CN103860498A - Rosuvastatin calcium dispersible tablet and preparation method thereof - Google Patents
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Abstract
The invention belongs to the field of medical preparations, and particularly relates to a rosuvastatin calcium dispersible tablet and a preparation method thereof. Rosuvastatin calcium is low in bioavailability after being orally taken and absorbed, and the individuals for medication have large difference, therefore, the invention provides the rosuvastatin calcium dispersible tablet which comprises rosuvastatin calcium, hydroxypropyl-beta-cyclodextrin, a filler, a disintegrating agent, a binder and a lubricant. Rosuvastatin calcium is easily dissolved into water after being coated by hydroxypropyl-beta-cyclodextrin (HP-beta-CD), the stability of the tablet can be enhanced, the release and absorption of the drug in a human body can be promoted, the bioavailability can be improved, and the difference of the individuals for medication can be reduced.
Description
Invention field
The present invention relates to chemical pharmacy field, be specifically related to a kind of Rosuvastatin calcium dispersible tablet and preparation method thereof.
Background of invention
Cardiovascular disease is one of disease that harm humans health (particularly person in middle and old age) is the most common, the most serious, dyslipidemia is the important risk factor of atherosclerosis, coronary heart disease and other cardiovascular and cerebrovascular disease, fat regulation medicine can reduce incidence rate and the mortality rate of these diseases, and the control of cardiovascular disease is produced to positive effect and far-reaching influence.Along with the arrival of social population's aging, the disease ratios such as the hypertension being caused by hyperlipidemia in old people's cardiovascular disease are just being increases trend year by year, and people's life security in serious threat.Therefore, seek that curative effect is showing, safe and reliable blood lipid-lowering medicine, be always one of the world of medicine for a long time and rather popular research topic.
Hyperlipoproteinemia, refers to the class disease that cholesterol in the blood plasma that a variety of causes causes and/or triglyceride level raise.All lipoproteins all contain lipid, therefore as long as lipoprotein excessive (hyperlipoproteinemia) will cause blood lipid level rising (hyperlipemia).Hyperlipemia and hyperlipoproteinemia look it is two different concepts, but because blood fat is to turn round with the form of lipoprotein in blood, therefore in fact namely hyperlipoproteinemia of hyperlipemia.
From clinically, hyperlipemia can be divided into following four classes: 1) hypercholesterolemia: serum TC level increases; 2) combined hyperlipidemia familial: serum TC and TG level all increase; 3) hypertriglyceridemia: serum TG level increases; 4) low hdl mass formed by blood stasis: Serum HDL-C level lowers.
Statins is 3-hydroxy-3-methyl glutaryl base-coenzyme A (HMG-CoA) reductase inhibitor, and HMG-CoA is the early stage and rate-limiting step of the solid liquor-saturated biosynthesis pathway of gallbladder to the conversion of mevalonic acid.This step is by reductase catalysis, and inhibin can suppress this conversion reaction of HMG-CoA reduction contribute to a feast catalysis.Therefore, HMG-CoA reductase inhibitor is effective lipid lowerers.
Rosuvastatin (Rosuvastatin) is to have carried out broad research both at home and abroad also at the HMG-CoA of multinational listing reductase inhibitor, it is by optionally suppressing in vivo the rate-limiting enzyme HMG-CoA reductase in cholesterol biosynthesis process, make the synthetic minimizing of cholesterol, also make the synthetic increase of low density lipoprotein receptor, Main Function position is at liver, result reduces cholesterolemia and low-density lipoprotein cholesterol level, the control generation effect to atherosclerosis and coronary heart disease thus.This product also reduces serum triglyceride level and increases blood hdl level.Rosuvastatin has 5,10,20 and the tablet of 40mg.In clinical trial, most clothes for patients with 5 or the starting dose of 10mg just reached the target LDL-C level that NCEP (National Cholesterol Education Program) is recommended.20mg dosage can be used as the patient's that cholesterol levels is very high predose, and the dosage of 40mg only should use in the time that 20mg dosage treatment curative effect is not enough.Professor Shepherd has completed the clinical trial of statins effect for reducing fat comparison recently, the medication result of 8 weeks shows: Rosuvastatin 10mg (n=539) LDL-C compliance rate is 80%, and atorvastatin 10mg (n=529) compliance rate is 63% (P<0.001), atorvastatin 20mg (n=925) LDL-C compliance rate is 74% (P<0.01).Jones PH studies show that: Rosuvastatin 10mg reduces LDL-C46%, and atorvastatin is incremented to 20mg, 40mg from 10mg, and LDL-C reduces respectively 37% (P<0.001), 43% and 48%; Simvastatin is incremented to 20mg, 40mg from 10mg, and LDL-C reduces respectively 28%, 35% and 39% (the equal <0.001 of P value); Pravastatin is incremented to 20mg, 40mg from 10mg, reduces LDL-C and is respectively 20%, 24% and 30% (the equal <0.001 of P value).The Lipid-lowering activities of Rosuvastatin and safety and pravastatin and simvastatin have been carried out the clinical randomized controlled research of 52 weeks by Brown WV etc., result shows, in medication after 12 weeks, the low-density lipoprotein cholesterol (LDL-C) of Rosuvastatin 5mg and 10mg dosage group has declined respectively 39.1% and 47.4%, and there were significant differences (P<0.05) with pravastatin 20mg group (decline 26.5%) and simvastatin 20mg group (decline 34.6%).After medication 52 weeks, Rosuvastatin 5mg and 10mg group reach u.s. national cholesterol education program and recommend the ratio of LDL-C target to be respectively 88% and 87.5%, and pravastatin group is only 60%, simvastatin group is 72.5%, the equal well-tolerated of (at latter 40 weeks, the patient dose that does not reach target doubled) all experimental group patients.Although Rosuvastatin has so potent advantage, but its untoward reaction and other statins are compared and are wanted serious, in clinical trial before listing, heavy dose of (80mg) group has 7 routine patients that life-threatening rhabdomyolysis has occurred, and therefore query has just been in its safety at that time.In listing pre-Clinical, also find, Rosuvastatin also can damage some patients' renal function (do not observe other Statins and have similar untoward reaction).Finally, FDA ratifies its listing because considering the advantage (drug effect is slightly better than other Statins) of Rosuvastatin, but advises that taking dose is from 5mg～10mg, and maximal dose is no more than 40mg.
Dispersible tablet is a kind of novel form being born in recent years, and records in British Pharmacopoeia and Chinese Pharmacopoeia.Dispersible tablet is put into water disintegrate rapidly, disperses to form the suspension of equal Uniform, has taking convenience, the feature that bioavailability is high, and preparation method, working condition and the production technology of dispersible tablet are simple; Its instructions of taking is more flexible, can as ordinary tablet, swallow, and also can be distributed to wet suit and use.
The oral organism-absorbing availability of rosuvastain calcium in human body is not high, and scope is generally 10-50% widely, has very large individual difference, comprises interindividual variation and individual interior difference.The dissolubility of rosuvastain calcium depends on pH, and rosuvastain calcium dissolubility in sour environment is very little, but solvable in gastrointestinal neutral environment.The permeability of rosuvastain calcium is very low and be also to rely on PH environment, and in gastrointestinal tract, in the time that environment pH is increased to neutrality from acidity, the permeability of rosuvastain calcium reduces.Due to the biopharmaceutics character of rosuvastain calcium complexity, the dosage form with less individual variation and raising bioavailability of research and development rosuvastain calcium is challenging.
HP-β-CD (Η Ρ-β-CD) is amorphous, very easily water-soluble.It has a hydrophobic pocket to carry out enclose to medicine, aspect pharmaceutical preparation, has a wide range of applications.Be mainly manifested in it and be widely used in the solubilising of insoluble drug and improve the stability of medicine, can also promote medicine release in vivo, increase and absorb, improve bioavailability, have certain effect covering aspect adverse drug abnormal smells from the patient also tool.
Summary of the invention
In order to increase the stability of medicine, further improve bioavailability, the reduction toxic and side effects of medicine and the individual difference of medication of rosuvastain calcium, the invention provides a kind of dispersible tablet of rosuvastain calcium, it contains rosuvastain calcium, hydroxypropyl cyclodextrin and filler, disintegrating agent, binding agent, lubricant.Described filler is selected from one or more in amylum pregelatinisatum, dextrin, lactose, microcrystalline Cellulose and mannitol, and especially, described filler is amylum pregelatinisatum, microcrystalline Cellulose and manna.
The dissolubility of rosuvastain calcium in water is lower, after HP-β-CD hydrophobic pocket enclose, has improved dissolubility and the stability of medicine, has promoted medicine release in vivo, increases and absorbs, and improves bioavailability.
The object of the present invention is to provide a kind of Rosuvastatin calcium dispersible tablet that can improve bioavailability and preparation method thereof, and through repetition test, each component screening is arrived to weight ratio of the present invention, be surprised to find that the dispersible tablet steady quality obtaining, stripping is fast, in body, distribute rapidly, bioavailability is high.
On the one hand, the invention provides a kind of Rosuvastatin calcium dispersible tablet, it is made up of rosuvastain calcium, HP-β-CD, filler, binding agent, lubricant and disintegrating agent, wherein said rosuvastain calcium and HP-β-CD weight ratio are 1:1-3, and rosuvastain calcium and HP-β-CD formation clathrate; Described filler is amylum pregelatinisatum, microcrystalline Cellulose and mannitol; Described binding agent is selected from 2% polyvinylpyrrolidone aqueous solution; Described lubricant is selected from one or more in magnesium stearate, Pulvis Talci and Stepanol MG; Described disintegrating agent is selected from one or more in microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose and low-substituted hydroxypropyl cellulose.
Some embodiments therein, dispersible tablet of the present invention, wherein said rosuvastain calcium, filler, disintegrating agent, binding agent and lubricant according to the proportioning of weight portion are:
In other embodiments, described dispersible tablet, wherein said rosuvastain calcium, filler, disintegrating agent, binding agent and lubricant according to the proportioning of weight portion are:
Some embodiments therein, dispersible tablet of the present invention, wherein said lubricant is Pulvis Talci, described disintegrating agent is low-substituted hydroxypropyl cellulose.
Some embodiments therein, dispersible tablet of the present invention, wherein said rosuvastain calcium and the weight ratio of hydroxypropyl cyclodextrin are 1:3.
On the other hand, the present invention relates to a kind of preparation method of Rosuvastatin calcium dispersible tablet, it comprises following steps: first form clathrate with hydroxypropyl-cyclodextrin and rosuvastain calcium, wherein the weight ratio of rosuvastain calcium and HP-β-CD is 1:1-3, again by gained clathrate, mannitol, starch and microcrystalline Cellulose, mix equal Uniform, add 2% polyvinylpyrrolidone aqueous solution and make soft material, with 18 mesh sieve granulations; Granule is at 40-70 ℃ of dry 5-6 hour; Granule adds low-substituted hydroxypropyl cellulose and Pulvis Talci to mix after drying, 20 mesh sieve granulate, last tabletting.
Some embodiments therein, preparation method of the present invention, the preparation process of wherein said clathrate is: get HP-β-CD and be dissolved in right amount in appropriate water and make saturated aqueous solution, rosuvastain calcium is crossed 120 mesh sieves, be dissolved in appropriate ethanol, under magnetic agitation, the alcoholic solution of rosuvastain calcium is slowly added in the saturated aqueous solution of HP-β-CD, all add continuation under rear room temperature and stir 2-4 hour, 40-50 ℃ of rotary evaporation removed most ethanol, pack tray into, put in freezer compartment of refrigerator, the pre-freeze time is 12h, temperature is-50 ℃, when in freeze drying box, condenser temperature reaches-50 ℃, put into sample, evacuation, pressure is no more than 20 Ρ a, sublimation drying 24h, obtain clathrate.
The present invention has specifically described Rosuvastatin calcium dispersible tablet and preparation technology thereof by embodiment 1-3.The present invention is not limited only to the embodiment of this part, and the replacement of the adjuvant of any identical function, the change of identical or close adjuvant weight are apparent for a person skilled in the art, and are included among the present invention.
The present invention is also by the bioavailability study of embodiment 4 Rosuvastatin calcium dispersible tablets, utilize rosuvastain calcium ordinary tablet of the prior art as reference reagent, using healthy Beagle dog as animal subject, result of the test shows that the rosuvastain calcium ordinary tablet bioavailability that Rosuvastatin calcium dispersible tablet provided by the invention provides compared with prior art obviously improves.And the rosuvastain calcium ordinary tablet that Rosuvastatin calcium dispersible tablet provided by the invention provides compared with prior art is smaller at interindividual variation, and there is statistical significance (P<0.05).
In a word, Rosuvastatin calcium dispersible tablet provided by the invention compared with prior art has advantages of as follows: 1) improved bioavailability.Compared with the rosuvastain calcium ordinary tablet that Rosuvastatin calcium dispersible tablet provided by the invention provides with prior art, ln (AUC
0-∞), lnC
maxbetween medicament, difference has statistical significance (P<0.05), Rosuvastatin calcium dispersible tablet of the present invention is 118.83 scholars 20.60% to the relative bioavailability of rosuvastain calcium ordinary tablet, this illustrates that Rosuvastatin calcium dispersible tablet of the present invention is compared with rosuvastain calcium ordinary tablet, and bioavailability obviously improves.
2) reduced the interindividual variation of medication.Rosuvastain calcium is very easily water-soluble after HP-β-CD (Η Ρ-β-CD) enclose, and improve the stability of medicine, reduce the dependency of rosuvastain calcium biological metabolism to pH, therefore reduced the interindividual variation of medication, and confirmed this conclusion by embodiment 4.
The specific embodiment
Further explain the present invention below in conjunction with embodiment, but embodiment does not limit in any form to the present invention.
Embodiment 1
Preparation technology:
Getting recipe quantity HP-β-CD is dissolved in right amount in appropriate water and makes saturated aqueous solution, rosuvastain calcium is crossed 120 mesh sieves, be dissolved in appropriate ethanol, under magnetic agitation, the alcoholic solution of rosuvastain calcium is slowly added in the saturated aqueous solution of hydroxypropyl cyclodextrin, all add under rear room temperature and continue to stir 3 hours, 45 ℃ of rotary evaporations are removed most ethanol.Pack tray into, put in freezer compartment of refrigerator, the pre-freeze time is 12h, and temperature is-50 ℃, when condenser temperature reaches-50 ℃ in freeze drying box, puts into sample, evacuation, and pressure is no more than 20Pa, and sublimation drying 24h, obtains clathrate.
Microcrystalline Cellulose is crossed 100 mesh sieves, and rosuvastain calcium hydroxypropyl-cyclodextrin clathrate, mannitol, starch and microcrystalline Cellulose are mixed to equal Uniform, adds 2% polyvinylpyrrolidone aqueous solution and makes soft material, with 18 mesh sieve granulations;
Granule is dried 5 hours at 45 ℃; Granule adds low-substituted hydroxypropyl cellulose and Pulvis Talci to mix after drying, 20 mesh sieve granulate, last tabletting.
Embodiment 2
Preparation technology:
Getting recipe quantity HP-β-CD is dissolved in right amount in appropriate water and makes saturated aqueous solution, rosuvastain calcium is crossed 120 mesh sieves, be dissolved in appropriate ethanol, under magnetic agitation, the alcoholic solution of rosuvastain calcium is slowly added in the saturated aqueous solution of HP-β-CD, all add under rear room temperature and continue to stir 4 hours, 45 ℃ of rotary evaporations are removed most ethanol.Pack tray into, put in freezer compartment of refrigerator, the pre-freeze time is 12h, and temperature is-50 ℃, when condenser temperature reaches-50 ℃ in freeze drying box, puts into sample, evacuation, and pressure is no more than 20Pa, and sublimation drying 24h, obtains clathrate;
Microcrystalline Cellulose is crossed 100 mesh sieves, and rosuvastain calcium hydroxypropyl-cyclodextrin clathrate, mannitol, starch and microcrystalline Cellulose are mixed to equal Uniform, adds 2% polyvinylpyrrolidone aqueous solution and makes soft material, with 18 mesh sieve granulations;
Granule is dried 4 hours at 70 ℃; Granule adds low-substituted hydroxypropyl cellulose and magnesium stearate, Stepanol MG to mix after drying, 20 mesh sieve granulate, last tabletting.
Embodiment 3
Preparation technology:
Getting recipe quantity HP-β-CD is dissolved in right amount in appropriate water and makes saturated aqueous solution, rosuvastain calcium is crossed 120 mesh sieves, be dissolved in appropriate ethanol, under magnetic agitation, the alcoholic solution of rosuvastain calcium is slowly added in the saturated aqueous solution of hydroxypropyl cyclodextrin, all add under rear room temperature and continue to stir 2 hours, 40 ℃ of rotary evaporations are removed most ethanol.Pack tray into, put in freezer compartment of refrigerator, the pre-freeze time is 12h, and temperature is-50 ℃, when condenser temperature reaches-50 ℃ in freeze drying box, puts into sample, evacuation, and pressure is no more than 20Pa, and sublimation drying 24h, obtains clathrate;
Microcrystalline Cellulose is crossed 100 mesh sieves, and rosuvastain calcium hydroxypropyl-beta-cyclodextrin inclusion, mannitol, starch and microcrystalline Cellulose are mixed to equal Uniform, adds 2% polyvinylpyrrolidone aqueous solution and makes soft material, with 18 mesh sieve granulations;
Granule is dried 6 hours at 40 ℃; Granule adds cross-linking sodium carboxymethyl cellulose and magnesium stearate to mix after drying, 20 mesh sieve granulate, last tabletting.
Biological test
Embodiment 4 Rosuvastatin calcium dispersible tablet Study on relative bioavailability
1 materials and methods
1.1 medicines and reagent
Test preparation: Rosuvastatin calcium dispersible tablet I, prepares specification 80mg/ sheet according to the embodiment of the present invention 1; Reference preparation: commercially available rosuvastain calcium ordinary tablet II, specification 5mg/ sheet, AstraZeneca pharmaceutical Co. Ltd.
1.2 instruments and high performance liquid chromatography (HPLC) condition
SPD-10Avp UV-detector, LC-10ADvp infusion pump, is Japanese Shimadzu company and produces; N2000 chromatographic data workbench software, Zhejiang University's intelligence reaches Information Technology Co. Ltd and produces; AT-130 post case, AUTOSCIENCE company produces; High speed micro centrifuge, Beijing Medical Centrifugal Machine Factory; BT25S electronic balance, Sartorius produces.Chromatographic condition: HigginsC
18post, 250mmX4.6mm, I.D.5 μ m, column temperature is; 35 ℃, mobile phase: organic facies (methanol: acetonitrile 400:275): water (acetic acid: water=1:60): 70:30, flow velocity 1.0ml/min. detects wavelength 225nm, sensitivity 0.005AUFS.
1.3 sample process
The accurate serum 0.2ml that draws is placed in 2ml tool plug centrifuge tube, and precision adds nimesulide (interior mark) solution (22 μ g/ml) 20 μ l, vortex 1min.Precision adds acetonitrile 0.6ml, vortex 2min, and 16000r/min high speed centrifugation 10min, gets supernatant 20 μ 1 sample introductions.
The foundation of 1.4 serum standard curves
Get blank test tube and add respectively not commensurability standard solution, dry up with nitrogen, then add the blank serum of 0.2ml, make its concentration be respectively 0.0388,0.097,0.194,0.485,0.97,1.94,3.8 μ g/ml, by " sample process " lower operation, record the peak area of rosuvastain calcium and internal standard substance.With rosuvastain calcium peak area (Ai) and the ratio (Ai/As) of internal standard substance peak area (As), concentration (X, μ g/ml) is carried out to linear regression.
1.5 precision and determination of recovery rates
Basic, normal, high by (0.097 with blank serum preparation, 0.485,1.94 μ g/ml) the rosuvastain calcium standard series of 3 variable concentrations, each concentration is carried out 5 sample analyses, by " sample process " lower operation, calculate in a few days, the coefficient of variation in the daytime, extraction recovery, the preci-sion and accuracy of evaluation methodology.
1.6 animal subjects are selected
12 male dogs of healthy Beagle, body weight 10 scholar 1kg; 6 monthly ages of age.Complete physical examination is all normal, comprising auscultation of lung, liver palpation of spleen, electrocardiogram, heart rate, blood pressure, hepatic and renal function, routine blood test, routine urinalysis etc.
1.7 EXPERIMENTAL DESIGN
12 healthy Beagle dogs are divided into 2 groups at random, adopt the random trial design of single dose binary cycle, and twice intertrial interval phase is 1 week; Each cycle dosage is 5mg; Start fasting 12h the first 1 day evening in test day, starts test the 2nd day 7: 30 morning.Give rosuvastain calcium is subject to test preparation or reference preparation to single dose on an empty stomach.Before administration and after administration 0.5,1,1.5,2,2.5,3,3.5,4,4.5,5,6,8,12,24h venous blood collection 3ml.Blood sample is through centrifuging and taking serum, put in-20 ℃ of refrigerators, preserve to be measured.Take medicine behind pond and freely intake, unified feed after 4h.The tested dog adverse events of tight observation.Tested dog avoids aggravating activities after taking medicine.
1.8 date processing and statistical method
According to surveyed rosuvastain calcium blood drug level-time data, adopt DAS2.0 pharmacokinetics program, calculate main pharmacokinetic parameter (Cmax, the Tmax measured value of rosuvastain calcium test preparation and reference preparation, AUCmax adopts trapezoidal method to calculate), Tmax adopts rank test, Cmax and AUCmax go respectively to adopt t check after ln logarithm, and carry out (1～2 α) Confidence interval analysis, and evaluate the bioavailability of Rosuvastatin calcium dispersible tablet I to rosuvastain calcium ordinary tablet II.
2 results
2.1 pharmacokinetic parameter
According to surveyed rosuvastain calcium serum-concentration-time data, utilize DAS2.0 pharmacokinetics program to calculate main pharmacokinetic parameters Tmax, Cmax, AUC
0-∞with relative bioavailability F(%) (in table 1).
The pharmacokinetic parameter of table 1 Rosuvastatin calcium dispersible tablet I and rosuvastain calcium ordinary tablet II
| Parameter | Rosuvastatin calcium dispersible tablet I | Rosuvastain calcium ordinary tablet |
| AUC 0-∞（μg/ml） | 116.45±6.89 | 95.36±10.25 |
| ln?AUC 0-∞ | 4.68±0.08 | 4.34±0.15 |
| Cmax（mg/ml） | 25.56±3.67 | 17.05±4.35 |
| lnCmax | 3.18±0.12 | 2.75±0.25 |
| Tmax（h） | 2.26±0.45 | 2.70±0.65 |
| F（%） | 115.96 scholars 18.80% | ? |
Tmax is through rank test difference not statistically significant (P>0.05); Rosuvastatin calcium dispersible tablet Tmax, Cmax, AUC
0-∞numerical value is through to number conversion, and the results of analysis of variance shows, Rosuvastatin calcium dispersible tablet I compared with rosuvastain calcium ordinary tablet II, ln (AUC
0-∞), lnC
maxbetween medicament, difference has statistical significance (P<0.05), Rosuvastatin calcium dispersible tablet I is 115.96 scholars 18.80% to the relative bioavailability of rosuvastain calcium ordinary tablet II, this explanation Rosuvastatin calcium dispersible tablet I is compared with rosuvastain calcium ordinary tablet II, and bioavailability obviously improves.
Owing to having described the present invention according to above embodiment, any to be equal to replacement be all apparent for a person skilled in the art, and be included among the present invention.
Claims (7)
1. a Rosuvastatin calcium dispersible tablet, it is made up of rosuvastain calcium, HP-β-CD, filler, binding agent, lubricant and disintegrating agent, wherein said rosuvastain calcium and HP-β-CD weight ratio are 1:1-3, and rosuvastain calcium and HP-β-CD formation clathrate; Described filler is amylum pregelatinisatum, microcrystalline Cellulose and mannitol; Described binding agent is selected from 2% polyvinylpyrrolidone aqueous solution; Described lubricant is selected from one or more in magnesium stearate, Pulvis Talci and Stepanol MG; Described disintegrating agent is selected from one or more in microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose and low-substituted hydroxypropyl cellulose.
2. dispersible tablet according to claim 1, wherein said rosuvastain calcium, filler, disintegrating agent, binding agent and lubricant according to the proportioning of weight portion are:
3. dispersible tablet according to claim 2, wherein said rosuvastain calcium, filler, disintegrating agent, binding agent and lubricant according to the proportioning of weight portion are:
4. according to the arbitrary described dispersible tablet of claim 1-3, wherein said lubricant is Pulvis Talci, and described disintegrating agent is low-substituted hydroxypropyl cellulose.
5. dispersible tablet according to claim 1, wherein said rosuvastain calcium and the weight ratio of hydroxypropyl cyclodextrin are 1:3.
6. the preparation method of a Rosuvastatin calcium dispersible tablet, it comprises following steps: first form clathrate with hydroxypropyl-cyclodextrin and rosuvastain calcium, wherein the weight ratio of rosuvastain calcium and HP-β-CD is 1:1-3, again by gained clathrate, mannitol, starch and microcrystalline Cellulose, mix equal Uniform, add 2% polyvinylpyrrolidone aqueous solution and make soft material, with 18 mesh sieve granulations; Granule is at 40-70 ℃ of dry 5-6 hour; Granule adds low-substituted hydroxypropyl cellulose and Pulvis Talci to mix after drying, 20 mesh sieve granulate, last tabletting.
7. preparation method according to claim 6, the preparation process of wherein said clathrate is: get HP-β-CD and be dissolved in right amount in appropriate water and make saturated aqueous solution, rosuvastain calcium is crossed 120 mesh sieves,
Be dissolved in appropriate ethanol, under magnetic agitation, the alcoholic solution of rosuvastain calcium slowly added in the saturated aqueous solution of HP-β-CD, all add under rear room temperature and continue to stir 2-4 hour, 40-50 ℃ of rotary evaporation removed most ethanol, packs tray into, put in freezer compartment of refrigerator, the pre-freeze time is 12h, and temperature is-50 ℃, when in freeze drying box, condenser temperature reaches-50 ℃, put into sample, evacuation, pressure is no more than 20 Ρ a, sublimation drying 24h, obtains clathrate.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107811989A (en) * | 2016-09-14 | 2018-03-20 | 南京先声东元制药有限公司 | A kind of Rosuvastatin calcium medicine compound and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1557319A (en) * | 2004-02-09 | 2004-12-29 | 杨喜鸿 | Rosuvastatin dispersion tablet and its preparation method |
| CN101972260A (en) * | 2010-11-24 | 2011-02-16 | 天津市汉康医药生物技术有限公司 | Rosuvastatin calcium oral drug composition |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1557319A (en) * | 2004-02-09 | 2004-12-29 | 杨喜鸿 | Rosuvastatin dispersion tablet and its preparation method |
| CN101972260A (en) * | 2010-11-24 | 2011-02-16 | 天津市汉康医药生物技术有限公司 | Rosuvastatin calcium oral drug composition |
Non-Patent Citations (1)
| Title |
|---|
| AKBARI B.V ET.AL: "DEVELOPMENT AND EVALUATION OF ORODISPERSIBLE TABLETS OF ROSUVASTATIN CALCIUM-HP-β-CD INCLUSION COMPLEX BY USING DIFFERENT SUPERDISINTEGRANTS", 《INTERNATIONAL JOURNAL OF PHARMACY&TECHNOLOGY》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107811989A (en) * | 2016-09-14 | 2018-03-20 | 南京先声东元制药有限公司 | A kind of Rosuvastatin calcium medicine compound and preparation method thereof |
| WO2018049989A1 (en) * | 2016-09-14 | 2018-03-22 | 南京先声东元制药有限公司 | Rosuvastatin calcium pharmaceutical composition and preparation method therefor |
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