CN101103964B - Sustained-release preparation containing felodipine and preparation method thereof - Google Patents
Sustained-release preparation containing felodipine and preparation method thereof Download PDFInfo
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- CN101103964B CN101103964B CN2006100365468A CN200610036546A CN101103964B CN 101103964 B CN101103964 B CN 101103964B CN 2006100365468 A CN2006100365468 A CN 2006100365468A CN 200610036546 A CN200610036546 A CN 200610036546A CN 101103964 B CN101103964 B CN 101103964B
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Abstract
The invention provides a preparation method of a sustained-release preparation containing felodipine. The invention is characterized in that the felodipine and bond are dissolved in ethanol absolute solution or water solution containing more than 60 percent ethanol, then are fixed with matrix sustained-release necessities and filling agent and finally are moistened and granulated by the ethanol absolute solution or the water solution of ethanol. The invention also provides the sustained-release preparation prepared by the method and usage in preparation of medicine for treating hypertension.
Description
Technical field
The present invention relates to a kind of depressor, particularly relating to a kind of is the slow releasing preparation of active substance with the felodipine.
Technical background
Ideal antihypertensive drugs should be evenly controlling blood pressure, do not influence lipid and carbohydrate metabolism, and improve existing target organ damage, do not have simultaneously or minimum untoward reaction.Calcium ion antagonist is used for the treatment of hypertension, coronary heart disease, angina pectoris and is known by people.As the felodipine of third generation calcium ion antagonist, structural formula is 2,6-dimethyl-4-(2, the 3-Dichlorobenzene base)-1, and 4-dihydro-3,5-pyridinedicarboxylic acid methyl ethyl ester:
Since appearance in 1988, through studies have shown that in a large number, but unique selectivity expansion artery and vein is not had influence, there is not the negativity myocardial contraction effect of other calcium antagonists, plump ventricle is obviously disappeared, the case that is associated with diabetes, renal insufficiency or asthma can be used safely, and it with other calcium antagonists, beta-2 adrenoceptor blocker, ACE inhibitor same curative effect is arranged at least aspect blood pressure lowering or than more effective, toleration is better.
Felodipine is mainly passed through liver metabolism in vivo, and metabolic rate is very high, and oral have a very high first pass effect, causes its bioavailability low like this, therefore, should adopt suitable measure to make it continue to discharge, and has high bioavailability in vivo to guarantee it.Felodipine dissolubility in water is low, and the later stage is difficult to discharge fully, therefore, should adopt suitable measure to guarantee that the later stage discharges fully.
In patent CN1025150C, introduced a kind of method: reactive compound is dissolved or dispersed in the non-ionic solubilizer of semisolid or liquid, and the weight of solubilizing agent needs and being equal in weight of reactive compound at least, incorporate into then in the suitable delivery system and make dosage units, wherein non-ionic solubilizer be selected from polyethoxy Oleum Ricini, polyethoxy castor oil hydrogenated, from the polyethoxy fatty acid of Oleum Ricini or from the polyethoxy fatty acid of castor oil hydrogenated.And have in the embodiment felodipine is dissolved in Cremophor after, with carrier mix homogeneously such as polyvinylpyrrolidone, celluloses, make it granulation with water-wet at last again.
This patent is to improve the common method of insoluble drug release at present in fact, promptly uses suitable solubilizing agent, and the medicine that water solublity is bad is made solution, suspension, microemulsion or fusion.Though can reach the purpose that improves drug release, fast back is slow before occurring when discharging, and the later stage discharges incomplete phenomenon.
Summary of the invention
The invention provides a kind of felodipine sustained-release preparation and preparation method thereof that contains, control drug release is to reach ideal treatment effectively, make human body obtain to treat stably blood drug level, make the dosage optimization, simultaneously, solved the release problem of preparation of Chinese medicine, guaranteed to continue to discharge, the later stage discharges fully.
The present invention is achieved by the following scheme:
Principal agent composition and binding agent are dissolved in ethanol solution or the 60% above ethanol water, mix with skeleton slow-release auxiliary material and filler again, at last with dehydrated alcohol or alcoholic acid aqueous solution moistening granulation.Wherein, the principal agent composition is a felodipine, and percentage by weight is 0.1%-15%, preferred 1%-7%; Binding agent is a 30 POVIDONE K 30 BP/USP 30, and the skeleton slow-release auxiliary material is hypromellose K100M CR, hypromellose K4M CR or their mixture, and percentage by weight is 20%-80%, preferred 20%-35%; Filler is microcrystalline Cellulose, lactose or their mixture, and percentage by weight is 20%-80%, preferred 50%-70%.Simultaneously, also in slow releasing preparation, add lubricant or fluidizer or their mixture.Lubricant can be magnesium stearate, and fluidizer can be silicon dioxide.At last, slow releasing preparation is adopted Opadry carry out film coating.
The present invention also provides the slow releasing preparation that adopts the preparation of above preparation method and has been used for the treatment of purposes in the medicine of hypertension in preparation.
The present invention is unlike the prior art:
The slow releasing preparation that contains felodipine of the present invention's preparation does not have to adopt the common method that improves the insoluble drug release at present, promptly uses suitable solubilizing agent, and the medicine that water solublity is bad is made solution, suspension, microemulsion or fusion.Because the felodipine sustained-release tablets that adopts this method to make, though can reach the purpose that improves drug release, fast back is slow before occurring when discharging, and the later stage discharges incomplete phenomenon.And the preparation method that provides in this patent is to adopt felodipine and binding agent are dissolved in ethanol solution or the 60% above ethanol water; mix with skeleton slow-release auxiliary material and filler again; then with dehydrated alcohol or alcoholic acid aqueous solution moistening granulation; oven dry; behind the granulate, add lubricant or fluidizer or their mixture mixing, tabletting, coating at last.The felodipine sustained-release tablets that makes like this preceding fast back occurs slowly in the time of can overcoming release, the later stage discharges incomplete phenomenon.And technology is fairly simple, is fit to suitability for industrialized production; After oral, no headache (blood plasma in norepinephrine effect), cardiopalmus, side effect such as dizzy; The active substance release was controlled at and was controlled at 42～68%, 10 hours in 10～30%, 6 hours greater than 75% in 2 hours; The efficacy of antihypertensive treatment longer duration can reach 24 hours pressure reduction effects; The bioavailability height.
Infer that the reason that produces this effect is: it is the most important condition of control drug release that hypromellose forms gel layer by suction, after the aquation, dosage surface forms gel layer, by delaying to spread the release that reaches the control medicine, simultaneously, the 30 POVIDONE K 30 BP/USP 30 that adds is as porogen, and the release of medicine is regulated by porogen, and medicine is in the end discharged fully.
The specific embodiment
The present invention is described in further detail below in conjunction with embodiment.
Specify the present invention in conjunction with the embodiments, but be not limited to following embodiment.Wherein " % " is meant " weight % ".
Embodiment 1
Preparation technology:
Hypromellose K100M CR pulverized 160 mesh sieves, and felodipine was pulverized 100 mesh sieves, and microcrystalline Cellulose PH102, lactose are crossed 80 mesh sieves respectively, and magnesium stearate is crossed 60 mesh sieves.Felodipine, hypromellose K100M CR, microcrystalline Cellulose PH102 and lactose mix homogeneously, the aqueous solution system soft material of reuse hypromellose K4M CR.Granulate, behind oven dry, the granulate, add the magnesium stearate mixing at last, 7mm scrobicula stamping (141mg/ sheet) adopts Opadry to carry out film coating.
Embodiment 2
Preparation technology:
Hypromellose K100M CR pulverized 160 mesh sieves, and felodipine was pulverized 100 mesh sieves, and microcrystalline Cellulose PH102, lactose are crossed 80 mesh sieves respectively, and magnesium stearate is crossed 60 mesh sieves, and silicon dioxide is crossed 40 mesh sieves.Felodipine, hypromellose K100MCR, microcrystalline Cellulose PH102 and lactose mix homogeneously, the ethanol water of reuse 50% is made wetting agent system soft material.Granulate, behind oven dry, the granulate, add silicon dioxide, magnesium stearate mixing at last, 7mm scrobicula stamping (145mg/ sheet) adopts Opadry to carry out film coating.
Embodiment 3
Preparation technology:
Hypromellose K100M CR, hypromellose K4M CR pulverize separately are crossed 160 mesh sieves, and microcrystalline Cellulose PH102, lactose are crossed 80 mesh sieves respectively, and magnesium stearate is crossed 60 mesh sieves.Felodipine and 30 POVIDONE K 30 BP/USP 30 are dissolved in the ethanol solution.Hypromellose K100M CR, hypromellose K4M CR, microcrystalline Cellulose PH102 and lactose mix homogeneously again with the mixed solution stirring and evenly mixing system soft material of supplementary material, if soft material is too dried, can be mended the ethanol water moistening into 50%.Granulate, behind oven dry, the granulate, add the magnesium stearate mixing at last, 7mm scrobicula stamping (145mg/ sheet) adopts Opadry to carry out film coating.
Embodiment 4
Preparation technology:
Hypromellose K100M CR pulverized 160 mesh sieves, and microcrystalline Cellulose PH102, lactose are crossed 80 mesh sieves respectively, and magnesium stearate is crossed 60 mesh sieves.Felodipine and 30 POVIDONE K 30 BP/USP 30 are dissolved in 70% ethanol water.Hypromellose K100M CR, microcrystalline Cellulose PH102 and lactose mix homogeneously again with the mixed solution stirring and evenly mixing system soft material of supplementary material, if soft material is too dried, can be mended into the ethanol solution moistening.Granulate, behind oven dry, the granulate, add the magnesium stearate mixing at last, 7mm scrobicula stamping (141mg/ sheet) adopts Opadry to carry out film coating.
Embodiment 5
Preparation technology:
Hypromellose K4M CR pulverized 160 mesh sieves, and lactose is crossed 80 mesh sieves, and magnesium stearate is crossed 60 mesh sieves.Felodipine and 30 POVIDONE K 30 BP/USP 30 are dissolved in 60% ethanol water.Hypromellose K4M CR and lactose mix homogeneously again with the mixed solution stirring and evenly mixing system soft material of supplementary material, if soft material is too dried, can be mended into the ethanol solution moistening.Granulate, behind oven dry, the granulate, add the magnesium stearate mixing at last, 7mm scrobicula stamping (145mg/ sheet) adopts Opadry to carry out film coating.
Preparation process is investigated
Investigation the results are shown in following table to embodiment 1～5 gained slow releasing tablet.
As can be seen from the above table, do not take felodipine is dissolved in the slow releasing tablet of prepared of the alcoholic solution of 30 POVIDONE K 30 BP/USP 30, embodiment 1 is difficult for granulating, and agglomerating phenomenon is arranged, and compressibility is bad; Embodiment 2 is difficult for granulating, and agglomerating phenomenon is arranged, and granule is loose frangible, and mobility of particle is bad, and compressibility is bad, and hardness is low.Take felodipine is dissolved in the slow releasing tablet of prepared of the alcoholic solution of 30 POVIDONE K 30 BP/USP 30, angle of repose is little, and mobility of particle is good, the hardness height, and compressibility is good.
The release test
According to dissolution method (2005 editions two appendix X C of Chinese Pharmacopoeia, first method), be dissolution medium with pH6.5 phosphate buffer and 1.0%SDS500ml, rotating speed is 150rpm, in accordance with the law operation.Measure according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2000) in accordance with the law, calculate release, the results are shown in following table.
As can be seen from the above table, do not take felodipine is dissolved in the slow releasing tablet of prepared of the alcoholic solution of 30 POVIDONE K 30 BP/USP 30, embodiment 1 medicine continues to discharge, and preceding fast back is slow, discharges at last not exclusively; Embodiment 2 drug releases are too fast.And according to the felodipine sustained-release tablets of prescription of the present invention and prepared, medicine continues to discharge, and preceding slow back is fast, discharges fully at last.
Claims (6)
1. felodipine sustained-release tablets; it is characterized in that making: felodipine and 30 POVIDONE K 30 BP/USP 30 are dissolved in ethanol solution or the 60% above ethanol water by following method; mix with skeleton slow-release auxiliary material and filler again; at last with dehydrated alcohol or alcoholic acid aqueous solution moistening granulation; oven dry; behind the granulate; add lubricant or fluidizer or their mixture mixing, tabletting, coating; wherein, described skeleton slow-release auxiliary material is hypromellose K100M CR, hypromellose K4M CR or their mixture.
2. felodipine sustained-release tablets according to claim 1, the percentage by weight that it is characterized in that described felodipine is 0.1%-15%.
3. felodipine sustained-release tablets according to claim 1 is characterized in that described lubricant is a magnesium stearate, and described fluidizer is a silicon dioxide.
4. felodipine sustained-release tablets according to claim 1 is characterized in that the percentage by weight of described hypromellose K100M CR, hypromellose K4M CR or their mixture is 20%-80%.
5. felodipine sustained-release tablets according to claim 1 is characterized in that described filler is microcrystalline Cellulose, lactose or their mixture, and the percentage by weight of described filler is 20%-80%.
6. felodipine sustained-release tablets according to claim 1 is characterized in that described coating material is an Opadry.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2006100365468A CN101103964B (en) | 2006-07-14 | 2006-07-14 | Sustained-release preparation containing felodipine and preparation method thereof |
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| CN2006100365468A CN101103964B (en) | 2006-07-14 | 2006-07-14 | Sustained-release preparation containing felodipine and preparation method thereof |
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| CN101103964A CN101103964A (en) | 2008-01-16 |
| CN101103964B true CN101103964B (en) | 2010-09-29 |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102188401B (en) * | 2011-05-10 | 2013-07-03 | 山东威高药业有限公司 | Felodipine sustained-release tablet and preparation method thereof |
| CN107875132B (en) * | 2016-09-30 | 2020-10-20 | 常州市第四制药厂有限公司 | Felodipine sustained-release preparation composition and preparation method thereof |
| WO2022042644A1 (en) * | 2020-08-26 | 2022-03-03 | 上海博志研新药物技术有限公司 | Edaravone sustained-release pharmaceutical composition, preparation method, and application |
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| EP0274176A2 (en) * | 1987-01-09 | 1988-07-13 | ELAN CORPORATION, Plc | Sustained release capsule or tablet formulation |
| US4803081A (en) * | 1986-04-11 | 1989-02-07 | Aktiebolaget Hassle | New pharmaceutical preparations with extended release |
| WO1997039050A1 (en) * | 1996-04-18 | 1997-10-23 | Edward Mendell Co., Inc. | Sustained release heterodisperse hydrogel systems - amorphous drugs |
| CN1319004A (en) * | 1999-07-20 | 2001-10-24 | 阿斯特拉曾尼卡有限公司 | New pharmaceutical formulation |
| CN1385151A (en) * | 2002-05-16 | 2002-12-18 | 中国人民解放军第二军医大学 | Slow-released dosage form of sodium ferulate and preparation process thereof |
| CN1454594A (en) * | 2003-01-28 | 2003-11-12 | 沈阳药科大学 | Nicardipine hydrochloride controlled-release preparation |
| CN1640400A (en) * | 2004-01-08 | 2005-07-20 | 曹德英 | Felodipine controlled-release preparation |
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2006
- 2006-07-14 CN CN2006100365468A patent/CN101103964B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4803081A (en) * | 1986-04-11 | 1989-02-07 | Aktiebolaget Hassle | New pharmaceutical preparations with extended release |
| EP0274176A2 (en) * | 1987-01-09 | 1988-07-13 | ELAN CORPORATION, Plc | Sustained release capsule or tablet formulation |
| WO1997039050A1 (en) * | 1996-04-18 | 1997-10-23 | Edward Mendell Co., Inc. | Sustained release heterodisperse hydrogel systems - amorphous drugs |
| CN1319004A (en) * | 1999-07-20 | 2001-10-24 | 阿斯特拉曾尼卡有限公司 | New pharmaceutical formulation |
| CN1385151A (en) * | 2002-05-16 | 2002-12-18 | 中国人民解放军第二军医大学 | Slow-released dosage form of sodium ferulate and preparation process thereof |
| CN1454594A (en) * | 2003-01-28 | 2003-11-12 | 沈阳药科大学 | Nicardipine hydrochloride controlled-release preparation |
| CN1640400A (en) * | 2004-01-08 | 2005-07-20 | 曹德英 | Felodipine controlled-release preparation |
Non-Patent Citations (2)
| Title |
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| 管清香等.尼莫地平缓释片的制备及体外释药特性的评价.吉林大学学报(医学版)28 2.2002,28(2),141-143. |
| 管清香等.尼莫地平缓释片的制备及体外释药特性的评价.吉林大学学报(医学版)28 2.2002,28(2),141-143. * |
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