CN102512394B - Nifedipine sustained release tablets and preparation process thereof - Google Patents
Nifedipine sustained release tablets and preparation process thereof Download PDFInfo
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- CN102512394B CN102512394B CN 201110419656 CN201110419656A CN102512394B CN 102512394 B CN102512394 B CN 102512394B CN 201110419656 CN201110419656 CN 201110419656 CN 201110419656 A CN201110419656 A CN 201110419656A CN 102512394 B CN102512394 B CN 102512394B
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Abstract
The invention discloses nifedipine sustained release tablets and a preparation process thereof. The nifedipine sustained release tablets are prepared from nifedipine, a sustained release agent, a bulking agent, a bonding agent, a solubilizer and a lubricant by the steps of pulverizing, sieving, mixing, granulating, drying, tabletting and film coating. The sustained release agent adopts chitosan, and weight percentages of the components are as follows: nifedipine 20%, chitosan 14-24%, bulking agent 50-60%, bonding agent 4%, solubilizer 1%, and lubricant 1%. The nifedipine sustained release tablets of the invention are simple in production process and long in sustained release action, the adverse reactions after administration are less and mild, and the curative effect on mild and moderate hypertension is definite. The nifedipine sustained release tablets can uniformly release nifedipine within 24 hours, can last the effective blood concentration over 24 hours, and only need to be administered once everyday.
Description
Technical field
The present invention relates to the medicament slow release preparation field, specifically a kind of Nifedipine sustained release tablets and preparation technology thereof.
Background technology
Nifedipine is a kind of in the calcium antagonist, is hypotensor, and its coronary artery dilator and peripheral arterial effect are very strong, and it is remarkable to suppress the vasospasm effect.Because half-life of nifedipine ordinary tablet lack (about 2.0 hours), hold time lack, the patient need repeatedly take medicine (every day 3～4 times) just can reach the blood pressure lowering purpose.Again because the rate of releasing drug of nifedipine ordinary preparation is unstable, cause the blood concentration fluctuation in the human body larger, easily produce the side effect such as dizziness, flushed face in the afternoon and cardiopalmus, so nifedipine should be made slow releasing preparation, medicine is entered behind the human body according to certain speed slowly, discharge equably, make drug effect mitigation, longer duration, side effect little.Domestic and international slow, the controlled release tablet of nifedipine successively released of producer has in recent years overcome the shortcoming of nifedipine ordinary tablet basically.But existing Nifedipine sustained release tablets still exist acting duration lack (be generally 12 hours, take every day 2 times), often with unsatisfactory parts such as untoward reaction; And adopt the Nifedipine controlled-release tablet of controlled-release technology, and although its release stability is better than slow releasing tablet, and only need take 1 time every day, all need adopt laser punching osmotic pump type controlled-release technology, there is complicated process of preparation, manufacturing cost is high, yields poorly to wait deficiency.At present, the hypertensive Drug therapy of International Medical bound pair advocates to adopt long-acting antihypertensive drugs, only need take medicine once in namely one day, reaches steady blood pressure lowering with this, reduces fluctuation of blood pressure, effectively controls the purpose of 24 hours blood pressures.The developing direction that relatively simple 24 hours long-acting type Nifedipine sustained release tablets of Development and Production technique are current this Field of Drug Discoveries.
Summary of the invention
It is long that technical problem to be solved by this invention is to propose a kind of acting duration, the rear untoward reaction rate of use is little and be slight, treatment is light, moderate hypertension determined curative effect and the simple Nifedipine sustained release tablets of production technology and preparation technology thereof, it can evenly discharge nifedipine in 24 hours, effective blood drug concentration is sustainable more than 24 hours, and only need take 1 every day.
For solving the problems of the technologies described above, a kind of Nifedipine sustained release tablets of the present invention is by nifedipine, slow releasing agent, filler, binding agent, solubilizing agent and lubricant, through pulverize, sieve, mix, granulate, drying, tabletting, film coating and make; Described slow releasing agent adopts chitosan, and described each weight percentages of components is: nifedipine 20%; Chitosan 14～24%; Filler 50～60%; Binding agent 4%; Solubilizing agent 1%; Lubricant 1%.
Above-mentioned a kind of Nifedipine sustained release tablets, described filler is dextrin, described binding agent is ethyl cellulose, described solubilizing agent is sodium lauryl sulphate, described lubricant is magnesium stearate, and per thousand Nifedipine sustained release tablets are made by nifedipine 20%, chitosan 20%, dextrin 54%, ethyl cellulose 4%, sodium lauryl sulphate 1% and magnesium stearate 1%.
A kind of preparation technology of Nifedipine sustained release tablets, it comprises the steps: I. after being pulverized, nifedipine crosses 200 order stainless steel sifts; II. nifedipine, slow releasing agent, filler, solubilizing agent are mixed by weight percentage; III. add binding agent soft material processed behind the mix homogeneously; IV. soft material is crossed 20 order stainless steel sifts make wet granular; V. wet granular is dry under 55 ℃～60 ℃ temperature conditions; Behind the particle drying with 20 order stainless steel sift granulate; VI. lubricant is added whole good granule, place altogether the three-dimensional mixer mix homogeneously; VII. granule is pressed into tablet; VIII. bag gastric solubility film-coat makes.
The preparation technology of above-mentioned a kind of Nifedipine sustained release tablets, described slow releasing agent is chitosan, and described filler is dextrin, and described solubilizing agent is sodium lauryl sulphate, and described lubricant is magnesium stearate.
The preparation technology of above-mentioned a kind of Nifedipine sustained release tablets in the III step, adds ethyl cellulose-alcoholic solution soft material processed behind the described supplementary material mix homogeneously.
The preparation technology of above-mentioned a kind of Nifedipine sustained release tablets, in the III step, behind the described supplementary material mix homogeneously, the weight concentration that adding makes by adding 80% ethanol in the ethyl cellulose is 8% ethyl cellulose-80% alcoholic solution, makes soft material.
A kind of preparation technology of Nifedipine sustained release tablets, it comprises the steps: I. after being pulverized, nifedipine crosses 200 order stainless steel sifts; II. in ethyl cellulose, add 80% dissolve with ethanol by recipe quantity and make ethyl cellulose-80% alcoholic solution; III. with nifedipine, chitosan, sodium lauryl sulphate and the dextrin mix homogeneously of recipe quantity, add ethyl cellulose-80% alcoholic solution soft material processed; IV. soft material is crossed 20 order stainless steel sifts make wet granular; Wet granular is dry under 55 ℃～60 ℃ temperature; Behind the particle drying with 20 order stainless steel sift granulate; VI. the magnesium stearate of recipe quantity is added whole good granule, place altogether the three-dimensional mixer mix homogeneously; VII. granule is pressed into tablet; VIII. bag gastric solubility film-coat makes.
The preparation technology of above-mentioned a kind of Nifedipine sustained release tablets in the VIII step, wraps yellow gastric solubility film-coat, to guarantee the stability in product use, transportation, the storage.
The present invention has been owing to adopted technique scheme, it in the body blood drug level as the final foundation of standard as Formulation and screening, during primary dcreening operation with the parameter of release as Formulation.The characteristics little according to the nifedipine dissolubility, that dissolution rate is slow have been taked following measures: (1) adopts chitosan as slow releasing agent.Chitosan is chitin product behind the deacetylate under alkali condition, and chitin derives from ectoskeleton and the cell walls of animals of the Crustaceans such as shrimp, Eriocheir sinensis.Chitosan is nontoxic to human body, causes without three, and degradation product easily absorbs, and no antigen, non-sensitization, without haemolysis without rejection phenomenon, have good biocompatibility, and the end product of vivo degradation is glucosamine.And glucosamine is human body chrondroitin, hyaluronic key component.The present invention adopts chitosan as slow releasing agent, can effectively control the rate of releasing drug of medicine, prolong drug release time, can in 24 hours, evenly discharge nifedipine, effective blood drug concentration is sustainable more than 24 hours, blood drug level is more steady, makes controlling of blood pressure stable, and only need take 1 every day; Production technology is simple, quality controllable, is convenient to produce in enormous quantities.(2) selecting 200 order nifedipine fine powders is raw material, reduces particle diameter, increases surface area, uses the dissolubility that increases nifedipine; (3) add an amount of solubilizing agent, improve the hydrophobicity of nifedipine, further improve the dissolubility of nifedipine; (4) adding water soluble macromolecular material (chitosan) is done slow releasing agent, makes erosion type tablet control rate of releasing drug, reaches absorption rate in the control volume, reduces peak valley phenomenon and toxic and side effects, prolongs the purpose of drug effect.Curative effect and the untoward reaction of the light Moderate Essential Hypertension of clinical observation Extended Release Nifedipine Tablets in treatment: (1) method: by the light moderate hypertension patients of 28 examples being adopted the research method of open self cross-reference, the patient stops using former curative after 2 weeks, take 1 of Nifedipine sustained release tablets of the present invention every day, took continuously for 4 weeks, measure blood pressure and heart rate, and 5 routine patients are wherein carried out 24h ambulatory blood pressure monitoring (ABPM), to understand it to the impact of 24h blood pressure.(2) result: 28 routine hyperpietics take rear produce effects 22 examples (obvious effective rate 78.6%) of 4 weeks of Nifedipine sustained release tablets, effective 4 examples (effective percentage 14.3%), invalid 2 examples (7.1%), total effective rate is 92.9%, 1 week was onset after taking medicine, and heart rate unchanged (F=1.079, P〉0.05) before and after the medication; ABPM show 5 routine patients take 24h average systolic behind the Nifedipine sustained release tablets, daytime average systolic and diastolic pressure all reduce.(3) conclusion: slow releasing function longer duration (24 hours), light, the moderate hypertension determined curative effect for the treatment of, after using the untoward reaction rate little and be slight, can spontaneous remission after the drug withdrawal, significantly improve patient's compliance.
Description of drawings
Fig. 1 is that the different grain size nifedipine is to the influence curve sketch map of release;
Fig. 2 is the cumulative release degree testing result curve synoptic diagram that adopts the Nifedipine sustained release tablets that dissimilar slow releasing agents make;
Fig. 3 is the release profiles contrast sketch map of Nifedipine sustained release tablets of the present invention and external controlled release tablet.
The specific embodiment
Embodiment 1
Nifedipine sustained release tablets of the present invention by following weight proportion former, adjuvant is formulated:
Nifedipine 20%
Chitosan 14%
Ethyl cellulose 4%
Sodium lauryl sulphate 1%
Magnesium stearate 1%
Wherein nifedipine is raw material, and chitosan is slow releasing agent, and dextrin is filler, and ethyl cellulose is binding agent, and sodium lauryl sulphate is solubilizing agent, and magnesium stearate is lubricant.
Preparation technology: nifedipine is pulverized the rear 200 order stainless steel sifts of crossing; Nifedipine, chitosan, sodium lauryl sulphate and dextrin are mixed by weight percentage; Behind the supplementary material mix homogeneously, the weight concentration that adding makes by adding 80% ethanol in the ethyl cellulose is 8% ethyl cellulose-80% alcoholic solution soft material processed; Soft material is crossed 20 order stainless steel sifts make wet granular; Wet granular is dry under 55 ℃～60 ℃ temperature conditions; Behind the particle drying with 20 order stainless steel sift granulate; Magnesium stearate is added whole good granule, place altogether the three-dimensional mixer mix homogeneously; The granule tabletting; Bag gastric solubility film-coat makes.
Nifedipine sustained release tablets of the present invention by following weight proportion former, adjuvant is formulated:
Nifedipine 20%
Chitosan 17%
Dextrin 57%
Ethyl cellulose 4%
Sodium lauryl sulphate 1%
Magnesium stearate 1%
Wherein nifedipine is raw material, and chitosan is slow releasing agent, and dextrin is filler, and ethyl cellulose is binding agent, and sodium lauryl sulphate is solubilizing agent, and magnesium stearate is lubricant.
Preparation technology: nifedipine is pulverized the rear 200 order stainless steel sifts of crossing; Nifedipine, chitosan, sodium lauryl sulphate and dextrin are mixed by weight percentage; Behind the supplementary material mix homogeneously, add ethyl cellulose-80% alcoholic solution soft material processed; Soft material is crossed 20 order stainless steel sifts make wet granular; Wet granular is dry under 55 ℃～60 ℃ temperature conditions; Behind the particle drying with 20 order stainless steel sift granulate; Magnesium stearate is added whole good granule, place altogether the three-dimensional mixer mix homogeneously; The granule tabletting; Bag gastric solubility film-coat makes.
Nifedipine sustained release tablets of the present invention by following weight proportion former, adjuvant is formulated:
Nifedipine 20%
Dextrin 54%
Ethyl cellulose 4%
Sodium lauryl sulphate 1%
Magnesium stearate 1%
Wherein nifedipine is raw material, and chitosan is slow releasing agent, and dextrin is filler, and ethyl cellulose is binding agent, and sodium lauryl sulphate is solubilizing agent, and magnesium stearate is lubricant.
Preparation technology: nifedipine is pulverized the rear 200 order stainless steel sifts of crossing; Nifedipine, chitosan, sodium lauryl sulphate and dextrin are mixed by weight percentage; Behind the supplementary material mix homogeneously, add ethyl cellulose-80% alcoholic solution soft material processed; Soft material is crossed 20 order stainless steel sifts make wet granular; Wet granular is dry under 55 ℃～60 ℃ temperature conditions; Behind the particle drying with 20 order stainless steel sift granulate; Magnesium stearate is added whole good granule, place altogether the three-dimensional mixer mix homogeneously; The granule tabletting; Bag gastric solubility film-coat makes.
Embodiment 4
Nifedipine sustained release tablets of the present invention by following weight proportion former, adjuvant is formulated:
Nifedipine 20%
Chitosan 24%
Dextrin 50%
Ethyl cellulose 4%
Sodium lauryl sulphate 1%
Magnesium stearate 1%
Wherein nifedipine is raw material, and chitosan is slow releasing agent, and dextrin is filler, and ethyl cellulose is binding agent, and sodium lauryl sulphate is solubilizing agent, and magnesium stearate is lubricant.
Preparation technology: nifedipine is pulverized the rear 200 order stainless steel sifts of crossing; Nifedipine, chitosan, sodium lauryl sulphate and dextrin are mixed by weight percentage; Behind the supplementary material mix homogeneously, the weight concentration that adding makes by adding 80% ethanol in the ethyl cellulose is 8% ethyl cellulose-80% alcoholic solution soft material processed; Soft material is crossed 20 order stainless steel sifts make wet granular; Wet granular is dry under 55 ℃～60 ℃ temperature conditions; Behind the particle drying with 20 order stainless steel sift granulate; Magnesium stearate is added whole good granule, place altogether the three-dimensional mixer mix homogeneously; The granule tabletting; Bag gastric solubility film-coat makes.
Correlational study to present embodiment is as follows:
1. dissolution medium, solubilizing agent the results are shown in following table to the impact of the dissolubility of nifedipine:
Table: different dissolution mediums and surfactant are on nifedipine dissolubility impact (n=3, μ g/ml)
The result shows in the table: add sodium lauryl sulphate in the nifedipine raw material, its dissolution increases respectively 150% and 149% in water, simulated gastric fluid, illustrates that sodium lauryl sulphate is improved the effect of the dissolubility of nifedipine.But in different concentration ethanol liquid, this effect is not obvious, and analyzing its reason mainly is because nifedipine dissolubility in ethanol is far longer than water, so can not show the solubilising effect of sodium lauryl sulphate.This results suggest is more suitable take water or simulated gastric fluid as release medium.
Figure 1 shows that the different grain size nifedipine affects release.Its result shows: granularity is that the tablet that 200 orders are made is compared with 100 orders, and there were significant differences for release, illustrates that granularity has a significant effect, and needs the granularity of control nifedipine raw material in this product research for this reason, reaches the quality of control tablet.
3. the screening of slow releasing agent: adopt dissimilar slow releasing agents as the erosion type material, add solubilizing agent and granulate, tabletting is measured release.The cumulative release degree of dissimilar blocker the results are shown in following table:
Adopt the cumulative release degree testing result (%) of the Nifedipine sustained release tablets that dissimilar slow releasing agents make:
| Time (h) | Hypromellose (K15) | Chitosan | Sodium alginate |
| 1 | 3 | 4 | 25 |
| 2 | 3.5 | 6 | 33 |
| 3 | 6 | 9 | 39 |
| 4 | 9 | 16 | 42 |
| 5 | 13 | 22 | 45 |
| 6 | 18 | 27 | 48 |
| 7 | 20 | 34 | 49 |
| 8 | 24 | 37 | 51 |
| 9 | 26 | 38 | 56 |
| 10 | 29 | 41 | 59 |
| 11 | 32 | 45 | 60 |
| 12 | 35 | 49 | 63 |
In conjunction with shown in Figure 2, the result shows: the prescription take chitosan as blocker, rate of releasing drug are comparatively moderate, and the prescription release take sodium alginate as blocker is too fast, and the prescription release take hypromellose (K15) as blocker is excessively slow, so the selection chitosan is slow releasing agent.
4. vitro release research
Take Nifedipine sustained release tablets of the present invention as sample, external Nifedipine controlled-release tablet is contrast, selection is release medium through degassed fresh purified water, adopt spectrophotography to investigate the vitro release of Nifedipine sustained release tablets of the present invention and external Nifedipine controlled-release tablet, by
tCheck comparative control product and sample formulation stripping behavior have zero difference.
Nifedipine sustained release tablets of the present invention and external controlled release tablet drug release determination result (n=12):
Figure 3 shows that Nifedipine sustained release tablets of the present invention and external controlled release tablet releasing curve diagram, warp
tCheck, and slow releasing tablet of the present invention and external controlled release tablet dissolution test data there was no significant difference (p〉0.05), illustrate that two kinds of preparations have similar release in vitro behavior.
Claims (1)
1. the preparation technology of a Nifedipine sustained release tablets is characterized in that, it comprises the steps: I. after being pulverized, nifedipine crosses 200 order stainless steel sifts; II. adding 80% dissolve with ethanol by recipe quantity in ethyl cellulose, to make weight concentration be 8% ethyl cellulose-80% alcoholic solution; III. with nifedipine, chitosan, sodium lauryl sulphate and the dextrin mix homogeneously of recipe quantity, add ethyl cellulose-80% alcoholic solution soft material processed; IV. soft material is crossed 20 order stainless steel sifts make wet granular; V. wet granular is dry under 55 ℃～60 ℃ temperature; Behind the particle drying with 20 order stainless steel sift granulate; VI. the magnesium stearate of recipe quantity is added whole good granule, place altogether the three-dimensional mixer mix homogeneously; VII. granule is pressed into tablet; VIII. bag gastric solubility film-coat makes; Wherein, each weight content former, adjuvant is respectively: nifedipine 20%, chitosan 20%, dextrin 54%, ethyl cellulose 4%, sodium lauryl sulphate 1% and magnesium stearate 1%.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1452966A (en) * | 2003-05-20 | 2003-11-05 | 广州贝氏药业有限公司 | Compound Atenolol-Nifedipine slow releasing prepn |
| CN101773485A (en) * | 2009-01-09 | 2010-07-14 | 北京利乐生制药科技有限公司 | Sustained-release preparation using S-metoprolol and dihydropyridine calcium channel blocker as active components and preparation method and use thereof |
| CN101869555A (en) * | 2009-04-21 | 2010-10-27 | 扬子江药业集团北京海燕药业有限公司 | Nifedipine controlled -release tablet and preparation technology thereof |
| CN101966164A (en) * | 2010-07-28 | 2011-02-09 | 安徽永生堂药业有限责任公司 | Nifedipine sustained release tablet |
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- 2011-12-15 CN CN 201110419656 patent/CN102512394B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1452966A (en) * | 2003-05-20 | 2003-11-05 | 广州贝氏药业有限公司 | Compound Atenolol-Nifedipine slow releasing prepn |
| CN101773485A (en) * | 2009-01-09 | 2010-07-14 | 北京利乐生制药科技有限公司 | Sustained-release preparation using S-metoprolol and dihydropyridine calcium channel blocker as active components and preparation method and use thereof |
| CN101869555A (en) * | 2009-04-21 | 2010-10-27 | 扬子江药业集团北京海燕药业有限公司 | Nifedipine controlled -release tablet and preparation technology thereof |
| CN101966164A (en) * | 2010-07-28 | 2011-02-09 | 安徽永生堂药业有限责任公司 | Nifedipine sustained release tablet |
Non-Patent Citations (1)
| Title |
|---|
| Thomas Chandy等.Chitosan beads and granules for oral sustained delivery of nifedipine：in vitro studies.《Biomaterials》.1992,第13卷(第13期), * |
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