CN104055740A - Amlodipine besylate oral preparation and preparation method thereof - Google Patents
Amlodipine besylate oral preparation and preparation method thereof Download PDFInfo
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- CN104055740A CN104055740A CN201310085303.3A CN201310085303A CN104055740A CN 104055740 A CN104055740 A CN 104055740A CN 201310085303 A CN201310085303 A CN 201310085303A CN 104055740 A CN104055740 A CN 104055740A
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Abstract
An amlodipine besylate oral preparation and a preparation method thereof. Microspheres are prepared from amlodipine besylate and acrylic resin E, and direct tabletting of the microspheres and pharmaceutically acceptable auxiliary materials is carried out to obtain the product.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of containing Amlodipine Besylate Tablet oral formulations and preparation method thereof.
background technology
Amlodipine Besylate Tablet is the long-acting dihydropyridine calcium channel antagonist of the third generation, its mainly suppress cardiac muscle and the storage calcium ability of vascular smooth muscle cell film and with the ability of calcium binding, making extracellular calcium in slow channel, flow myocyte reduces, direct vasodilator smooth muscle, blood vessel dilating small artery, reduce peripheral resistance, reach antihypertensive effect.Its long half time, bioavailability is high, effect action temperature and, slowly lasting, side effect is little, evident in efficacy, blood fat, the metabolism of blood glucose of not affecting easy to use is harmless to hepatic and renal function.Structural formula is as follows:
Amlodipine Besylate Tablet is slightly soluble in water, is slightly dissolved in ethanol.Tablet, due to preparation process and formula, causes the poor stability of Amlodipine Besylate Tablet, usually produces some unforeseeable side effect during clinical taking.
Patent documentation CN101161241A discloses a kind of preparation technology of amlodipine besylate tablets, by Amlodipine Besylate Tablet, filler, disintegrating agent, lubricant etc., it is main component, by adopting grinding and sieving, fluidized bed granulation, after spraying is dry, rotation tabletting is made, shortcoming is that to make product stability poor, and dissolution is low.
Patent documentation CN1686121A discloses a kind of Phenylsulfonic acid amido chloro diping dispersion tablet, by Amlodipine Besylate Tablet, microcrystalline Cellulose, Lactis Anhydrous, carboxymethyl starch sodium, micropowder silica gel and magnesium stearate, made, disintegrate is rapid, but the same poor shortcoming of existence and stability.
CN 101862302 B provide a kind of amlodipine besylate liposome tablet, mainly by Amlodipine Besylate Tablet, soybean lecithin, cholesterol, NaTDC and pharmaceutically acceptable excipient, made.Although improved dissolution, increased stability, liposome technology preparation is comparatively complicated.
Summary of the invention
In view of the deficiencies in the prior art, the invention provides a kind of good stability, stripping amlodipine besylate tablets rapidly.
First inventor considers, adopt solid dispersions technique to improve dissolution, consider Amlodipine Besylate Tablet facile hydrolysis simultaneously, therefore select dehydrated alcohol as solvent, citric acid is as dispersion carrier, experiment is found, although the dispersion dissolubility of preparation significantly improves, stability is poorer, after analysis reason may be a prepared composition prose style free from parallelism, medicine becomes unformed, and more easily hydrolysis causes.From structural analysis, in Amlodipine Besylate Tablet structure, contain ester bond, easily hydrolysis, fundamentally solve its stability problem, and in dosage form, amlodipine must be isolated as far as possible with water.
Inventor further contemplates, select water insoluble carrier material parcel Amlodipine Besylate Tablet, and this material can dissolve in gastric acid, can improve the stability in medicine storage process, on this basis, inventor selects Eudragit E, prepares Amlodipine Besylate Tablet resin dispersion, raw material packet is rolled in resin, to improve the stability of medicine.But in experiment, find, due to acrylic resin sheet alkalescence, the dispersion related substance of preparation is larger.
Further, inventor considers, while adopting acrylic resin to prepare dispersion, by acrylic resin ethanol solution, with citron acid for adjusting pH, is first acid, and then preparation dispersion.But in experiment, find to adopt solvent method to prepare solid dispersion, be difficult to dispersion to be taken out from container; Acrylic resin, Amlodipine Besylate Tablet fusing point are all higher, and Amlodipine Besylate Tablet is to poor heat stability, can not adopt fusion method, solvent fusion method to prepare dispersion.
How just can obtain simple, stay-in-grade technique, it is the biggest problem of puzzlement inventor, unexpectedly, inventor considers, the technology of microsphere is prepared in utilization, adopt solvent-nonsolvent method, by dispersion encystation, separated from medium, obtain the Amlodipine Besylate Tablet microsphere that acrylic resin wraps up, simultaneously before preparing microsphere, add citric acid, regulate the alkalescence of acrylic resin, and the citric acid adding is in stripping mensuration process, can also play porogen effect, impel medicine Fast Stripping.In dissolution determination process, because Eudragit E is dissolved in hydrochloric acid, play the effect of similar solid dispersion carrier in addition, can further improve drug dissolution.This invention technology, has obtained beyond thought effect.
In the present invention, inventor proposes to utilize Microspheres Technique parcel Amlodipine Besylate Tablet, use citric acid to regulate the alkalescence of micro-sphere material simultaneously, citric acid not only plays the effect of pH adjusting agent, also as the dispersible carrier of Amlodipine Besylate Tablet, play the effect that improves dissolution, the invention by solid dispersion technology and Microspheres Technique is creationary combines, obtain good stability, stripping amlodipine besylate tablets agent rapidly.
Specifically realize in the following way:
Described tablet and preparation method thereof, is that Amlodipine Besylate Tablet and Eudragit E are prepared into microsphere, then with pharmaceutics on acceptable adjuvant direct compression form.
Described tablet its preparation method, the weight ratio of Amlodipine Besylate Tablet and Eudragit E is 1: 3-12, further preferred ratio is 1: 5-8, most preferred ratio is 1: 7.
Described tablet and preparation method thereof, on pharmaceutics, acceptable adjuvant comprises filler, disintegrating agent and lubricant.
Described tablet and preparation method thereof, filler is one or more in lactose, microcrystalline Cellulose, starch, mannitol, pregelatinized Starch, preferably microcrystalline Cellulose.
Described tablet and preparation method thereof, disintegrating agent is one or more in polyvinylpolypyrrolidone, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, preferably polyvinylpolypyrrolidone.
Described tablet and preparation method thereof, lubricant is one or more in magnesium stearate, Pulvis Talci, micropowder silica gel, preferably Pulvis Talci.
Described tablet and preparation method thereof, is characterized in that adopting the method that is prepared as follows to prepare:
(1) acrylic resin is dissolved in dehydrated alcohol, and citron acid for adjusting pH is 3.0-7.0, adds Amlodipine Besylate Tablet, stirring and dissolving;
(2) add the liquid paraffin solution that contains span;
(3) be warming up to gradually 35 ℃, stir, filtration under diminished pressure, obtains microsphere;
(4) microsphere washs with normal hexane, removes the free Amlodipine Besylate Tablet in surface;
(5) microsphere is mixed homogeneously with microcrystalline Cellulose, polyvinylpolypyrrolidone, Pulvis Talci, tabletting and get final product.
Described tablet and preparation method thereof, is characterized in that citron acid for adjusting pH is 4.0-6.0, most preferably 5.5.
Compared with prior art, the present invention has following advantage:
(1) medicine stability improves greatly;
(2) drug-eluting is rapid;
(3) preparation technology is simple, is applicable to large need of production.
Specific embodiment
Now by following examples, further describe beneficial effect of the present invention, embodiment is only for the object of illustration, do not limit the scope of the invention, within the apparent change that those of ordinary skills make according to the present invention simultaneously and modification are also contained in the scope of the invention.
Embodiment 1
Preparation technology:
(1) Eudragit E is dissolved in dehydrated alcohol, and citric acid is adjusted pH to 3.0, adds Amlodipine Besylate Tablet, stirring and dissolving;
(2) add the liquid paraffin solution that contains span;
(3) be warming up to gradually 35 ℃, stir, filtration under diminished pressure, obtains microsphere;
(4) microsphere washs with normal hexane, removes the free Amlodipine Besylate Tablet in surface;
(5) microsphere is mixed homogeneously with lactose, polyvinylpolypyrrolidone, magnesium stearate, tabletting and get final product.
Embodiment 2
Preparation technology:
(1) Eudragit E is dissolved in dehydrated alcohol, and citric acid is adjusted pH to 7.0, adds Amlodipine Besylate Tablet, stirring and dissolving;
(2) add the liquid paraffin solution that contains span;
(3) be warming up to gradually 35 ℃, stir, filtration under diminished pressure, obtains microsphere;
(4) microsphere washs with normal hexane, removes the free Amlodipine Besylate Tablet in surface;
(5) microsphere is mixed homogeneously with lactose, polyvinylpolypyrrolidone, Pulvis Talci, tabletting and get final product.
Embodiment 3
Preparation technology:
(1) Eudragit E is dissolved in dehydrated alcohol, and citric acid is adjusted pH to 5.5, adds Amlodipine Besylate Tablet, stirring and dissolving;
(2) add the liquid paraffin solution that contains span;
(3) be warming up to gradually 35 ℃, stir, filtration under diminished pressure, obtains microsphere;
(4) microsphere washs with normal hexane, removes the free Amlodipine Besylate Tablet in surface;
(5) microsphere is mixed homogeneously with microcrystalline Cellulose, polyvinylpolypyrrolidone, Pulvis Talci, tabletting and get final product.
Comparative example 1
Preparation technology:
Amlodipine Besylate Tablet, acrylic resin are crossed to 100 mesh sieves, mix homogeneously with microcrystalline Cellulose, polyvinylpolypyrrolidone, Pulvis Talci, tabletting and get final product.
Comparative example 2
Preparation technology:
(1) Amlodipine Besylate Tablet, acrylic resin are dissolved in dehydrated alcohol;
(2) add the liquid paraffin solution that contains span;
(3) be warming up to gradually 35 ℃, stir, filtration under diminished pressure, obtains microsphere;
(4) microsphere washs with normal hexane, removes the free Amlodipine Besylate Tablet in surface;
(5) microsphere is mixed homogeneously with microcrystalline Cellulose, polyvinylpolypyrrolidone, Pulvis Talci, tabletting and get final product.
Comparative example 3
Preparation technology:
(1) Amlodipine Besylate Tablet is dissolved in dehydrated alcohol, and citric acid is adjusted pH to 5.5;
(2) add the liquid paraffin solution that contains span;
(3) be warming up to gradually 35 ℃, stir, filtration under diminished pressure, obtains microsphere;
(4) microsphere washs with normal hexane, removes the free Amlodipine Besylate Tablet in surface;
(5) microsphere is mixed homogeneously with microcrystalline Cellulose, polyvinylpolypyrrolidone, Pulvis Talci, tabletting and get final product.
Checking embodiment
Dissolution determination method: get this product, according to dissolution method (two appendix X c the second methods of < < Chinese Pharmacopoeia > version in 2010), hydrochloric acid solution (0.9-1000) 500ml of take is solvent, rotating speed is per minute 75 to turn, operation, in the time of 30 minutes, gets solution appropriate in accordance with the law, filter, get subsequent filtrate as need testing solution; Another precision takes that through 105oC, to be dried to the Amlodipine Besylate Tablet standard substance of constant weight appropriate, adds hydrochloric acid solution and makes every 1ml containing the solution of 10g amlodipine, in contrast product solution.Precision measures above-mentioned two kinds of solution, and each is appropriate, according to spectrophotography (two appendix VI A of < < Chinese Pharmacopoeia > version in 2010), wavelength place at 237nm measures respectively trap, calculates dissolution.
Determination of related substances method: get 10 of this product, porphyrize, makes the amlodipine solution that approximately contains 200 μ g/ml, as need testing solution by mobile phase; Precision measures in right amount, makes the amlodipine solution that approximately contains 2 μ g/ml, in contrast solution by mobile phase.Precision measures contrast solution 20 μ l, injection liquid chromatography.List must not mix 0.5%, always must not mix 1.0%.
Each embodiment measurement result.
Each embodiment 5min dissolution determination result of table 1
| Embodiment | 0 day result (%) | 40 ℃, 75%RH accelerates 6 months (%) |
| Embodiment 1 | 96.2 | 95.8 |
| Embodiment 2 | 98.1 | 97.9 |
| Embodiment 3 | 99.5 | 98.6 |
| Comparative example 1 | 32.1 | 28.2 |
| Comparative example 2 | 64.5 | 59.8 |
| Comparative example 3 | 43.0 | 38.4 |
As seen from Table 1: embodiment 1-3, basic stripping in 5 minutes is complete; Comparative example 1, do not adopt microsphere preparation technology, and medicine fails to be well dispersed in acrylic resin, and stripping is the poorest; Comparative example 2, prepared microsphere, but owing to not adding citric acid porogen the most, stripping is slow compared with embodiment; Comparative example 3, added citric acid, but do not prepare microsphere, and medicine fails to be well dispersed in acrylic resin, and stripping is poor.
Each embodiment determination of related substances result of table 2
| Embodiment | 0 day result (%) | 40 ℃, 75%RH accelerates 6 months (%) |
| Embodiment 1 | List mixes 0.10%, always mixes 0.21% | List mixes 0.15%, always mixes 0.33% |
| Embodiment 2 | List mixes 0.13%, always mixes 0.24% | List mixes 0.17%, always mixes 0.35% |
| Embodiment 3 | List mixes 0.08%, always mixes 0.15% | List mixes 0.12%, always mixes 0.24% |
| Comparative example 1 | List mixes 0.12%, always mixes 0.22% | List mixes 0.62%, always mixes 1.32% |
| Comparative example 2 | List mixes 0.34%, always mixes 0.54% | List mixes 1.12%, always mixes 2.31% |
| Comparative example 3 | List mixes 0.10%, always mixes 0.21% | List mixes 0.51%, always mixes 1.12% |
As seen from Table 2: embodiment 1-3, stability is better, and related substance does not increase substantially; Comparative example 1, do not prepare microsphere, cannot effectively avoid the impact of moisture on medicine, and degraded obviously; Comparative example 2, prepared microsphere, but owing to not regulating the basicity of acrylic resin, directly caused the degraded of medicine; Comparative example 3, added citric acid, but do not prepare microsphere, cannot effectively avoid the impact of moisture on medicine, and related substance increases obviously.
Embodiment measurement result, has further proved superiority of the present invention.
Claims (8)
1. amlodipine besylate tablets agent and preparation method thereof, is characterized in that: Amlodipine Besylate Tablet and Eudragit E be prepared into after microsphere with pharmaceutics on acceptable adjuvant direct compression form.
2. tablet its preparation method as claimed in claim 1, the weight ratio that it is characterized in that Amlodipine Besylate Tablet and Eudragit E is 1: 3-12, further preferred ratio is 1: 5-8, most preferred ratio is 1: 7.
3. tablet as claimed in claim 1 and preparation method thereof, is characterized in that on pharmaceutics, acceptable adjuvant comprises filler, disintegrating agent and lubricant.
4. tablet as claimed in claim 3 and preparation method thereof, is characterized in that filler is one or more in lactose, microcrystalline Cellulose, starch, mannitol, pregelatinized Starch, preferably microcrystalline Cellulose.
5. tablet as claimed in claim 3 and preparation method thereof, is characterized in that disintegrating agent is one or more in polyvinylpolypyrrolidone, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, preferably polyvinylpolypyrrolidone.
6. tablet as claimed in claim 3 and preparation method thereof, is characterized in that lubricant is one or more in magnesium stearate, Pulvis Talci, micropowder silica gel, preferably Pulvis Talci.
7. tablet as claimed in claim 1 and preparation method thereof, is characterized in that adopting being prepared as follows method preparation:
(1) acrylic resin is dissolved in dehydrated alcohol, and citron acid for adjusting pH is 3.0-7.0, adds Amlodipine Besylate Tablet, stirring and dissolving;
(2) add the liquid paraffin solution that contains span;
(3) be warming up to gradually 35 ℃, stir, filtration under diminished pressure, obtains microsphere;
(4) microsphere washs with normal hexane, removes the free Amlodipine Besylate Tablet in surface;
(5) microsphere is mixed homogeneously with microcrystalline Cellulose, polyvinylpolypyrrolidone, Pulvis Talci, tabletting and get final product.
8. tablet as claimed in claim 7 and preparation method thereof, is characterized in that preferred pH scope is 4.0-6.0, most preferably 7.5.
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| CN201310085303.3A CN104055740B (en) | 2013-03-18 | 2013-03-18 | A kind of Amlodipine Besylate Tablet oral formulations and preparation method thereof |
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| CN201310085303.3A CN104055740B (en) | 2013-03-18 | 2013-03-18 | A kind of Amlodipine Besylate Tablet oral formulations and preparation method thereof |
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| CN104055740B CN104055740B (en) | 2016-08-24 |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004010976A1 (en) * | 2002-07-30 | 2004-02-05 | Whan In Pharm. Co., Ltd | Solid dispersion comprising amlodipine, method thereof and pharmaceutical composition comprising the solid dispersion |
| CN1686121A (en) * | 2005-04-19 | 2005-10-26 | 昆明金殿制药有限公司 | Phenylsulfonic acid amido chloro diping dispersion tablet and its preparation method |
| WO2010118639A1 (en) * | 2009-04-15 | 2010-10-21 | 西安力邦医药科技有限责任公司 | Amlodipine microsphere agent, production method and use thereof |
| CN102512400A (en) * | 2011-12-31 | 2012-06-27 | 深圳万乐药业有限公司 | Preparation method of efonidipine hydrochloride tablet |
-
2013
- 2013-03-18 CN CN201310085303.3A patent/CN104055740B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004010976A1 (en) * | 2002-07-30 | 2004-02-05 | Whan In Pharm. Co., Ltd | Solid dispersion comprising amlodipine, method thereof and pharmaceutical composition comprising the solid dispersion |
| CN1686121A (en) * | 2005-04-19 | 2005-10-26 | 昆明金殿制药有限公司 | Phenylsulfonic acid amido chloro diping dispersion tablet and its preparation method |
| WO2010118639A1 (en) * | 2009-04-15 | 2010-10-21 | 西安力邦医药科技有限责任公司 | Amlodipine microsphere agent, production method and use thereof |
| CN102512400A (en) * | 2011-12-31 | 2012-06-27 | 深圳万乐药业有限公司 | Preparation method of efonidipine hydrochloride tablet |
Non-Patent Citations (1)
| Title |
|---|
| MINGSHI YANG ET AL.: "A novel pH-dependent gradient-release delivery system for nitrendipine II. Investigations of the factors affecting the release behaviors of the system", 《INTERNATIONAL JOURNAL OF PHARMACEUTICS》 * |
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