CN101574344A - Niacin and statin medicinal composition and preparation method thereof - Google Patents
Niacin and statin medicinal composition and preparation method thereof Download PDFInfo
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- CN101574344A CN101574344A CNA200910015984XA CN200910015984A CN101574344A CN 101574344 A CN101574344 A CN 101574344A CN A200910015984X A CNA200910015984X A CN A200910015984XA CN 200910015984 A CN200910015984 A CN 200910015984A CN 101574344 A CN101574344 A CN 101574344A
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Abstract
The invention provides a niacin and statin medicinal composition and a preparation method thereof. The composition comprises a niacin sustained-release tablet core, a statins coating layer and a protective layer, and is characterized in that: the statins coating layer comprises statins, polyvinyl alcohol-polyethylene glycol grafted copolymer or butyl hydroxy anisol. The preparation method comprises the following steps: firstly preparing a niacin sustained-release tablet; taking the tablet as a tablet core, attaching a coating layer containing the statins on the tablet core, and coating one or more layers of gastric-soluble film coatings on the coating layer containing the statins; and preparing the niacin and statin medicinal composition by taking the statins of coating fluid containing the statins as main medicaments, the polyvinyl alcohol-polyethylene glycol grafted copolymer as a main coating material, the butyl hydroxy anisol as an antioxidant, and ethanol solution containing water as solvent.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition and preparation thereof, particularly a kind of nicotinic acid and statin medicinal composition and preparation method thereof.
Background technology
Primary hypercholesterolemia is a kind of common clinical, frequently-occurring disease with mixing dyslipidemia, between the order of severity of cardiovascular disease such as serum cholesterol concentration and atherosclerosis, coronary heart disease significant correlation is arranged.When serum cholesterol concentration raise, atherosclerotic generation probability also increased substantially.The treatment of cardiovascular disease has become global problem, and its M ﹠ M is the first place, and the annual life that seizes 1,200 ten thousand people in the whole world is near 1/4 of the total death toll of world population.Hyperlipidemia is the one of the main reasons that causes coronary heart disease and apoplexy, and cardiovascular and cerebrovascular diseases such as coronary heart disease, apoplexy are the underlying cause of deaths of global population.
Point out according to China adult dyslipidemia guideline of prevention and treatment 2007 editions, the medicine of hyperlipemia mainly contains following several: (1) three hydroxyl trimethyl glutaryl-CoA-reductase inhibitors (Statins): this type of drug development is the fastest, and market has overwhelming superiority, after lovastatin in 1987 comes out, so far existing simvastatin (1988), pravastatin (1989), fluvastatin (1993), atorvastatin (1997), simvastatin (1997, the recession city), Pitavastatin launch such as (2003).This class medicine is that the synthetic rate-limiting enzyme of cell inner cholesterol is the inhibitor of trihydroxy trimethyl glutaryl coenzyme A (HMG-CoA) reductase, is a most widely used clinically at present class lipid lowerers.
Be used alone fat-reducing medicament and have problems: big (3) the adverse reaction rate height of (1) effect limitation (2) daily dosage.Therefore nicotinic acid and statins are made compound preparation, meet clinical application custom and therapeutics demand, have tangible characteristics and advantage: (1) effect for reducing blood fat mutual supplement with each other's advantages (2) reduces day dosages (3) and reduces a side effect incidence rate.
U.S. Pat 5260305 has been announced the compositions of pravastatin and nicotinic acid and derivant thereof first.Stipulated in this patent that the pravastatin dosage range is 10～40mg in every or the every capsules, the dosage range of nicotinic acid is 75～1500mg.Nicotinic acid and pravastatin are common quick releasing formulation in this patent.
European patent EP 0969838, Irish patent IE 970731, Canadian Patent CA 2273298, U.S. Pat 6090830, world patent WO 199917774 have announced the preparation method of a kind of nicotinic acid and statin medicinal composition, this method is that statins is made the common quick release microsphere, nicotinic acid is made sustained-release micro-spheres, and during two kinds of microspheres are incapsulated according to a certain percentage.The dosage of nicotinic acid big (minimum dose is at 500mg clinically) but this patent exists can not be with the powder fill of statins common quick release microsphere and niacin sustained release microsphere in No. 0 capsule.
U.S. KOS company discloses the compound recipe patent of more statins and niacin sustained-release preparation, European patent EP 1743644, EP1743630, EP1792616, world patent WO1999006035, WO1999006046, U.S. Pat 20010006644, US 20040053975, US 20050255158.The preparation method of said composition is nicotinic acid to be made the slow releasing tablet of administration once-a-day by the method for the folk prescription patent US 6080428 of niacin sustained-release preparation, then with this slow releasing tablet as label, coating one deck contains the clothing film of Statins on this label, compound preparation of making and conduct administration once-a-day.Embodiment in this patent exists the problem of dissolution defective (dissolution is lower than 75% in the 30min).In addition, owing to further do not wrap protective layer after having wrapped the simvastatin layer, so the preparation that this patent obtains has the problem that related substance exceeds standard in put procedure.
Korea S CHONG KUN DANG (Zhong Gentang) Pharmaceutical Co., Ltd has announced the compositions patent of some statinses and niacin sustained-release preparation in 2007, comprise Korean Patent KR20070063350, world patent WO2007069827.The preparation method of nicotinic acid is that nicotinic acid, HPMC, poly(ethylene oxide), silicon dioxide, sodium bicarbonate are crossed 30 mesh sieves, mixing in the said composition, adds stearic acid mixing again, and tabletting gets final product.The statins spy refers to simvastatin, and simvastatin is that the mode by coating wraps in outside the niacin sustained release layer.The simvastatin release layer is to be grouped into by one or more one-tenth such as simvastatin, HPMC, PEG-6000, polyvidone, polyvinylpolypyrrolidone, Pu Luoshamu 407, polyacrylic resin Eudragit EPO, HP-beta-schardinger dextrin-, ethanol, sorbitol, citric acid, BHA (butylated hydroxyanisole), dichloromethane, Tween 80, SLS, Pulvis Talci.In order to keep the stable of simvastatin, at the outer coating layer protective layer of simvastatin or be called sealing coat, this layer is made up of HPMC, PEG 6000 and titanium dioxide.But the preparation that this patent prepares has the problem that related substance exceeds standard in put procedure.
Chinese patent CN 03100575.6 relates to a kind of compositions for the treatment of hyperlipidemia, wherein contains the following compositions of effective dose: one or more in the derivant of (1) nicotinic acid or nicotinic acid; (2) one or more in the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor statin compound; And pharmaceutically useful adjuvant.Described effective amount of actives (1) is 5～100 with the weight ratio of effective amount of actives (2): 1.But this patent protection is the compositions of acipimox and lovastatin.
Chinese patent CN 02129253.1 relates to a kind of medicine that contains nicotinic acid and statins, be a kind of double-layer tablet, wherein one deck contains acceptable slow releasing preparation adjuvant on the nicotinic acid of clinical effective and the galenic pharmacy, and another layer contains acceptable rapid release or slow releasing preparation adjuvant on the statins of clinical effective and the galenic pharmacy.
Chinese patent CN 200580017017.7 has announced a kind of oral niacin sustained release composition that is used for, the carrier that is used for slow release and the pharmacy acceptable additive that comprise nicotinic acid, form by hydrophilic polymer and hydrophobic polymer, described hydrophilic polymer is poly(ethylene oxide) and natural gum, and described compositions can be kept the constant release rate of nicotinic acid.This patent is actually the folk prescription patent of preparation niacin slow-release tablet.
German patent DE 1081229B, DE 1094457B; British patent GB 922458A, GB 922459A have described the method for preparing the graft copolymer of polyvinyl alcohol on Polyethylene Glycol by the hydrolysed ethylene base, and in textile and cosmetics as the purposes of protecting colloid, water soluble package material, sizing agent and finishing agent.These patents are first polyvinyl alcohol-polyethyleneglycol-graft copolymer to be applied to commercial production.
On June 4th, 2008, drugs approved by FDA polyvinyl alcohol-polyethyleneglycol-graft copolymer (3: 1) be used for the rapid release coating material, commodity are by name
IR uses
After ibuprofen tablet new drug application (ANDA75-661) success of IR coating,
IR has also obtained approval thereupon.This is the safety evaluation that this novel polyethylene alcohol/polyethyleneglycol-graft copolymer passes through U.S. official first.
Functional and the safety of IR has all obtained sure assessment.
Polyvinyl alcohol-polyethyleneglycol-graft copolymer (
IR) compare with low viscous hypromellose (5mPas or 3mPas), it is lower to have viscosity, the advantage that film property is stronger.Can increase the dissolution of medicine as coating material.
Summary of the invention
Technical problem to be solved by this invention provides a kind of nicotinic acid and statin medicinal composition and preparation method thereof, is characterized in statins stable in properties in storage, and the stripping behavior can meet the release request of Chinese Pharmacopoeia version in 2005 to preparation.
The invention provides a kind of nicotinic acid and statin medicinal composition; contain niacin sustained release label, statins coatings and protective layer; it is characterized in that: described statins coatings contains statins, polyvinyl alcohol-polyethyleneglycol-graft copolymer or Butylated hydroxyanisole; the mass ratio of polyvinyl alcohol-polyethyleneglycol-graft copolymer and statins is 1: 2～2: 1, and the mass ratio of Butylated hydroxyanisole and statins is 1: 400～1: 40.
Said nicotinic acid of the present invention and statin medicinal composition are meant nicotinic acid and lovastatin compositions or nicotinic acid and simvastatin composite.Nicotinic acid is the slow releasing preparation of 24h, and statins is the common quick release preparation.
The preparation method for preparing this nicotinic acid and statin medicinal composition; be to prepare niacin slow-release tablet earlier; be label then with this tablet; coating contains the coatings of statins; and outside containing the coatings of statins again one or more layers stomach dissolution type film-coat layer of coating as protective layer; the coating solution that it is characterized in that containing statins is to be principal agent with the statins; polyvinyl alcohol-polyethyleneglycol-graft copolymer is main coating material; Butylated hydroxyanisole is as antioxidant, and aqueous ethanol liquid is made as solvent.
Wherein polyvinyl alcohol-polyethyleneglycol-graft copolymer is main coating material, can add common gastric solubility coating materials such as hypromellose (HPMC), methylcellulose, polyvidone in the coating material.
The ratio of polyvinyl alcohol-polyethyleneglycol-graft copolymer and statins is 1: 2～2: 1 (w/w).
Contain that BHA is an antioxidant in the coating solution of statins, the ratio of BHA and statins is 1: 400～1: 40 (w/w).
Solvent is that ethanol and purified water are mixed with a certain proportion of solvent, and the proportioning of ethanol and purified water is 9: 1～2: 8 (v/v).The ratio of solvent and statins is 150: 1～30: 1 (ml/g).
In order to make the statins coating attached on the niacin sustained release layer, the coating filmogen of selection must have moulding property, plasticity or pliability preferably.For make statins when the 45min dissolution more than 75%, must viscosity enough low of the film-coat that the coating filmogen of selection is prepared.Thin film coating material commonly used is HPMC, and for disintegrate and discharge medicine rapidly in gastrointestinal tract, generally selecting viscosity coefficient is 6mPas or 5mPas or 3mPas.But the pliability of this material is not enough, usually occurs " sliver " phenomenon in the coating process.In order to improve this sliver phenomenon, usually need to strengthen the HPMC consumption or in coating solution, add plasticizer, such as PEG400, Macrogol 4000, polyethylene glycol 6000 etc., the result who strengthens the HPMC consumption or add plasticizer in coating solution is that the dissolution of statins is lower when 45min, less than 75%.In order to improve the dissolution of statins, can in coating solution, add surfactant, such as (as having more embodiment to add one or more surfactants among Korean Patent KR20070063350 and the world patent WO 2007069827) such as sodium lauryl sulphate, Tween 80, sorbester p17s.Experimental result shows, adds the stripping that above-mentioned surfactant can improve statins, but in accelerated test was investigated, the related substance of statins exceeded standard.Though this can improve the stripping of statins with regard to the instruction card surface-active agent, but usually causes the statins instability, and is promptly relatively poor with the statins compatibility.
In order to solve this contradiction, (BASF Aktiengesellschaft produces, and commodity are by name to have selected polyvinyl alcohol-polyethyleneglycol-graft copolymer (3: 1)
IR) as the coating material of statins, accelerated test is investigated the result and is shown, under the same conditions, uses
IR is as coating material, and the related substance of statins is minimum, illustrates that the compatibility of this coating material and statins is better.In addition, because the viscosity of this material is low, pliability is strong, even do not add surfactant, the dissolution of statins is also higher.
According to document, owing to have unstable group in the simvastatin structure, be 4-hydroxyl-6 oxygenates-2H-pyranoid ring, oxidized easily, hydrolysis, dehydration and dimerization (George B.Smith, Lisa Di Michele, Lawrence F.Colwell, et al.Autooxidation of simvastatin[J] .Tetrahedron, 1993,49 (21), 4447-4462), need select for use suitable antioxidant to improve the stability of tablet at storage process.At the experiment initial stage, selected for use BHA for antioxidant with provide weakly acidic condition help simvastatin stable (Wang Yongjun. the selecting for use of antioxidant [J] in the simvastatin sheet. Shandong medical industry, 2000,19 (5): 34-35).
In the coating of protective layer, in order not influence the stripping of simvastatin, can carry out completely cutting off effectively with the simvastatin release layer with extraneous simultaneously, should select suitable protective layer.The 32K coating powder, OY transparent type coating powder of having selected to block the production of happy Kanggong department in the experiment are as protective layer.
Advantage of the present invention: statins can be at the 0.01molL that contains 0.5% sodium lauryl sulphate (SLS)
-1In the phosphate buffer (pH7.0), rotating speed is 100rpm, 37 ℃ of temperature, and dissolution is more than 75% during 45min.
Description of drawings
Fig. 1 is the structural representation of compound tablet of the present invention.
Fig. 2 is a nicotinic acid release in vitro curve among the embodiment 1.
Among the figure: 1 hydrochloric acid slow release label, 2 coatings, 3 protective layers
The specific embodiment
The preparation method of nicotinic acid and statin medicinal composition can be described in further detail the present invention by following embodiment.
Nicotinic acid and lovastatin preparation of compositions method are as follows:
A: the preparation of niacin sustained release layer
Nicotinic acid 500g
HPMC
K4M(in add) 92g
Polyvidone
K9016g
Purified water 190g
HPMC
K4M(adding) 95g
Stearic acid 7g
Make 1000 altogether
Take by weighing nicotinic acid, HPMC by recipe quantity
K4M(in add) and polyvidone
K90Place quick mixer granulator (KJZ-10 type; friendship pharmaceutical technology equipment company of last Hisense) mixes 15min in; with purified water as fountain solution; add in the quick mixer granulator and stir fast and THE ADIABATIC SHEAR IN 2min, wet granular 65 ± 5 ℃ of dry 8h in drying baker with making make moisture＜2% (wt); cross 16 mesh sieve granulate, add HPMC
K4M(adding) and stearic acid, mixing is at rotary tablet machine (C﹠amp; The C800 type, Beijing wound Bo Jiawei Science and Technology Ltd.) to go up and adopt the oval stamping of Φ 15.8 * 9.2mm, sheet heavily is 710mg, control tablet hardness is 150～200N.
B: the coating of lovastatin layer
Prescription:
Lovastatin 20g
BHA 0.1g
95% ethanol (v/v) 400g
Purified water 300g
Get 95% alcohol of recipe quantity, successively add BHA and lovastatin, stir evenly, add successively again purified water,
IR stirs evenly, as coating solution.Get the tablet of niacin sustained release layer, place high-efficiency coating machine (BGB-5B type, Pharmaceutical Equipment Factory, Wenzhou City), the temperature of control air inlet is 60 ℃, and the control air inlet is pressed and is 0.3MPa, and the control strip temperature remains on 34～40 ℃, and the rotating speed of control coating machine is 7～12rpm.The coating terminal point is to be undertaken by the weightening finish of control tablet.Before the beginning coating, get it filled 50 at random, weigh, calculate every average weight W
0In the coating process and when finishing, get it filled 50 at random, weigh, calculate every average weight W
1When the coating terminal point, satisfy W
1≈ 1.053W
0The time stop coating.
C: the coating of protective layer
The preparation solid content is 10% (w/w) 32K type stomach dissolution type (production of the happy Kanggong of Shanghai card department) coating solution, and the preparation solid content is 8% (w/w) OY type stomach dissolution type (production of the happy Kanggong of Shanghai card department) coating solution.Get the tablet that wraps behind the lovastatin layer, place high-efficiency coating machine (BGB-5B type, Pharmaceutical Equipment Factory, Wenzhou City), the temperature of control air inlet is 70 ℃, the control air inlet is pressed and is 0.3MPa, and the control strip temperature remains on 35～45 ℃, and the rotating speed of control coating machine is 7～12rpm.The coating terminal point is to be undertaken by the weightening finish of control tablet.The weightening finish of 32K layer tablet is at about 2.5% (w/w), and the weightening finish of OY layer tablet is at about 1.2% (w/w).
The preparation method of nicotinic acid and simvastatin composite is as follows:
A: the preparation of niacin sustained release layer is with embodiment 1.
B: the coating coating method of simvastatin layer is with embodiment 1.It is as follows to write out a prescription:
Simvastatin 20g
BHA 0.1g
95% ethanol (v/v) 900g
Purified water 500g
The coating terminal point is to be undertaken by the weightening finish of control tablet.Before the beginning coating, get it filled 50 at random, weigh, calculate every average weight W
0In the coating process and when finishing, get it filled 50 at random, weigh, calculate every average weight W
1When the coating terminal point, satisfy W
1≈ 1.057W
0The time stop coating.
C: the coating of protective layer is with embodiment 1.
Nicotinic acid and lovastatin preparation of compositions method.
Obtain different lovastatin layer coating solutions by table 1 preparation.The preparation of niacin sustained release layer, lovastatin layer coating, protective layer coating are seen embodiment 1.
The prescription of lovastatin layer coating solution among table 1 embodiment 3～7
Embodiment 8～12
The preparation method of nicotinic acid and simvastatin composite.
Obtain different simvastatin layer coating solutions by table 2 preparation.The preparation of niacin sustained release layer, simvastatin layer coating, protective layer coating are seen embodiment 2.
The prescription of simvastatin layer coating solution among table 2 embodiment 8～12
The ultra-violet analysis of nicotinic acid content:
Sample thief is according to " method in Chinese pharmacopoeia version appendix in 2005 the ultraviolet determination method is the content that operation wavelength is measured nicotinic acid with 263nm.
The mensuration of nicotinic acid release:
Sample thief, according to " method in Chinese pharmacopoeia version appendix in 2005 drug release determination method and the dissolution method is a dissolution medium with water, and volume is 900mL, rotating speed is 100rpm, respectively 1,3,6,9,12,16,20 and 24h take out 2mL, replenish solution simultaneously with volume, filter, get subsequent filtrate and add the solution that water is made suitable concentration, as need testing solution, it is an amount of that in addition precision takes by weighing the nicotinic acid reference substance, be dissolved in water and quantitatively dilution to make concentration be 10 μ gmL
-1Solution, product solution in contrast.Measure trap respectively at 263nm wavelength place.Calculate the release of nicotinic acid with external standard method at each sampling time point.The release profiles of nicotinic acid is seen Fig. 2 among the embodiment 1.Among the figure as can be seen, nicotinic acid release behavior basically identical after 6 months accelerated tests.
The HPLC of simvastatin/lovastatin analyzes
Chromatographic column: Agilent ZORBAX SB-C
18Chromatographic column (4.6 * 150mm, 5 μ m);
Mobile phase: acetonitrile-0.025molL
-1Sodium dihydrogen phosphate (pH4.5) (65: 35);
Detect wavelength: 238nm;
Flow velocity: 1.0mLmin
-1
Column temperature: 35 ℃;
Sample size: 10 μ L.
The dissolution determination of simvastatin or lovastatin
6 of sample thiefs are according to the operation of dissolution determination first method, to contain the 0.01molL of 0.5% sodium lauryl sulphate (SLS)
-1Phosphate buffer (pH7.0) is a dissolution medium, and rotating speed is 100rpm, and operation when 45min, is got the dissolution fluid subsequent filtrate as need testing solution in accordance with the law.Other gets simvastatin or the lovastatin reference substance is an amount of, accurate claims surely, adds above-mentioned solution dissolving and makes the solution product solution in contrast that contains 10 μ g among every 1mL approximately.Get each 10 μ L of need testing solution and reference substance solution respectively, inject chromatograph of liquid, the record chromatogram is with the dissolution of simvastatin or lovastatin in every tablet of medicine of external standard method calculating.
The dissolution of 0 day and 60 ± 1 ℃ of accelerated tests simvastatin/lovastatin in the time of 14 days sees Table 1.
Table 1 dissolution determination result
| 0 |
60 ± 1 ℃ 14 | |
| Embodiment | ||
| 1 | 91％ | 90 |
| Embodiment | ||
| 2 | 90％ | 92 |
| Embodiment | ||
| 3 | 89％ | 91％ |
| Embodiment 4 | 92％ | 91 |
| Embodiment | ||
| 5 | 90％ | 88 |
| Embodiment | ||
| 6 | 91％ | 93％ |
| Embodiment 7 | 89％ | 92％ |
| Embodiment 8 | 94％ | 91％ |
| Embodiment 9 | 93％ | 92 |
| Embodiment | ||
| 10 | 92％ | 92％ |
| Embodiment 11 | 85％ | 86％ |
| Embodiment 12 | 86％ | 89％ |
The determination of related substances of simvastatin/lovastatin
10 of sample thiefs place the 200mL volumetric flask, add second eyeball-0.05molL
-1Sodium acetate solution (pH4.0) (80: 20), ultrasonic 15min leaves standstill, and filters, and precision is measured subsequent filtrate 5mL, is diluted to 25mL with above-mentioned buffer, shakes up, as need testing solution.Get need testing solution 20 μ L, inject chromatograph of liquid, the record chromatogram is with the related substance of area normalization method calculating simvastatin.
The same simvastatin of the mensuration of lovastatin related substance.
The stability test of compound preparation
Get the foregoing description sample 1～12 simulation commercially available back, under 40 ± 3 ℃ of conditions of temperature, placed 6 months, quicken to investigate stability of sample.Because nicotinic acid is all more stable under room temperature and higher temperature, thus nicotinic acid is not carried out stability study, and simvastatin or lovastatin are studied.According to the method for " method of the determination of related substances of simvastatin/lovastatin ", calculate the stability of embodiment sample 1～12, see Table 2.
Table 2 stability test result
| 0 |
40 ± 3 ℃ of | |
| Embodiment | ||
| 1 | 0.51％ | 0.92 |
| Embodiment | ||
| 2 | 0.58％ | 0.91 |
| Embodiment | ||
| 3 | 0.58％ | 0.90％ |
| Embodiment 4 | 0.57％ | 0.89 |
| Embodiment | ||
| 5 | 0.58％ | 0.91 |
| Embodiment | ||
| 6 | 0.57％ | 0.90％ |
| Embodiment 7 | 0.56％ | 0.91％ |
| Embodiment 8 | 0.58％ | 0.90％ |
| Embodiment 9 | 0.52％ | 0.91 |
| Embodiment | ||
| 10 | 0.58％ | 0.92％ |
| Embodiment 11 | 0.56％ | 0.91％ |
| Embodiment 12 | 0.58％ | 0.90％ |
Claims (5)
1, a kind of nicotinic acid and statin medicinal composition; contain niacin sustained release label, statins coatings and protective layer; it is characterized in that: described statins coatings contains statins, polyvinyl alcohol-polyethyleneglycol-graft copolymer or Butylated hydroxyanisole; the mass ratio of polyvinyl alcohol-polyethyleneglycol-graft copolymer and statins is 1: 2～2: 1, and the mass ratio of Butylated hydroxyanisole and statins is 1: 400～1: 40.
2, nicotinic acid according to claim 1 and statin medicinal composition is characterized in that described statins is lovastatin or simvastatin.
3, a kind of preparation method for preparing claim 1 or 2 described nicotinic acid and statin medicinal composition; be to prepare niacin slow-release tablet earlier; be label then with this tablet; coating contains the coatings of statins; and outside containing the coatings of statins again one or more layers stomach dissolution type film-coat layer of coating as protective layer; the coating solution that it is characterized in that containing statins is to be principal agent with the statins; polyvinyl alcohol-polyethyleneglycol-graft copolymer is main coating material; Butylated hydroxyanisole is as antioxidant, and aqueous ethanol liquid is made as solvent.
4, preparation method according to claim 3 is characterized in that described polyvinyl alcohol-polyethyleneglycol-graft copolymer is main coating material, adds common gastric solubility coating materials such as hypromellose, methylcellulose or polyvidone in the coating material.
5, preparation method according to claim 3 is characterized in that described solvent is that ethanol and purified water are formulated, and the volume proportion of ethanol and purified water is 9: 1～2: 8, and the ratio of solvent and statins is 30～150ml/g.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8632807B2 (en) | 2011-05-20 | 2014-01-21 | Astrazeneca Uk Limited | Pharmaceutical composition |
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2009
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8632807B2 (en) | 2011-05-20 | 2014-01-21 | Astrazeneca Uk Limited | Pharmaceutical composition |
| US10028953B2 (en) | 2011-05-20 | 2018-07-24 | Astrazeneca Uk Limited | Pharmaceutical composition of rosuvastatin calcium |
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Application publication date: 20091111 |