CN108186589A - A kind of Azelnidipine composition - Google Patents
A kind of Azelnidipine composition Download PDFInfo
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- CN108186589A CN108186589A CN201810252562.3A CN201810252562A CN108186589A CN 108186589 A CN108186589 A CN 108186589A CN 201810252562 A CN201810252562 A CN 201810252562A CN 108186589 A CN108186589 A CN 108186589A
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- azelnidipine
- meglumine
- composition
- mannitol
- hydroxypropyl cellulose
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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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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of Azelnidipine composition compositions and preparation method thereof, belong to pharmaceutical technology field.The technical scheme is that：A kind of Azelnidipine tablets composition contains in the composition of unit dose：6 12mg of Azelnidipine, 50 100mg of mannitol, 20 40mg of low-substituted hydroxypropyl cellulose, 3 8mg of meglumine, 15 30mg of polyoxyethylene sorbitan monoleate, superfine silica gel powder 26 35mg, magnesium stearate 1.6mg.Technical solution of the present invention had not only solved the stability of Azelnidipine preparation, but also solve the problems, such as that dissolution rate is not up to standard by the introducing of the reasonable compatibility of various supplementary materials, especially polyoxyethylene sorbitan monoleate.A kind of safe and stable, effective product is provided for clinic.
Description
Technical field
The present invention relates to a kind of Azelnidipine composition compositions and preparation method thereof, belong to pharmaceutical technology field.
Background technology
Azelnidipine belongs to dihydropyridine（DHP）Class calcium channel blocker（CCB）, CCB classes are as a line hypertension therapeutic
Drug is widely used since antihypertensive effect is reliable.Azelnidipine be with " antihypertensive effect ease up with persistently, and to heart pierce
Swash few preferable CCB hypotensors object " it is developed for target.The antihypertensive effect of the drug and the DHP class CCB class medicines of the third generation
Object Amlodipine is quite similar, and acting duration is long and effect is gentle.Research shows that Azelnidipine has diuresis, the heart
Protective effect, renal protection and anti arteriosclerosis effect.There is the Azelnidipine of these features as the ideal channel
Blocking medicine has an epoch-marking significance for hypertension therapeutic.
Azelnidipine belongs to insoluble drug, is dissolved in acetone, acetonitrile, ethyl acetate, ethyl alcohol etc., is insoluble in water.In preparation
Preparation process in, stability and dissolution rate are the two big difficult points for perplexing insider.To increase dissolution rate, Chinese patent
201310137029.X disintegrant of more than two kinds is added in selection；Again because the related content of material of preparation is more difficult up to standard, during original is ground
01810943 .8 of state's patent takes and adds the silicates basic auxiliaries such as alkali silicate, alkaline-earth-metal silicate in prescription, non-
Ionic surface active agent controls its aqueous solution or dispersion liquid pH value to be at least 8；201410668889 .0 of Chinese patent is disclosed
A kind of Azelnidipine preparation, using meglumine, calcium carbonate, magnesia three joint as alkaline protective agents, to improve preparation
Stability, wherein meglumine, calcium carbonate, magnesia accounts for the 2~20% of pharmaceutical composition total amount respectively.Alkaline components it is excessive
It uses, first, influencing the hardness of slice, thin piece, second is that alkalinity is excessive, there is certain side effect to stomach.
201310211425 .2 of Chinese patent discloses a kind of Azelnidipine tablets, which contains acrylic acid tree
Fat E and tromethamine, Azelnidipine are 1 with the weight ratio of Eudragit E and tromethamine:2-6:0.3-2.5 is solved molten
It is slow to go out speed, and the problem of preparation is unstable, but the side effect of tromethamine includes：Irritation is stronger, as parenteral solution intravenous infusion
When, if leakage is in outside blood vessel, can causing tissue necrosis, and can cause thrombosis or phlebitis；During a large amount of quick instillations, it can cause
Central respiration repression or even stop breathing；Renal insufficiency person uses with caution.In view of these side effects of tromethamine, are uncomfortable
It is preferably used as what auxiliary material used, if used as auxiliary material, huge security risk will be generated to patient.
For these reasons, a kind of safe and effective Azelnidipine preparation is provided for clinic, is the effort of drug producer
Direction.
Invention content
In view of the deficiencies of the prior art, it is an object of the present invention to provide a kind of stabilization, safe and effective Azelnidipine tablets
Composition.
The technical scheme is that：A kind of Azelnidipine tablets composition contains in the composition of unit dose：Ah Zhe
Horizon 6-12mg, mannitol 50-100mg, low-substituted hydroxypropyl cellulose 20-40mg, meglumine 3-8mg, polyoxyethylene sorbitan monoleate
15-30mg, superfine silica gel powder 26-35mg, magnesium stearate 1.6mg.
Preferably, Azelnidipine composition of the present invention contains in the composition of unit dose：Azelnidipine 6-
12mg, mannitol 60-90mg, low-substituted hydroxypropyl cellulose 25-36mg, meglumine 4-6mg, polyoxyethylene sorbitan monoleate 18-25mg,
Superfine silica gel powder 28-32mg, magnesium stearate 1.6mg.
Preferably, Azelnidipine composition of the present invention contains in the composition of unit dose：Azelnidipine 6mg is sweet
Reveal alcohol 90mg, low-substituted hydroxypropyl cellulose 25mg, meglumine 4mg, polyoxyethylene sorbitan monoleate 18g, superfine silica gel powder 28g, magnesium stearate
1.6mg。
Preferably, Azelnidipine composition of the present invention contains in the composition of unit dose：Azelnidipine 12mg,
Mannitol 60mg, low-substituted hydroxypropyl cellulose 36mg, meglumine 6mg, polyoxyethylene sorbitan monoleate 25mg, superfine silica gel powder 32mg, firmly
Fatty acid magnesium 1.6mg.
Preferably, Azelnidipine composition of the present invention contains in the composition of unit dose：Azelnidipine 8mg is sweet
Reveal alcohol 80mg, low-substituted hydroxypropyl cellulose 30mg, meglumine 5mg, polyoxyethylene sorbitan monoleate 20mg, superfine silica gel powder 30mg, stearic acid
Magnesium 1.6mg.
The composition of the present invention, using the technology of polyoxyethylene sorbitan monoleate package superfine silica gel powder, the excellent adsorptivity of superfine silica gel powder
The addition of polyoxyethylene sorbitan monoleate is enough significantly increased, both ensure that the dissolving out capability of main ingredient, in turn ensures the stability of main ingredient, and micro-
Powder silica gel property is mild, avoids the stimulation to human gastrointestinal tract.
It is laggard to be prepared into suitable particulate for the composition of the present invention, the technique that wet granulation or dry granulation may be used
Row tabletting or directly filling capsule, take facility.
The preparation method of Azelnidipine tablets of the present invention, includes the following steps：
The polyoxyethylene sorbitan monoleate of first step recipe quantity is added in the superfine silica gel powder of recipe quantity, is stirred evenly；
The Azelnidipine of second step recipe quantity is uniformly mixed with first step gained, is jointly smashed into and sieves with 100 mesh sieve；
Third step mannitol, low-substituted hydroxypropyl cellulose, magnesium stearate, meglumine cross 80 mesh sieve respectively；
Obtained by 4th step second step, the meglumine with half recipe quantity, mannitol, low-substituted hydroxypropyl cellulose mixing is
It is even；
The meglumine of 5th step residue recipe quantity is dissolved in water, prepares the aqueous solution that mass percent is 1-3%, adds it to the
It in mixture obtained by four steps, is uniformly mixed, wet granular is made, 20 mesh sieve is crossed in 45 DEG C of dryings.
The magnesium stearate of recipe quantity is added in particle obtained by the 5th step of 6th step, is uniformly mixed, tabletting.
The composition of the present invention can use fluidized bed granulation, aqueous megiumine solution is sprayed into or dry granulation work
Skill, then carry out tabletting or filling.
Advantageous effect：Technical solution of the present invention passes through drawing for the reasonable compatibility of various supplementary materials, especially polyoxyethylene sorbitan monoleate
Enter, on the one hand can improve preparation stability, on the other hand, and can solve the problems, such as that dissolution rate is not up to standard.Present invention combination
Object solves the problems, such as that polyoxyethylene sorbitan monoleate is difficult to largely add in, and the dissolution of drug is substantially improved using technique for packing.
Embodiment 1. Azelnidipine 8g, mannitol 80g, low-substituted hydroxypropyl cellulose 30g, meglumine 5g, superfine silica gel powder
30g, polyoxyethylene sorbitan monoleate 20g, magnesium stearate 1.6g prepare 1000 according to preparation method described in technical solution part.
Embodiment 2. Azelnidipine 8g, mannitol 80g, low-substituted hydroxypropyl cellulose 30g, meglumine 4g, superfine silica gel powder
30g, polyoxyethylene sorbitan monoleate 20g, magnesium stearate 1.6g prepare 1000 according to preparation method described in technical solution part.
Embodiment 3. Azelnidipine 8g, mannitol 90g, low-substituted hydroxypropyl cellulose 26g, meglumine 5g, superfine silica gel powder
30g, polyoxyethylene sorbitan monoleate 20g, magnesium stearate 1.6g prepare 1000 according to preparation method described in technical solution part.
Embodiment 4. Azelnidipine 6g, mannitol 100g, low-substituted hydroxypropyl cellulose 20g, meglumine 3g, superfine silica gel powder
35g, polyoxyethylene sorbitan monoleate 15g, magnesium stearate 1.6g prepare 1000 according to preparation method described in technical solution part.
Embodiment 5. Azelnidipine 12g, mannitol 50g, low-substituted hydroxypropyl cellulose 20g, meglumine 8g, micro mist silicon
Glue 26g, polyoxyethylene sorbitan monoleate 30g, magnesium stearate 1.6g prepare 1000 according to preparation method described in technical solution part.
Reference examples 1（With reference to embodiment 1）
Azelnidipine 8g, mannitol 80g, low-substituted hydroxypropyl cellulose 30g, meglumine 5g, superfine silica gel powder 30g, stearic acid
Magnesium 1.6g prepares 1000 by following preparation methods：
The Azelnidipine of first step recipe quantity is uniformly mixed with the superfine silica gel powder of recipe quantity, is jointly smashed into and sieves with 100 mesh sieve；
Second step low-substituted hydroxypropyl cellulose, magnesium stearate, meglumine cross 80 mesh sieve respectively；
Meglumine obtained by the third step first step with half recipe quantity, mannitol, low-substituted hydroxypropyl cellulose mixing are equal
It is even；
The meglumine of 4th step residue recipe quantity is dissolved in water, is prepared as 1-3% aqueous solutions, adds it to third step gained and mixes
It in object, is uniformly mixed, wet granular is made, 20 mesh sieve is crossed in 45 DEG C of dryings.
5th step magnesium stearate is added in particle obtained by the 4th step, is uniformly mixed, tabletting.
Reference examples 2（With reference to embodiment 2）
Azelnidipine 8g, mannitol 80g, low-substituted hydroxypropyl cellulose 30g, meglumine 4g, polyoxyethylene sorbitan monoleate 20g, firmly
Fatty acid magnesium 1.6g.1000 are prepared according to preparation method described in reference examples 1.
3. reference examples of reference examples, 1 prescription prepares 1000 by following preparation methods.
First step Azelnidipine sieves with 100 mesh sieve；Other auxiliary materials cross 80 mesh sieve；
Second step weighs the Azelnidipine, superfine silica gel powder, mannitol of recipe quantity, and low-substituted hydroxypropyl cellulose is uniformly mixed；
The meglumine of third step recipe quantity is dissolved in water, is prepared as the aqueous solution of 1-3%, adds it to mixture obtained by second step
In, it is uniformly mixed, wet granular is made, 20 mesh sieve is crossed in 45 DEG C of dryings.
4th step magnesium stearate is added in third step gained particle, is uniformly mixed, tabletting.
4. reference examples of reference examples, 2 prescription, preparation method prepares 1000 as described in reference examples 3.
Test example 1, stability experiment
It respectively by embodiment 1-5 and the product of reference examples 1-4, is placed in climatic chamber, carries out 70 DEG C of high temperature influence factor examinations
It tests, detects related substance and dissolution rate respectively at 0 day, 10 days, 30 days, be as a result recorded in table 1, table 2 respectively.
Table 1 is in relation to substance result
1 data of table illustrate that embodiment 1-5 products obtained therefroms in 70 DEG C of hot tests, significantly better than reference examples 1-4 produce by stability
Product, illustrate prescription of the present invention and and preparation method combination, obtain highly stable product.
2 dissolution results of table
2 data of table illustrate that embodiment 1-5 products obtained therefroms are in 70 DEG C of hot tests, the influence of dissolution rate not shrinkage temperature, and right
Product as usual, with the extension of time, its dissolution rate reduces trend in apparent.
Claims (6)
1. a kind of Azelnidipine tablets composition, it is characterized in that, contain in the composition of unit dose：Azelnidipine 6-12mg,
Mannitol 50-100mg, low-substituted hydroxypropyl cellulose 20-40mg, meglumine 3-8mg, polyoxyethylene sorbitan monoleate 15-30mg, micro mist
Silica gel 26-35mg, magnesium stearate 1.6mg, preparation method include the following steps：
The polyoxyethylene sorbitan monoleate of first step recipe quantity is added in the superfine silica gel powder of recipe quantity, is stirred evenly；
The Azelnidipine of second step recipe quantity is uniformly mixed with first step gained, is jointly smashed into and sieves with 100 mesh sieve；
Third step mannitol, low-substituted hydroxypropyl cellulose, magnesium stearate, meglumine cross 80 mesh sieve respectively；
Obtained by 4th step second step, the meglumine with half recipe quantity, mannitol, low-substituted hydroxypropyl cellulose mixing is
It is even；
The meglumine of 5th step residue recipe quantity is dissolved in water, prepares the aqueous solution that mass percent is 1-3%, adds it to the
It in mixture obtained by four steps, is uniformly mixed, wet granular is made, 20 mesh sieve is crossed in 45 DEG C of dryings.
2. adding in the magnesium stearate of recipe quantity in particle obtained by the 5th step of the 6th step, it is uniformly mixed, tabletting.
3. according to Azelnidipine composition described in claim 1, it is characterized in that, contain in the composition of unit dose：Ah Zhe ground
Flat 6-12mg, mannitol 60-90mg, low-substituted hydroxypropyl cellulose 25-36mg, meglumine 4-6mg, polyoxyethylene sorbitan monoleate 18-
25mg, superfine silica gel powder 28-32mg, magnesium stearate 1.6mg.
4. according to Azelnidipine composition described in claim 1, it is characterized in that, contain in the composition of unit dose：Ah Zhe ground
Flat 6mg, mannitol 90mg, low-substituted hydroxypropyl cellulose 25mg, meglumine 4mg, polyoxyethylene sorbitan monoleate 18g, superfine silica gel powder 28g,
Magnesium stearate 1.6mg.
5. according to Azelnidipine composition described in claim 1, it is characterized in that, contain in the composition of unit dose：Ah Zhe ground
Flat 12mg, mannitol 60mg, low-substituted hydroxypropyl cellulose 36mg, meglumine 6mg, polyoxyethylene sorbitan monoleate 25mg, superfine silica gel powder
32mg, magnesium stearate 1.6mg.
6. according to Azelnidipine composition described in claim 1, it is characterized in that, contain in the composition of unit dose：Ah Zhe ground
Flat 8mg, mannitol 80mg, low-substituted hydroxypropyl cellulose 30mg, meglumine 5mg, polyoxyethylene sorbitan monoleate 20mg, superfine silica gel powder
30mg, magnesium stearate 1.6mg.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810252562.3A CN108186589B (en) | 2018-03-26 | 2018-03-26 | Azelnidipine composition |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810252562.3A CN108186589B (en) | 2018-03-26 | 2018-03-26 | Azelnidipine composition |
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| CN108186589A true CN108186589A (en) | 2018-06-22 |
| CN108186589B CN108186589B (en) | 2020-08-07 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102688237A (en) * | 2012-04-11 | 2012-09-26 | 迪沙药业集团有限公司 | Stable Azelnidipine composition |
| CN102921008A (en) * | 2012-11-16 | 2013-02-13 | 南京正大天晴制药有限公司 | Stable drug composition containing calcium blockers |
| CN104473888A (en) * | 2014-11-20 | 2015-04-01 | 南京正大天晴制药有限公司 | Pharmaceutical composition of azelnidipine |
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2018
- 2018-03-26 CN CN201810252562.3A patent/CN108186589B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102688237A (en) * | 2012-04-11 | 2012-09-26 | 迪沙药业集团有限公司 | Stable Azelnidipine composition |
| CN102921008A (en) * | 2012-11-16 | 2013-02-13 | 南京正大天晴制药有限公司 | Stable drug composition containing calcium blockers |
| CN104473888A (en) * | 2014-11-20 | 2015-04-01 | 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 |