe quantity is mixed homogeneously with Li Gelieting, is subsequently adding appropriate granulation liquid and makes soft material, crosses 20 eye mesh screens and pelletizes, obtains Li Gelieting wet granular；
3) above-mentioned Li Gelieting wet granular is dried under the conditions of 40 DEG C to moisture less than 5%, obtains the dry granule of Li Gelieting；
4) dry for above-mentioned Li Gelieting granule is crossed 20 eye mesh screen granulate, add lubricant, mix homogeneously, tabletting and get final product.
The present invention by prescription screening determine Li Gelieting and diluent, disintegrating agent assemble application, prepared Li Gelieting tablet stability is good, and dissolution is preferable.Prescription screening test and result see below:
From above result of the test: prescription 1-3 dissolution trend is superior to prescription 4.
Additionally, pharmaceutical composition of the present invention can also contain biguanides, described biguanides is preferably metformin, and preferred pharmaceutical dosage is 500mg.
It is a further object to provide the preparation method of a kind of Li Gelieting pharmaceutical composition, comprise the steps:
1) Li Gelieting, diluent and disintegrating agent are dried, pulverize, sieve, and taking adhesive is dissolved in pure water, produce granulation liquid；
2) adjuvant taking recipe quantity is mixed homogeneously with Li Gelieting, is subsequently adding appropriate granulation liquid and makes soft material, crosses 20 eye mesh screens and pelletizes, obtains Li Gelieting wet granular；
3) above-mentioned Li Gelieting wet granular is dried under the conditions of 40 DEG C to moisture less than 5%, obtains the dry granule of Li Gelieting；
4) dry for above-mentioned Li Gelieting granule is crossed 20 eye mesh screen granulate, add lubricant, mix homogeneously, tabletting, film coating and get final product.
In above-mentioned preparation method, sieving of step 1) was 100 mesh sieves.
Remix after former, adjuvant is pulverized, sieved by the present invention, former, adjuvant can be made to be evenly distributed, mixing more uniform, so that medicine preferably plays drug effect.
Additionally, heating can cause the degraded of Li Gelieting, accordingly, it is determined that the baking temperature being suitable for is critically important.Li Gelieting granule is dried under the conditions of 40 DEG C by the present invention to moisture less than 5%, obtains the dry granule of Li Gelieting, not only avoid the heating degraded to Li Gelieting, and drying effect is good.
The Li Gelieting pharmaceutical composition of the present invention has the advantage that
1) Li Gelieting pharmaceutical composition provided by the present invention is for improving the yield of this product, reducing production cost, and being preferably applied to clinical treatment has the biggest help.
2)
New Li Gelieting compositions provided by the present invention is through industrialized great production and study on the stability, it was demonstrated that constant product quality.
3)
The preparation method of new Li Gelieting compositions provided by the present invention, the method is simple, prepared Li Gelieting pharmaceutical composition reliable in quality.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described in further detail, it should be understood that the non-scope being only limitted to these embodiments of the scope of the present invention.
Embodiment
1
The formula composition that Li Gelieting pharmaceutical composition makes 1000 is as follows:
Li Gelieting
5g
Mannitol
122g
Pregelatinized Starch 18g
Corn starch
20g
Copolyvidone
5g
Magnesium stearate
1g
Film coating agent 5g
Preparation method
1) Li Gelieting, mannitol, pregelatinized Starch and corn starch are dried, pulverize, cross 100 mesh sieves, and take copolyvidone and be dissolved in pure water, produce granulation liquid；
2) adjuvant taking recipe quantity is mixed homogeneously with Li Gelieting, is subsequently adding appropriate granulation liquid and makes soft material, crosses 20 eye mesh screens and pelletizes, obtains Li Gelieting wet granular；
3) above-mentioned Li Gelieting wet granular is dried under the conditions of 40 DEG C to moisture less than 5%, obtains the dry granule of Li Gelieting；
4) dry for above-mentioned Li Gelieting granule is crossed 20 eye mesh screen granulate, add magnesium stearate, mix homogeneously, tabletting, film coating and get final product.
Embodiment
2
The formula composition that Li Gelieting pharmaceutical composition makes 1000 is as follows:
Li Gelieting
5g
Mannitol
108g
Pregelatinized Starch 18g
Corn starch 25g
Copolyvidone
5g
Magnesium stearate
1g
Film coating agent 5g
Preparation method is with embodiment 1.
Embodiment 3
The formula composition that Li Gelieting pharmaceutical composition makes 1000 is as follows:
Li Gelieting
5g
Mannitol
157g
Pregelatinized Starch 18g
Corn starch 15g
Copolyvidone
5g
Magnesium stearate
1g
Film coating agent 5g
Preparation method is with embodiment 1.
Embodiment 4
The formula composition that Li Gelieting metformin compound recipe makes 1000 is as follows:
Li Gelieting
5g
Metformin
500g
Mannitol
122g
Pregelatinized Starch 18g
Corn starch
20g
Copolyvidone
10g
Magnesium stearate
2g
Film coating agent 10g
Preparation method
1) Li Gelieting, metformin, mannitol, pregelatinized Starch and corn starch are dried, pulverize, cross 100 mesh sieves, and take copolyvidone and be dissolved in pure water, produce granulation liquid；
2) take the mannitol of recipe quantity, pregelatinized Starch and corn starch to mix homogeneously with Li Gelieting, be subsequently adding appropriate granulation liquid and make soft material, cross 20 eye mesh screens and pelletize, obtain the wet granular of compound recipe；
3) wet granular of above-mentioned Li Gelieting metformin is dried under the conditions of 30 DEG C to moisture less than 5%, obtains the dry granule of compound recipe；
4) dry for above-mentioned compound recipe granule is crossed 20 eye mesh screen granulate, add magnesium stearate, mix homogeneously, tabletting, film coating and get final product.
The study on the stability of [test example 1] product of the present invention
The Li Gelieting sheet using the method for the embodiment of the present invention 1 to prepare, places under the conditions of high temperature 60 DEG C, RH92.5% and intensity of illumination 4500Lx ± 500Lx, respectively at 5 days, sampling in 10 days, detection, and compares with 0 day, and experimental result see table.
Conclusion: factors influencing under high temperature, high humidity, illumination condition, every Testing index and compare no significant difference, good stability for 0 day, impurity content is few, has preferable dissolution simultaneously.
The mensuration of the dissolution of [test example 2] product of the present invention Li Gelieting sheet
The dissolution determination test carried out with embodiment of the present invention 1-3 product, result is as follows:
Test example 3
The dissolution determination of the embodiment of the present invention 4
According to 2010 editions dissolution methods of Chinese Pharmacopoeia (annex XC the second method), with the HCl solution 900mL of pH 1.2 as solvent, temperature is 37 ± 0.5 DEG C, rotating speed is 50r/min, solution 10mL is taken respectively at 0,5,10,15,30,45,60 min, filter with 0.45 μm microporous filter membrane, take subsequent filtrate, and immediately supplement in a reservoir
PH 1.2 HCl solution 10mL.Take subsequent filtrate sample introduction 20 μ L, record chromatographic peak area, measurement result substitute into standard curve and try to achieve the stripping quantity of a time point Li Gelieting, calibrated after i.e. obtain accumulation dissolution.Take in subsequent filtrate 1mL to 10mL volumetric flask, sample introduction 20 μ L after constant volume, record chromatographic peak area, measurement result substitute into standard curve and try to achieve the stripping quantity of time point metformin, calibrated after i.e. obtain accumulation dissolution.Medicine total release percentage is calculated as follows: wherein CiFor drug level (μ g mL-1)；For release medium volume (mL)；For fluid replacement volume (mL)；W is example weight (mg)；FPercentage composition (%) for preparation of Chinese medicine.
The dissolution test result of Li Gelieting, metformin in embodiment 4
Claims (8)
1. a stable Li Gelieting pharmaceutical composition, it is characterised in that said composition is containing favourable Ge Lieting, diluent and disintegrating agent, and Li Gelieting: diluent: the weight ratio of disintegrating agent is 1:25-35:3-5.
Li Gelieting pharmaceutical composition the most according to claim 1, it is characterised in that possibly together with binding agent and lubricant.
Li Gelieting pharmaceutical composition the most according to claim 1, it is characterised in that diluent is selected from mannitol and pregelatinized Starch.
Li Gelieting pharmaceutical composition the most according to claim 3, it is characterised in that mannitol is 6-9 with the weight ratio of pregelatinized Starch.
Li Gelieting pharmaceutical composition the most according to claim 4, it is characterised in that possibly together with biguanide antidiabetic medicament.
Li Gelieting pharmaceutical composition the most according to claim 4, it is characterised in that the formula composition making 1000 is as follows:
Li Gelieting 5g
Mannitol
108-157g
Pregelatinized Starch
18g
Disintegrating agent
15-25g
Binding agent
5g
Lubricant
1g
Film coating agent
5g。
Li Gelieting pharmaceutical composition the most according to claim 6, it is characterised in that the formula composition making 1000 is as follows:
Li Gelieting
5g
Mannitol
122g
Pregelatinized Starch
18g
Disintegrating agent
20g
Binding agent
5g
Lubricant
1g
Film coating agent
5g。
8. the preparation method of the Li Gelieting pharmaceutical composition described in an any one of claim 6-7, it is characterised in that described preparation method comprises the steps:
1) Li Gelieting, diluent and disintegrating agent are dried, pulverize, sieve, and taking adhesive is dissolved in pure water, produce granulation liquid；
2) adjuvant taking recipe quantity is mixed homogeneously with Li Gelieting, is subsequently adding appropriate granulation liquid and makes soft material, crosses 20 eye mesh screens and pelletizes, obtains Li Gelieting wet granular；
3) above-mentioned Li Gelieting wet granular is dried under the conditions of 40 DEG C to moisture less than 5%, obtains the dry granule of Li Gelieting；
4) dry for above-mentioned Li Gelieting granule is crossed 20 eye mesh screen granulate, add lubricant, mix homogeneously, tabletting, film coating and get final product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510137463.7A CN106138059A (en) | 2015-03-27 | 2015-03-27 | A kind of stable Li Gelieting pharmaceutical composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510137463.7A CN106138059A (en) | 2015-03-27 | 2015-03-27 | A kind of stable Li Gelieting pharmaceutical composition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106138059A true CN106138059A (en) | 2016-11-23 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510137463.7A Pending CN106138059A (en) | 2015-03-27 | 2015-03-27 | A kind of stable Li Gelieting pharmaceutical composition |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019203755A2 (en) | 2017-12-15 | 2019-10-24 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | A solid oral dosage form comprising linagliptin |
| WO2022173406A1 (en) * | 2021-02-15 | 2022-08-18 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | A process for formulations of linagliptin or a pharmaceutically acceptable salt thereof |
| CN115227661A (en) * | 2022-09-22 | 2022-10-25 | 北京惠之衡生物科技有限公司 | Linagliptin tablet and preparation method thereof |
| CN115501195A (en) * | 2022-10-20 | 2022-12-23 | 北京惠之衡生物科技有限公司 | Linagliptin tablet and preparation method thereof |
-
2015
- 2015-03-27 CN CN201510137463.7A patent/CN106138059A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019203755A2 (en) | 2017-12-15 | 2019-10-24 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | A solid oral dosage form comprising linagliptin |
| WO2019203755A3 (en) * | 2017-12-15 | 2020-01-16 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | A solid oral dosage form comprising linagliptin |
| WO2022173406A1 (en) * | 2021-02-15 | 2022-08-18 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | A process for formulations of linagliptin or a pharmaceutically acceptable salt thereof |
| CN115227661A (en) * | 2022-09-22 | 2022-10-25 | 北京惠之衡生物科技有限公司 | Linagliptin tablet and preparation method thereof |
| CN115227661B (en) * | 2022-09-22 | 2022-12-13 | 北京惠之衡生物科技有限公司 | Linagliptin tablet and preparation method thereof |
| CN115501195A (en) * | 2022-10-20 | 2022-12-23 | 北京惠之衡生物科技有限公司 | Linagliptin tablet and preparation method thereof |
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| PB01 | Publication | ||
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Application publication date: 20161123 |