CN108186589B - Azelnidipine composition - Google Patents
Azelnidipine composition Download PDFInfo
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- CN108186589B CN108186589B CN201810252562.3A CN201810252562A CN108186589B CN 108186589 B CN108186589 B CN 108186589B CN 201810252562 A CN201810252562 A CN 201810252562A CN 108186589 B CN108186589 B CN 108186589B
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- azelnidipine
- meglumine
- mannitol
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- magnesium stearate
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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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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Abstract
The invention relates to an azelnidipine composition and a preparation method thereof, belonging to the technical field of pharmacy. The technical scheme of the invention is as follows: an azelnidipine tablet composition comprising, in unit dose: 6-12mg of azelnidipine, 50-100mg of mannitol, 20-40mg of low-substituted hydroxypropyl cellulose, 3-8mg of meglumine, 8015-30mg of polysorbate, 26-35mg of aerosil and 1.6mg of magnesium stearate. According to the technical scheme, through reasonable compatibility of various raw and auxiliary materials, particularly through introduction of polysorbate 80, the stability of the azelnidipine preparation is improved, and the problem that the dissolution rate does not reach the standard is solved. Provides a safe, stable and effective product for clinic.
Description
Technical Field
The invention relates to an azelnidipine composition and a preparation method thereof, belonging to the technical field of pharmacy.
Background
Azelnidipine belongs to Dihydropyridine (DHP) Calcium Channel Blockers (CCB), and the CCB is widely applied as a first-line hypertension treatment drug due to reliable antihypertensive effect. Azelnidipine is developed with the aim of 'ideal CCB antihypertensive drug with mild and lasting antihypertensive effect and little stimulation to heart'. The antihypertensive effect of the medicine is very similar to that of the third-generation DHP CCB medicine amlodipine, and the effect lasts for a long time and is mild. Research shows that azelnidipine has diuretic, heart protecting, kidney protecting and arteriosclerosis resisting effects. Azelnidipine with these characteristics has epoch-making significance for treating hypertension as an ideal channel blocking medicament.
Azelnidipine belongs to a slightly soluble drug, is dissolved in acetone, acetonitrile, ethyl acetate, ethanol and the like, and is slightly soluble in water. In the preparation process of the preparation, the stability and the dissolution rate are two major difficulties which are puzzling the industry people. In order to increase the dissolution rate, more than 2 disintegrants are selected and added in Chinese patent 201310137029. X; because the content of related substances of the preparation is difficult to reach the standard, the original developed Chinese patent 01810943.8 adopts the technical proposal that silicate basic auxiliary materials such as alkali metal silicate, alkaline earth metal silicate and the like and nonionic surfactant are added in the prescription, and the pH value of the aqueous solution or dispersion liquid is controlled to be at least 8; chinese patent 201410668889.0 discloses an azelnidipine preparation, which adopts the combination of meglumine, calcium carbonate and magnesium oxide as an alkaline protective agent to improve the stability of the preparation, wherein the meglumine, the calcium carbonate and the magnesium oxide respectively account for 2-20% of the total amount of the pharmaceutical composition. The excessive use of alkaline components influences the hardness of the tablets, and the excessive alkalinity has certain side effects on intestines and stomach.
Chinese patent 201310211425.2 discloses an azelnidipine tablet, which contains acrylic resin E and tromethamine in a weight ratio of 1:2-6:0.3-2.5, and solves the problems of slow dissolution rate and unstable preparation, but the side effects of the tromethamine include: the irritation is strong, and when the injection is used as intravenous drip, if the injection leaks outside blood vessels, tissue necrosis can be caused, and thrombosis or phlebitis can be caused; when a large amount of the medicine is rapidly dripped, the respiratory center can be inhibited, and even the respiration can be stopped; it should be used with cautions for renal insufficiency. In view of these side effects of tromethamine, it is not suitable for use as an adjuvant, and if it is used as an adjuvant, it will cause a great safety hazard to patients.
In view of the above, it is an effort of pharmaceutical manufacturers to provide a safe and effective azelnidipine preparation for clinical use.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a stable, safe and effective azelnidipine tablet composition.
The technical scheme of the invention is as follows: an azelnidipine tablet composition comprising, in unit dose: 6-12mg of azelnidipine, 50-100mg of mannitol, 20-40mg of low-substituted hydroxypropyl cellulose, 3-8mg of meglumine, 8015-30mg of polysorbate, 26-35mg of aerosil and 1.6mg of magnesium stearate.
Preferably, the azelnidipine composition of the present invention comprises, in unit dose: 6-12mg of azelnidipine, 60-90mg of mannitol, 25-36mg of low-substituted hydroxypropyl cellulose, 4-6mg of meglumine, 8018-25mg of polysorbate, 28-32mg of aerosil and 1.6mg of magnesium stearate.
Preferably, the azelnidipine composition of the present invention comprises, in unit dose: 6mg of azelnidipine, 90mg of mannitol, 25mg of low-substituted hydroxypropyl cellulose, 4mg of meglumine, 8018 g of polysorbate, 28g of aerosil and 1.6mg of magnesium stearate.
Preferably, the azelnidipine composition of the present invention comprises, in unit dose: 12mg of azelnidipine, 60mg of mannitol, 36mg of low-substituted hydroxypropyl cellulose, 6mg of meglumine, 8025 mg of polysorbate, 32mg of aerosil and 1.6mg of magnesium stearate.
Preferably, the azelnidipine composition of the present invention comprises, in unit dose: 8mg of azelnidipine, 80mg of mannitol, 30mg of low-substituted hydroxypropyl cellulose, 5mg of meglumine, 8020 mg of polysorbate, 30mg of aerosil and 1.6mg of magnesium stearate.
According to the composition, the technology that polysorbate 80 wraps the superfine silica gel powder is adopted, the excellent adsorbability of the superfine silica gel powder can obviously increase the addition amount of the polysorbate 80, the dissolution performance of the main drug is guaranteed, the stability of the main drug is guaranteed, and the superfine silica gel powder is mild in property and avoids stimulation to the gastrointestinal tract of a human body.
The composition can be prepared into proper granules by adopting a wet granulation or dry granulation process, and then tabletting is carried out, or capsules are directly filled, so that the composition is convenient to take.
The preparation method of the azelnidipine tablet comprises the following steps:
adding polysorbate 80 of the formula amount into micropowder silica gel of the formula amount, and uniformly stirring;
uniformly mixing the azelnidipine with the amount of the prescription obtained in the first step, and crushing the mixture until the powder is sieved by a 100-mesh sieve;
thirdly, respectively sieving mannitol, low-substituted hydroxypropyl cellulose, magnesium stearate and meglumine through a 80-mesh sieve;
the fourth step, the mixture obtained in the second step is uniformly mixed with half of the prescription amount of meglumine, mannitol and low-substituted hydroxypropyl cellulose;
and fifthly, dissolving the residual meglumine in the prescription amount in water to prepare 1-3% of water solution, adding the water solution into the mixture obtained in the fourth step, uniformly mixing, preparing wet granules, drying at 45 ℃, and sieving by a 20-mesh sieve.
And sixthly, adding magnesium stearate in the prescription amount into the granules obtained in the fifth step, uniformly mixing, and tabletting.
The composition of the invention can be granulated by using a fluidized bed, and the aqueous solution of the meglumine is sprayed in, or a dry granulation process is carried out, and then tabletting or filling is carried out.
Has the advantages that: according to the technical scheme, through reasonable compatibility of various raw and auxiliary materials, particularly through introduction of polysorbate 80, on one hand, the stability of the preparation can be improved, and on the other hand, the problem that the dissolution rate does not reach the standard can be solved. The composition solves the problem that the polysorbate 80 is difficult to be added in a large amount, and greatly improves the dissolution of the medicament by adopting a wrapping technology.
Example 1-8 g of azelnidipine, 80g of mannitol, 30g of low-substituted hydroxypropyl cellulose, 5g of meglumine, 30g of aerosil, 8020g of polysorbate, and 1.6g of magnesium stearate, and 1000 tablets are prepared according to the preparation method described in the technical scheme.
Example 2, 8g of azelnidipine, 80g of mannitol, 30g of low-substituted hydroxypropyl cellulose, 4g of meglumine, 30g of aerosil, 8020g of polysorbate, and 1.6g of magnesium stearate were prepared into 1000 tablets according to the preparation method described in the technical scheme.
Example 3-8 g of azelnidipine, 90g of mannitol, 26g of low-substituted hydroxypropyl cellulose, 5g of meglumine, 30g of aerosil, 8020g of polysorbate, and 1.6g of magnesium stearate, and 1000 tablets are prepared according to the preparation method described in the technical scheme.
Example 4, 6g of azelnidipine, 100g of mannitol, 20g of low-substituted hydroxypropyl cellulose, 3g of meglumine, 35g of aerosil, 8015 g of polysorbate and 1.6g of magnesium stearate are prepared into 1000 tablets according to the preparation method in the technical scheme.
Example 5, 12g of azelnidipine, 50g of mannitol, 20g of low-substituted hydroxypropyl cellulose, 8g of meglumine, 26g of aerosil, 8030 g of polysorbate, and 1.6g of magnesium stearate are prepared into 1000 tablets according to the preparation method in the technical scheme part.
Comparative example 1 (see example 1)
8g of azelnidipine, 80g of mannitol, 30g of low-substituted hydroxypropyl cellulose, 5g of meglumine, 30g of aerosil and 1.6g of magnesium stearate, and 1000 tablets are prepared according to the following preparation method:
firstly, uniformly mixing azelnidipine with a prescription amount of micropowder silica gel, and crushing to pass through a 100-mesh sieve;
secondly, respectively sieving the low-substituted hydroxypropyl cellulose, the magnesium stearate and the meglumine through a 80-mesh sieve;
thirdly, uniformly mixing the mixture obtained in the first step with half of the formula amount of meglumine, mannitol and low-substituted hydroxypropyl cellulose;
and fourthly, dissolving the residual meglumine in the prescription amount in water to prepare 1-3% aqueous solution, adding the aqueous solution into the mixture obtained in the third step, uniformly mixing, preparing wet granules, drying at 45 ℃, and sieving by a 20-mesh sieve.
And fifthly, adding magnesium stearate into the granules obtained in the fourth step, uniformly mixing, and tabletting.
Comparative example 2 (see example 2)
8g of azelnidipine, 80g of mannitol, 30g of low-substituted hydroxypropyl cellulose, 4g of meglumine, 8020g of polysorbate and 1.6g of magnesium stearate. 1000 tablets were prepared according to the preparation method described in comparative example 1.
Comparative example 3. comparative example 1 the following preparation method was used to prepare 1000 tablets.
Firstly, filtering azelnidipine through a 100-mesh sieve; sieving other adjuvants with 80 mesh sieve;
secondly, weighing azelnidipine, micropowder silica gel, mannitol and low-substituted hydroxypropyl cellulose in the formula amount, and uniformly mixing;
dissolving meglumine in the prescribed amount in water to prepare 1-3% aqueous solution, adding the aqueous solution into the mixture obtained in the second step, uniformly mixing, preparing wet granules, drying at 45 ℃, and sieving with a 20-mesh sieve.
And fourthly, adding magnesium stearate into the granules obtained in the third step, uniformly mixing and tabletting.
Comparative example 4. comparative example 2 1000 tablets were prepared according to the preparation method described in comparative example 3.
Test example 1, stability test
The products of examples 1 to 5 and comparative examples 1 to 4 were placed in a constant temperature and humidity chamber, subjected to a 70 ℃ high temperature influencing factor test, and the test results were recorded in tables 1 and 2, after testing the relevant substances and dissolution rates for 0 day, 10 days and 30 days, respectively.
TABLE 1 results for the materials
The data in Table 1 show that the products obtained in examples 1-5 have significantly better stability in the high temperature test at 70 ℃ than the products of comparative examples 1-4, indicating that the formulations of the present invention and the combination with the preparation process result in very stable products.
Table 2 dissolution results
The data in Table 2 show that the dissolution rates of the products obtained in examples 1-5 are not affected by the temperature in the high temperature test at 70 ℃, while the dissolution rates of the products in the comparative examples are in a significant reduction trend with the time.
Claims (5)
1. An azelnidipine tablet composition is characterized in that a unit dose of the composition consists of 6-12mg of azelnidipine, 50-100mg of mannitol, 20-40mg of low-substituted hydroxypropyl cellulose, 3-8mg of meglumine, 8015-30mg of polysorbate, 26-35mg of aerosil and 1.6mg of magnesium stearate, and the preparation method comprises the following steps:
adding polysorbate 80 of the formula amount into micropowder silica gel of the formula amount, and uniformly stirring;
uniformly mixing the azelnidipine with the amount of the prescription obtained in the first step, and crushing the mixture until the powder is sieved by a 100-mesh sieve;
thirdly, respectively sieving mannitol, low-substituted hydroxypropyl cellulose, magnesium stearate and meglumine through a 80-mesh sieve;
the fourth step, the mixture obtained in the second step is uniformly mixed with half of the prescription amount of meglumine, mannitol and low-substituted hydroxypropyl cellulose;
fifthly, dissolving the remaining prescription amount of meglumine in water to prepare 1-3% of water solution, adding the water solution into the mixture obtained in the fourth step, uniformly mixing, preparing wet granules, drying at 45 ℃, and sieving by a 20-mesh sieve;
and sixthly, adding magnesium stearate in the prescription amount into the granules obtained in the fifth step, uniformly mixing, and tabletting.
2. The azelnidipine tablet composition according to claim 1, wherein the unit dose of the composition comprises 6-12mg of azelnidipine, 60-90mg of mannitol, 25-36mg of low-substituted hydroxypropyl cellulose, 4-6mg of meglumine, 8018-25mg of polysorbate, 28-32mg of aerosil and 1.6mg of magnesium stearate.
3. The azelnidipine tablet composition of claim 1, wherein the unit dose of the composition comprises 6mg of azelnidipine, 90mg of mannitol, 25mg of low-substituted hydroxypropylcellulose, 4mg of meglumine, polysorbate 8018 m g, aerosil 28m g, and magnesium stearate 1.6 mg.
4. The azelnidipine tablet composition according to claim 1, wherein the unit dose of the composition comprises 12mg of azelnidipine, 60mg of mannitol, 36mg of low-substituted hydroxypropylcellulose, 6mg of meglumine, 8025 mg of polysorbate, 32mg of aerosil and 1.6mg of magnesium stearate.
5. The azelnidipine tablet composition according to claim 1, wherein the unit dose of the composition comprises 8mg of azelnidipine, 80mg of mannitol, 30mg of low-substituted hydroxypropylcellulose, 5mg of meglumine, 8020 mg of polysorbate, 30mg of aerosil and 1.6mg of magnesium stearate.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810252562.3A CN108186589B (en) | 2018-03-26 | 2018-03-26 | Azelnidipine composition |
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| CN201810252562.3A CN108186589B (en) | 2018-03-26 | 2018-03-26 | Azelnidipine composition |
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| CN108186589B true CN108186589B (en) | 2020-08-07 |
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| CN102688237A (en) * | 2012-04-11 | 2012-09-26 | 迪沙药业集团有限公司 | Stable Azelnidipine composition |
| CN102921008B (en) * | 2012-11-16 | 2014-01-01 | 南京正大天晴制药有限公司 | Stable drug composition containing calcium blockers |
| CN104473888B (en) * | 2014-11-20 | 2017-01-18 | 南京正大天晴制药有限公司 | Pharmaceutical composition of azelnidipine |
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Effective date of registration: 20200630 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 -1-4 South Road, Weihai economic and Technological Development Zone, Shandong, Qingdao Applicant before: DISHA PHARMACEUTICAL GROUP Co.,Ltd. Applicant before: WEIHAI DISU PHARMACEUTICAL Co.,Ltd. |
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Effective date of registration: 20210827 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: Azerdipine composition Effective date of registration: 20211025 Granted publication date: 20200807 Pledgee: Bank of China Limited Weihai Branch Pledgor: DISHA PHARMACEUTICAL GROUP Co.,Ltd. Registration number: Y2021980010533 |
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