CN101953837A - Felodipine sustained-release tablets and preparation method thereof - Google Patents
Felodipine sustained-release tablets and preparation method thereof Download PDFInfo
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- CN101953837A CN101953837A CN2010102914771A CN201010291477A CN101953837A CN 101953837 A CN101953837 A CN 101953837A CN 2010102914771 A CN2010102914771 A CN 2010102914771A CN 201010291477 A CN201010291477 A CN 201010291477A CN 101953837 A CN101953837 A CN 101953837A
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Abstract
The invention belongs to the technical field of medicament preparation, and particularly relates to felodipine sustained-release tablets for treating hypertension and a preparation method thereof. The invention aims to solve the technical problems of high oxide content, unstable quality and unsteady dosage release of the conventional felodipine sustained-release tablets. The felodipine sustained-release tablets are prepared from the following components: felodipine cyclodextrin clathrate compound, framework sustained-release material, retardant, filling agent, microcrystalline cellulose, lubricant and flow aid, wherein the components are mixed together to prepare tablet cores, and then the tablet cores are coated by Opadry coating powder. The preparation method specifically comprises the following steps of: firstly, preparing the felodipine cyclodextrin clathrate compound from a cyclodextrin material and felodipine; secondly, preparing the tablet cores from the felodipine cyclodextrin clathrate compound and other components; and finally, coating the tablet cores in a coating machine to obtain the felodipine sustained-release tablets. The felodipine sustained-release tablets have the advantages of stable quality, steady medicament release, simple and convenient operation, high production efficiency, low cost and the like.
Description
Technical field
The invention belongs to field of medicine preparing technology, be specifically related to hypertensive felodipine sustained-release tablets of a kind of treatment and preparation method thereof.
Background technology
Domestic and international large-scale clinical trial (as HOT international research, HOT Chinese research, Chinese FEVER research) prove, and felodipine can effectively prevent and reduce brain that hypertension causes finally and the generation of other complication.Felodipine is a third generation dihydropyridine calcium ion antagonist, have in clinical use that dosage is little, blood vessel selectivity height, can significantly bring high blood pressure down and total peripheral vascular resistance, coronary blood flow increasing, do not influence lipid and carbohydrate metabolism, improve cardiac function and collateral circulation, no negativity conduction and negative inotropic action, the effect of the left ventricular hypertrophy that obviously disappears is arranged, and blood pressure lowering steadily, obvious advantage such as length of holding time, better tolerance, toxic and side effects is little, become one of hypertensive pillar medicine of state's internal therapy.
Because felodipine sustained-release preparation drug release instability, bioavailability is lower, guarantees that therefore it continues steadily to discharge in human body, keeps high bioavailability, is bottleneck in this medication preparation with the purpose that reaches steady controlling blood pressure.At present, the method that improves felodipine sustained-release preparation dissolubility and release mainly contains three kinds: (1) directly adds the solubilizing agent of anion surfactant class in medicament composing prescription, make through granulation, mixing, tabletting, bag film-coat; (2) after effective nonionic solubilizer of use and felodipine were made solution, suspension, microemulsion or fusion, granulation in suitable delivery systme was made slow releasing preparation; (3) adopt The suitable solvent (as ethanol solution or 60% above ethanol water),, granulate with skeleton slow-release material and other adjuvant moistenings again, make slow releasing preparation felodipine and adhesive dissolving.Though all can reaching, above-mentioned three kinds of methods improve and improve the felodipine purpose of dissolubility and release in vivo, but the direct adding of anion surfactant class solubilizing agent in the method one, caused the oxidation product of felodipine preparation to increase, and change oxidation product in time and continue to increase, influence the quality of preparation, may produce untoward reaction when serious; Occurring the time period in early stage when preparation that method two is made discharges discharges fast, middle and late stage time period and discharges slow, time period in latter stage and discharge incomplete phenomenon; The preparation that method three is made has solved the slow problem in the preceding fast back of release, and felodipine dissolubility in water is hanged down and the problem of light stability difference but present technology does not fundamentally solve.
Summary of the invention
The objective of the invention is to have the oxide content height at present felodipine sustained-release tablets, quality instability, dose discharge jiggly technical problem, and a kind of steady quality, drug release felodipine sustained-release tablets stably is provided.
Another object of the present invention provides the preparation method of this felodipine sustained-release tablets.
A kind of felodipine sustained-release tablets of the present invention is to be mixed and made into label with following compositions in weight portion, to make behind the Opadry coating powder coating:
The felodipine cyclodextrin is clathrate 10～500, skeleton slow-release material 10～100, blocker 50～200, filler 30～200, microcrystalline Cellulose 1～50, lubricant 1～10, fluidizer 1～30;
Wherein said blocker is one or both the mixture in polyacrylic resin II, the stearic acid; Described filler is one or both the mixture in lactose, the citric acid; Described lubricant is one or both the mixture in magnesium stearate, the stearic acid; Described fluidizer is a kind of in silicon dioxide or the micropowder silica gel.
The preparation method of felodipine sustained-release tablets of the present invention may further comprise the steps:
1) getting 10～500 parts of cyclodextrin is material, it is solution that the water that to be dissolved in 1～50 times of cyclodextrin under 20～50 ℃ be substance weight is made cyclodextrin, again under continuous condition of stirring, 1～10 part of felodipine powder or 1～15 part of felodipine solution were added cyclodextrin in 2～3 hours be in the solution, agitating solution is to clear, remove solvent, obtaining the felodipine cyclodextrin after the drying is clathrate;
2) 10～500 parts of felodipine cyclodextrin will crossing behind 60～80 mesh sieves are that clathrate, 10～100 parts of skeleton slow-release materials, 50～200 parts of blocker, 30～200 parts of filleies, 1～50 part of microcrystalline Cellulose and 1～30 part of fluidizer drop into mixer successively, mix and stir 20～30 minutes;
3) lubricant of getting 1～10 part again drops into mixer, mixes and stirs 20～30 minutes, makes mixed powder, with the mixed powder tabletting, makes label according to a conventional method;
4) get in 80% ethanol that 1.5～60 parts Opadry coating powder is dissolved in 40～700 parts, and Opadry coating powder alcoholic solution is sprayed into the coating machine;
5) according to a conventional method label coating to label quality in the coating machine being increased by 1.0～5.0% makes.
Wherein said skeleton slow-release material is one or more the mixture among hydroxypropyl emthylcellulose K100M, hydroxypropyl emthylcellulose 90SH-100000 and the hydroxypropyl emthylcellulose E50.
In described dry employing oven dry, drying under reduced pressure or the spray drying any one.
Described felodipine solution is that mix homogeneously in 1～15 part of solvent of 1 part of felodipine powder adding is made, and solvent wherein is methanol, ethanol or acetone.
To be material be one or more the mixture in alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin, HP-, dihydroxypropyl-beta-schardinger dextrin-, hydroxyethyl-, methyl-beta-schardinger dextrin-, sulfonic acid group-beta-cyclodextrin, glucose group-beta-cyclodextrin, the acetyl-gamma-cyclodextrin to described cyclodextrin.
Described spray drying condition is 100 ℃～160 ℃ of inlet temperatures, 60 ℃～100 ℃ of outlet temperatures, flow velocity 5～15 ml/min, sprinkler pressure 0.2～0.6Mpa/cm
2
The present invention is prepared gained felodipine sustained-release tablets convenience sampling detect, press 2005 editions two appendix drug release determination methods of Chinese Pharmacopoeia (first method), adopt the device of dissolution method second method.With 0.4% cetyl trimethyl ammonium bromide phosphate buffer (pH6.5) 500ml is solvent, 200 rev/mins of rotating speeds, design temperature are 37 ± 0.5 ℃, take a sample respectively at 1h, 4h, 7h, measure absorption degree, A=A with ultraviolet visible spectrophotometry respectively at the wavelength place of 362nm and 450nm
362-A
450, with standard substance contrasts, calculating the burst size of felodipine sustained-release tablets of the present invention institute sample drawing respectively at different time, related data sees Table 1.
Table 1 felodipine sustained-release tablets of the present invention was 1,4 and 7 hour burst size
On data, felodipine sustained-release tablets of the present invention all in critical field, illustrates that the made felodipine sustained-release tablets of the present invention discharges fully 1,4 and 7 hour burst size, and the content of effective ingredient felodipine is 98.8% in addition, oxidation product 0.4% meets the national drug standards.
The present invention compared with prior art has following beneficial effect:
1, the present invention adopts inclusion technique also to be called " molecular capsule " technology, felodipine low to dissolubility in the water and the light stability difference is that material carries out enclose with cyclodextrin, and with hydroxypropyl emthylcellulose K100M, the mixture of one or more among hydroxypropyl emthylcellulose 90SH-100000 and the hydroxypropyl emthylcellulose E50 is the skeleton slow-release material, detect data show, the content of felodipine sustained-release tablets effective ingredient felodipine of the present invention is 98.8%, oxidation product is 0.4%, 1,4 and 7 hours burst size is respectively 12.1%, 56.0%, 96.9%, all meet the national drug standards, illustrate that drug release of the present invention is steady, the bioavailability height, steady quality;
2, this preparation method adopts the dry powder direct tabletting method, has advantages such as easy and simple to handle, that production efficiency is high, cost is low.
The specific embodiment
Embodiment 1
Felodipine sustained-release tablets in the present embodiment is to be mixed and made into label with following compositions in weight portion, to make behind the Opadry coating powder coating:
The felodipine cyclodextrin is 10 kilograms of clathrates, 10 kilograms of hydroxypropyl emthylcellulose K100M, polyacrylic resin II50 kilogram, 30 kilograms of lactose, 1 kilogram of microcrystalline Cellulose, 1 kilogram of magnesium stearate, silica 1 kilogram.
Concrete preparation method may further comprise the steps:
1) gets 10 kilograms of alpha-cyclodextrins, under 20 ℃, be dissolved in 10 kg water and make alpha-cyclodextrin solution, again under continuous condition of stirring, alpha-cyclodextrin solution will be added in 2 kilograms of felodipine powder 2 hours, agitating solution is to clear, remove solvent, obtaining the felodipine cyclodextrin after the oven dry is clathrate;
2) 10 kilograms of felodipine cyclodextrin getting behind 60 mesh sieves are to drop into mixer successively behind clathrate, 10 kilograms of hydroxypropyl emthylcellulose K100M, 50 kg polypropylene acid resin II, 30 kilograms of lactose, 1 kilogram of microcrystalline Cellulose and 1 kilogram of silicon dioxide, mix and stir 20 minutes;
3) get 1 kilogram of magnesium stearate again and drop into mixer, mix and stirred 20 minutes, make mixed powder, with the mixed powder tabletting, make label according to a conventional method;
4) get in 80% ethanol that 1.5 kilograms Opadry coating powder is dissolved in 40 kilograms, Opadry coating powder alcoholic solution is sprayed into the coating machine with spray gun;
5) according to a conventional method label coating to label quality in the coating machine being increased by 1.0% makes.
Embodiment 2
Felodipine sustained-release tablets in the present embodiment is to be mixed and made into label with following compositions in weight portion, to make behind the Opadry coating powder coating:
The felodipine cyclodextrin is 200 kilograms of clathrates, hydroxypropyl emthylcellulose 90SH-10000050 kilogram, 120 kilograms of stearic acid, 120 kilograms of citric acids, 30 kilograms of microcrystalline Cellulose, 5 kilograms of stearic acid, 15 kilograms of micropowder silica gels.
Concrete preparation method may further comprise the steps:
1) gets 200 kilograms of HP-, under 35 ℃, be dissolved in 4000 kg water and make HP-solution, again under continuous condition of stirring, the felodipine solution that 20 kilograms of felodipines and 200 kilograms of methanol are made added in the HP-solution in 2.5 hours, agitating solution is to clear, is that 100 ℃, outlet temperature are 60 ℃, flow velocity 5 ml/min, sprinkler pressure 0.2Mpa/cm in inlet temperature
2Obtaining the felodipine cyclodextrin under the condition after the spray drying is clathrate;
2) 200 kilograms of felodipine cyclodextrin getting behind 70 mesh sieves are that clathrate, 50 kilograms of hydroxypropyl emthylcellulose 90SH-100000,120 kilograms of stearic acid, 120 kilograms of citric acids, 30 kilograms of microcrystalline Cellulose and 15 kilograms of micropowder silica gels drop into mixer successively, mix and stir 25 minutes;
3) get 5 kilograms of input mixers of stearic acid again, mix and stirred 25 minutes, make mixed powder, with the mixed powder tabletting, make label according to a conventional method;
4) get in 80% ethanol that 18 kilograms Opadry coating powder is dissolved in 270 kilograms, Opadry coating powder alcoholic solution is sprayed into the coating machine with spray gun;
5) according to a conventional method label coating to label quality in the coating machine being increased by 3% makes.
Embodiment 3
Felodipine sustained-release tablets in the present embodiment is to be mixed and made into label with following compositions in weight portion, to make behind the Opadry coating powder coating:
The felodipine cyclodextrin is 30 kilograms in 500 kilograms of clathrates, hydroxypropyl emthylcellulose E50 and hydroxypropyl emthylcellulose K100M mixture double centner, polyacrylic resin II and 200 kilograms of stearic acid mixtures, lactose and 200 kilograms of citric acid mixture, 50 kilograms of microcrystalline Cellulose, magnesium stearate and 10 kilograms of stearic acid mixtures, silicon dioxide and a micropowder silica gel mixture.
Concrete preparation method may further comprise the steps:
1) gets 500 kilograms of methyl-beta-schardinger dextrin-s and sulfonic acid group-beta-cyclodextrin mixture, under 50 ℃, be dissolved in 25000 kg water and make cyclodextrin solution, again under continuous condition of stirring, the felodipine solution that 45 kilograms of felodipine powder and 600 kilograms of acetone are made added in the cyclodextrin solution in 3 hours, agitating solution is to clear, remove solvent, obtaining the felodipine cyclodextrin behind the drying under reduced pressure is clathrate;
2) got 500 kilograms of felodipine clathrates, double centner hydroxypropyl emthylcellulose E50 and hydroxypropyl emthylcellulose K100M mixture, 200 kg polypropylene acid resin II and stearic acid mixture behind 80 mesh sieves, 200 kilograms of lactose and citric acid mixture, 50 kilograms of microcrystalline Cellulose, 30 kilograms of silicon dioxide and micropowder silica gel mixture and dropped into mixer successively, and mixed and stirred 30 minutes;
3) get 10 kilograms of magnesium stearate and stearic acid mixture again and drop into mixer, mix and stirred 30 minutes, make mixed powder, with the mixed powder tabletting, make label according to a conventional method;
4) get in 80% ethanol that 60 kilograms Opadry coating powder is dissolved in 700 kilograms, Opadry coating powder alcoholic solution is sprayed into the coating machine with spray gun;
5) according to a conventional method label coating to label quality in the coating machine being increased by 5.0% makes.
Claims (7)
1. a felodipine sustained-release tablets is characterized in that being mixed and made into label with following compositions in weight portion, to make behind the Opadry coating powder coating:
The felodipine cyclodextrin is clathrate 10～500, skeleton slow-release material 10～100, blocker 50～200, filler 30～200, microcrystalline Cellulose 1～50, lubricant 1～10, fluidizer 1～30;
Wherein said blocker is one or both the mixture in polyacrylic resin II, the stearic acid; Described filler is one or both the mixture in lactose, the citric acid; Described lubricant is one or both the mixture in magnesium stearate, the stearic acid; Described fluidizer is a kind of in silicon dioxide or the micropowder silica gel.
2. the preparation method of a felodipine sustained-release tablets is characterized in that may further comprise the steps:
1) getting 10～500 parts of cyclodextrin is material, it is solution that the water that to be dissolved in 1～50 times of cyclodextrin under 20～50 ℃ be substance weight is made cyclodextrin, again under continuous condition of stirring, 1～10 part of felodipine powder or 1～15 part of felodipine solution were added cyclodextrin in 2～3 hours be in the solution, agitating solution is to clear, remove solvent, obtaining the felodipine cyclodextrin after the drying is clathrate;
2) 10～500 parts of felodipine cyclodextrin will crossing behind 60～80 mesh sieves are that clathrate, 10～100 parts of skeleton slow-release materials, 50～200 parts of blocker, 30～200 parts of filleies, 1～50 part of microcrystalline Cellulose and 1～30 part of fluidizer drop into mixer successively, mix and stir 20～30 minutes;
3) lubricant of getting 1～10 part again drops into mixer, mixes and stirs 20～30 minutes, makes mixed powder, with the mixed powder tabletting, makes label according to a conventional method;
4) get in 80% ethanol that 1.5～60 parts Opadry coating powder is dissolved in 40～700 parts, and Opadry coating powder alcoholic solution is sprayed into the coating machine;
5) according to a conventional method label coating to label quality in the coating machine being increased by 1.0～5.0% makes.
3. according to the described felodipine sustained-release tablets of claim 1, it is characterized in that described skeleton slow-release material is one or more the mixture among hydroxypropyl emthylcellulose K100M, hydroxypropyl emthylcellulose 90SH-100000 and the hydroxypropyl emthylcellulose E50.
4. according to the preparation method of the described felodipine sustained-release tablets of claim 2, it is characterized in that described drying adopts any one in oven dry, drying under reduced pressure or the spray drying.
5. according to the preparation method of the described felodipine sustained-release tablets of claim 2, it is characterized in that described felodipine solution is that mix homogeneously in 1～15 part of solvent of 1 part of felodipine powder adding is made, solvent wherein is methanol, ethanol or acetone.
6. according to the preparation method of the described felodipine sustained-release tablets of claim 2, it is characterized in that described cyclodextrin is material and is one or more the mixture in alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin, HP-, dihydroxypropyl-beta-schardinger dextrin-, hydroxyethyl-, methyl-beta-schardinger dextrin-, sulfonic acid group-beta-cyclodextrin, glucose group-beta-cyclodextrin, the acetyl-gamma-cyclodextrin.
7. require the preparation method of 4 described felodipine sustained-release tablets according to profit, it is characterized in that described spray drying condition is, 100 ℃～160 ℃ of inlet temperatures, 60 ℃～100 ℃ of outlet temperatures, flow velocity 5～15 ml/min, sprinkler pressure 0.2～0.6Mpa/cm
2
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| CN2010102914771A CN101953837B (en) | 2010-09-20 | 2010-09-20 | Felodipine sustained-release tablets and preparation method thereof |
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| CN2010102914771A CN101953837B (en) | 2010-09-20 | 2010-09-20 | Felodipine sustained-release tablets and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102784128A (en) * | 2012-07-31 | 2012-11-21 | 北京协和药厂 | Felodipine sustained release preparation and preparation method of felodipine sustained release preparation |
| CN102920677A (en) * | 2011-08-12 | 2013-02-13 | 重庆药友制药有限责任公司 | Felodipine sustained release preparation and its preparation method |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002056883A1 (en) * | 2001-01-18 | 2002-07-25 | Wockhardt Limited | Preparation of micron-size felodipine particles by microfluidization |
| WO2003043602A1 (en) * | 2001-11-20 | 2003-05-30 | Korea Dds Pharmaceutical Co., Ltd. | Solid dispersions containing substituted cyclodextrin and insoluble drug and their preparations |
-
2010
- 2010-09-20 CN CN2010102914771A patent/CN101953837B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002056883A1 (en) * | 2001-01-18 | 2002-07-25 | Wockhardt Limited | Preparation of micron-size felodipine particles by microfluidization |
| WO2003043602A1 (en) * | 2001-11-20 | 2003-05-30 | Korea Dds Pharmaceutical Co., Ltd. | Solid dispersions containing substituted cyclodextrin and insoluble drug and their preparations |
Non-Patent Citations (1)
| Title |
|---|
| 《Journal of Inclusion Phenomena and Molecular Recognition in Chemistry》 19981231 JADWIGA MIELCAREK Studies on Inclusion Complexes of Felodipine with beta-Cyclodextrin 243-252 1-7 第30卷, 2 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102920677A (en) * | 2011-08-12 | 2013-02-13 | 重庆药友制药有限责任公司 | Felodipine sustained release preparation and its preparation method |
| CN102920677B (en) * | 2011-08-12 | 2016-06-08 | 重庆药友制药有限责任公司 | A kind of felodipine sustained-release preparation and preparation method thereof |
| CN102784128A (en) * | 2012-07-31 | 2012-11-21 | 北京协和药厂 | Felodipine sustained release preparation and preparation method of felodipine sustained release preparation |
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| CN101953837B (en) | 2012-04-18 |
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