CN102028658B - Solid preparation containing rosuvastain calcium liposome - Google Patents
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Abstract
The invention discloses a solid preparation containing rosuvastain calcium liposome and particularly relates to the solid preparation containing rosuvastain calcium liposome and a preparation method thereof. The rosuvastain calcium liposome mainly comprises 1 part of rosuvastain calcium, 2-25 parts of soyabean lecithin, 0.5-10 parts of cholesterol, 0.5-12 parts of tween 80 and 0.05-10 parts of sodium desoxycholate. The rosuvastain calcium solid preparation prepared from the liposome not only increases the dissolution, but also improves the stability and the bioavilability. The quality of preparation products is improved and the toxic or side effects are reduced.
Description
Technical field
The present invention relates to a kind of rosuvastain calcium lipidosome solid preparation and method for making thereof, particularly a kind of amorphous rosuvastatin calcium lipidosome solid preparation and method for making thereof belong to medical technical field.
Background technology
Cardiovascular disease is the disease of one type of serious harm human health, and in recent years, worldwide its M & M can be in any more all the time, is human at present No.1 killer.According to World Health Organization's statistics, annual nearly 1,500 ten thousand people in the whole world die from cardiovascular and cerebrovascular disease.Raising in China along with living standards of the people, the growth of aging population (the present aged more than 60 years old has accounted for 10.7% of national population, reaches 1.3 hundred million more than).The quickening of rhythm of life, dietary habit are also to hyperpyrexia, high fat development.Blood circulation diseases such as coronary heart disease (CHD), hypertension, angina pectoris, hyperlipidemia and sickness rate and mortality rate appear and continue the trend that rises; Occupied the first place in the city; And in 70% the rural area that accounts for national population; Cardiovascular and cerebrovascular disease also leaps to the 3rd, and its sickness rate is up to 8%, and mortality rate accounts for 50% of general mortality rate.
Research data shows that high-cholesterol disease and lipid metabolism are the principal element that causes cardiovascular disease unusually.Wherein hypercholesterolemia is that coronary heart disease and hypertensive main hazard factor take place; Dysbolism of blood fat not only has confidential relation with atherosclerotic generation and development, and to coronary heart disease acute events and unstable angina pectoris, acute myocardial infarction and arteria coronaria sudden death) play an important role.
Rosuvastain calcium (Rosuvastain Calcium) is a kind of selectivity HMG-CoA reductase inhibitor, the HMG-CoA reductase inhibitor be change 3-hydroxy-3-methylglutaryl-coenzyme A be first valerate-precursor of cholesterol-rate-limiting enzyme.The main site of action of rosuvastain calcium is the target organs of liver-cholesterol reducing.Rosuvastain calcium has increased liver LDL cell surface receptor number, promotes absorption and the catabolism of LDL, and the liver that has suppressed VLDL is synthetic, reduces the sum of VLDL and LDL microgranule thus.Rosuvastain calcium is developed by the wild justice of Japanese salt (Osaka Shionogi company), belongs to synthetic type of his spit of fland medicine, transfers Britain Astrazeneca AB (AstraZeneca) in April, 1998.In December, 2000 AstraZeneca is decided to be " can decide " (Crestortm) with the trade name of rosuvastain calcium; April calendar year 2001 next year, Japan at first went on the market; Got the Green Light in the U.S. in August, 2003, becomes the 7th statins that comes into the market thus in Holland's listing in 2002.Be mainly used in treatment constitutional, familial hypercholesterolemia and mixed type dyslipidemias mass formed by blood stasis, and clinical test results shows: other each statinses that its effect that reduces LDL-C and rising HDL-C is superior to having gone on the market.
Also there is defective in rosuvastain calcium, for example in higher temperature or higher levels of humidity environment, degrades easily; The primary product that forms is (3R; 5S) lactone catabolite and oxidation product, thus the formulated product operating difficulties caused, and the pharmaceutical composition for preparing does not reach the requirement of storage life.This unstability is to be determined by its structure itself, and the β in the rosuvastain calcium molecule on the heptenoic acid chain, δ-hydroxyl are very unstable; Wherein, The hydroxyl that carbon-to-carbon double bond is adjacent is easy to be oxidized to ketone, also molecule inner ring condensation can take place, and generates lactone.
Therefore, a kind of Rosuvastatin calcium medicine compound of keeping supplying the long-term stability of selling in the city be obtained, just its problem of degraded easily must be solved.
WO 01/54669 discloses a kind of tablet of the HMGCoA of containing digestive enzyme inhibitor, and the characteristic of this tablet is to contain Rosuvastatin and pharmaceutically acceptable salt and inorganic multivalent salts.This disclosure of the Invention through improving the stability of principal agent in the tablets in tablet, adding multivalent salts such as Mg salt, Zn salt, Al salt.But it only still increases comparatively fast through the method impurity content that adds inorganic multivalent salts raising stability, and does not have long-acting study on the stability.
CN1557319A discloses a kind of Rosuvastatin dispersible tablet and preparation method thereof.This dispersible tablet is made up of rosuvastain calcium and pharmaceutic adjuvant, adopts the wet granule compression tablet preparation.This dispersible tablet has that drug release rate is fast, taking convenience, can improve the onset speed and the bioavailability of oral Rosuvastatin.But its preparation technology is relatively loaded down with trivial details.
CN200610000665.8 discloses a kind of Rosuvastatin soft capsule and preparation method thereof.This soft capsule has improved the stripping quantity of Rosuvastatin, has improved curative effect of medication, but also more complicated of its technology.
CN200780034516.6 discloses a kind of new pharmaceutical composition that comprises amorphous rosuvastatin calcium; Comprise magnesium hydroxide and/or calcium acetate or calcium gluconate or calcium glycerophosphate or aluminium hydroxide as stabilization additives, and one or more acceptable for pharmaceutical excipient.But the adding of a large amount of alkaline agents also is unfavorable for the preparations shaping of pharmaceutical composition, get in the body after alkaline agent also possibly cause multiple unforeseeable side effect, even possibly cause the reduction of bioavailability.
Liposome (liposomes) is dispersed in phospholipid by Britain scholar Bangham and Standish at first and finds when carrying out electron microscopic observation in the water.Phospholipid is dispersed in and forms multilamelar vesicles, every layer of bilayer that is lipid in the water naturally; Separated by water between vesicle central authorities and each layer, the about 4nm of bilayer thickness, the bimolecular folliculus with this similar biofilm structure became liposome afterwards.
Liposome research is that liposome is meant that the earliest the natural grease compounds is suspended in the vesicle with double seal structure that forms in the water, now also can be prepared by the phosphatide cpd of synthetic when the active field of previous ten minutes.People such as late 1960s Rahman at first use liposome as pharmaceutical carrier; In recent years, along with the continuous progress of biotechnology, liposome preparation technology is progressively perfect; The liposome mechanism of action is further illustrated; Liposome is fit to vivo degradation, avirulence and non-immunogenicity in addition, and particularly great number tested data proof liposome can improve the Drug therapy index, reduces drug toxicity and reduce drug side effect as pharmaceutical carrier, and reduces advantage such as drug dose.
How to overcome above technological deficiency, obtain to comprise the solid preparation of stable unbodied rosuvastain calcium, and improve the key that its bioavailability becomes the present invention's research.
Summary of the invention
The objective of the invention is to develop a kind of stable pharmaceutical composition of rosuvastain calcium, especially unbodied rosuvastain calcium.The inventor is through long-term conscientious research; Beyond thought discovery is applied to contain a kind of liposome of targeting drug delivery system in the solid preparation of rosuvastain calcium; The targeting property that not only can strengthen principal agent can also improve preparation drug effect and bioavailability; Simultaneously improve the stability of active component in the preparation widely, got unforeseeable technique effect.
One of the object of the invention provides a kind of rosuvastain calcium Liposomal formulation, is mainly processed by rosuvastain calcium, phospholipid, additives.
Preparation Liposomal formulation membrane material commonly used is phospholipid and additives; Wherein phospholipid can be selected natural phospholipid and synthetic phospholipid for use usually, and said natural phospholipid is one or more in Ovum Gallus domesticus Flavus lecithin, hydrogenation egg yolk lecithin, EPG, egg yolk lecithin acyl serine, egg yolk lecithin acyl inositol, soybean lecithin, hydrogenated soya phosphatide, soybean phospholipid acyl glycerol, soy phosphatidylserine, the soybean phospholipid acyl inositol; Said synthetic phospholipid is one or more in dioleoyl phospholipid phatidylcholine, distearyl acid phosphatidylcholine, dipalmitoyl phosphatidyl choline, dimyristoyl phosphatidyl choline, two Laurel phosphatidyl cholines, DOPG, distearyl acid phosphatidyl glycerol, two palmityl phosphatidyl glycerols, GLYCEROL,DIMYRISTOYL PHOSPHATIDYL, the two lauroyl phosphatidyl glycerols.The membrane material of additives commonly used has cholesterol, 18-amine., phosphatidic acid, sodium deoxycholate and poloxamer 188.The membrane material that is used to prepare Liposomal formulation also has PHOSPHATIDYL ETHANOLAMINE, cholesterol second fat, paddy to carry alcohol, natrii tauroglycocholas, phosphatidyl silk amino acid, stearmide, single stearoyl phosphatidic acid, single stearoyl PHOSPHATIDYL ETHANOLAMINE, two cetyl phosphate (DCP), two palmityl PHOSPHATIDYL ETHANOLAMINEs, single palmityl PHOSPHATIDYL ETHANOLAMINE, two myristoyl PHOSPHATIDYL ETHANOLAMINEs.Additives generally are used for regulating membrane structure, change charged character, like cholesterol liposome bimolecular tunic are solidified, thereby reduce the generation of free radical, have reduced oxidation level, and liposome stability is significantly strengthened.
Particularly; The present invention provides a kind of rosuvastain calcium liposome; Mainly be to process, and count by weight: 1 part of rosuvastain calcium, soybean lecithin 2-25 part, cholesterol 0.5-10 part, Tween 80 0.5-12 part and sodium deoxycholate 0.05-10 part by rosuvastain calcium, soybean lecithin, cholesterol, Tween 80 and sodium deoxycholate.
Preferably, above-mentioned rosuvastain calcium liposome, by weight, component is: 1 part of rosuvastain calcium, soybean lecithin 8-20 part, cholesterol 3-10 part, Tween 80 0.5-10 part and sodium deoxycholate 1-6 part.
The phospholipid that liposome preparation adopts among the present invention is not only the excipient as liposome; Its important function also is to infiltrate platelet; Making it that form take place changes; And then suppress the inductive platelet of institute such as ADP and take off granule secretion and protein phosphorylation effect, therefore, have stronger antiplatelet aggregation, activatory effect.In addition, can obviously reduce and pour into myocardium ARR generation again, directly protect vascular endothelial cell and blood capillary system, help the recovery of ischemic myocardium function, save ischemic myocardium, alleviate myocardial ischemia reperfusion injury, dwindle myocardial infarction area.
Another object of the present invention provides a kind of method for preparing above-mentioned rosuvastain calcium liposome, may further comprise the steps:
(1) rosuvastain calcium, soybean lecithin, cholesterol, Tween 80, sodium deoxycholate are dissolved in the solvent, mix homogeneously removes the immobilized artificial membrane that make the back of desolvating;
(2) add buffer salt solution and make the complete aquation of immobilized artificial membrane, become liposome turbid liquor;
(3) with obtaining the rosuvastain calcium liposome after the suspension spray drying.
The present invention also further provides a kind of method for preparing above-mentioned rosuvastain calcium liposome, and concrete steps comprise:
(1) rosuvastain calcium, soybean lecithin, cholesterol, Tween 80, sodium deoxycholate are dissolved in the organic solvent, placing reduces pressure on the rotating thin film evaporimeter eliminates organic solvent, has obtained immobilized artificial membrane;
(2) add buffer solution and make the complete aquation of immobilized artificial membrane, reuse tissue mashing machine spares matter emulsifying, and the solution mix homogeneously is incubated under 50～70 ℃ of states supersound process 40-60 minute, makes liposome turbid liquor;
(3) above-mentioned steps (2) gained solution is carried out spray drying, make rosuvastain calcium liposome powder.
Further, adopt the conventional spray-dired technology of this area to be prepared into the liposome powder, lyophilization possibly destroy its crystal form.
Wherein, Above-mentioned described buffer solution is that pH value is the pharmaceutically acceptable buffer solution of 4-7.5; For example buffer solution is selected from one or more in phosphate buffer, citrate buffer, carbonate buffer solution, the acetate buffer, and the amount that adds buffer solution is the 10-40 weight portion.
The above-mentioned described rosuvastain calcium liposome of the present invention, wherein said organic solvent for example is selected from ethanol, methanol, the tert-butyl alcohol, n-butyl alcohol, isopropyl alcohol, acetone, benzyl alcohol, the normal hexane one or more, is preferably methanol.
Above-mentioned described rosuvastain calcium liposome wherein, adds buffer salt solution and makes the complete aquation of immobilized artificial membrane, and reuse tissue mashing machine spares matter emulsifying, becomes liposome turbid liquor.
One of the object of the invention provides a kind of rosuvastain calcium lipidosome solid preparation, has good bioavailability equally.
Specifically; The combination of soybean lecithin, cholesterol, Tween 80, sodium deoxycholate and active component rosuvastain calcium through certain content; Adopt the thin film dispersion technology to process the rosuvastain calcium liposome, be mixed and made into various solid preparations with certain adjuvant again, strengthened bioavailability significantly; Strengthened targeting property, obtained gratifying technique effect liver.
The said solid preparation that contains the rosuvastain calcium liposome is made up of above-mentioned described rosuvastain calcium liposome and pharmaceutically acceptable other excipient, like solid preparations such as granule, tablet, capsule, dry suspension.
The above-mentioned described rosuvastain calcium solid preparation of the present invention; The not special restriction of wherein said adjuvant; Can specifically process: 1 part of rosuvastain calcium liposome, filler 9-11.5 part, disintegrating agent 0-0.6 part, binding agent 0.12-0.3 part, correctives 0-5.15 part, aromatic 0-0.15 part and lubricant 0-0.36 part for the pharmaceutical necessities of solid preparation commonly used in the pharmaceutics by following component by weight.
As preferably, wherein:
Described filler is selected from one or more in microcrystalline Cellulose, starch, pregelatinized Starch, dextrin, lactose, mannitol, calcium sulfate, the calcium hydrogen phosphate, is preferably pregelatinized Starch and lactose.
Described disintegrating agent is selected from one or more in carboxymethylstach sodium, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, the dried starch, is preferably polyvinylpolypyrrolidone.
Described binding agent is selected from one or more in polyvidone, hypromellose, starch slurry, the syrup, is preferably 30 POVIDONE K 30 BP/USP 30.
Described correctives is selected from one or more in sucrose, aspartame, saccharin sodium, the steviosin, is preferably sucrose.
Described aromatic is selected from one or more in Fructus Citri tangerinae essence, strawberry essence, chocolate essence, Herba Menthae essence, the milk flavour, is preferably strawberry essence.
Described lubricant is selected from one or more in magnesium stearate, Pulvis Talci, micropowder silica gel, the sodium lauryl sulphate etc., is preferably magnesium stearate.
Another object of the present invention provides a kind of method for preparing for preparing the rosuvastain calcium lipidosome solid preparation, comprises the steps:
(1) the rosuvastain calcium liposome is pulverized, crossed 80 mesh sieves, subsequent use;
(2) with pulverizing such as filler, disintegrating agent, correctivess, cross 80 mesh sieves, mix, subsequent use;
(3) with above-mentioned supplementary material mix homogeneously, add binding agent, aromatic system soft material, the granulation of sieving, oven dry, the adding mix lubricant is even, granulate;
(4) dried granules is carried out packing or tabletting, the rosuvastain calcium solid preparation of system.
The present invention is through specific adjuvant and supplementary material proportioning; Make the rosuvastain calcium liposome, rosuvastain calcium liposome provided by the invention and rosuvastain calcium solid preparation, compared with prior art; Have beyond thought effect, the principal agent advantage is following:
(1) the present invention is through with rosuvastain calcium and suitable excipients, processes solid preparation with conventional pharmaceutic adjuvant again after processing the rosuvastain calcium liposome, improved the drug effect and the bioavailability of preparation, guaranteed product quality.
(2) because the therapeutic activity of rosuvastain calcium has been worked in coordination with in the absorption of phospholipid, it is high further to have improved bioavailability.
(3) production technology is simple, and cost is low, can industrial-scale production.
(4) lipidosome solid preparation that makes has improved the product quality of preparation, has reduced toxic and side effects.
The specific embodiment
Below further specify the present invention through embodiment, but should not be construed as limitation of the present invention.
Embodiment 1
The preparation of rosuvastain calcium liposome
Prescription rosuvastain calcium 100g
Soybean lecithin 800g
Cholesterol 300g
Tween 80 50g
Sodium deoxycholate 100g
Preparation technology
(1) 100g rosuvastain calcium, 800g soybean lecithin, 300g cholesterol, 50g Tween 80 and 100g sodium deoxycholate are dissolved in the 5000ml methanol, mix homogeneously, methanol is removed in decompression on rotary film evaporator, makes immobilized artificial membrane;
(2) phosphoric acid-sodium dihydrogen phosphate buffer 2500ml of adding pH=4.5 stirs and makes the complete aquation of immobilized artificial membrane, the emulsifying 20min of reuse tissue mashing machine; Rotating speed 12000r/min; The solution mix homogeneously was incubated under 50 ℃ of states supersound process 60 minutes, made liposome turbid liquor;
(3) with above-mentioned steps (2) gained suspension spray drying, make the rosuvastain calcium liposome.
Comparative Examples 1
The preparation of rosuvastain calcium liposome
Prescription: rosuvastain calcium 100g
Cholesterol 48g
Tween 80 45g
Sodium deoxycholate 4g
Preparation technology is with instance 1, and the weight portion of choosing outside the component preferable range of the present invention is formed, and makes the rosuvastain calcium liposome.
Embodiment 2
The preparation of rosuvastain calcium liposome
Prescription: rosuvastain calcium 200g
Soybean lecithin 5000g
Cholesterol 2000g
Tween 80 2400g
Sodium deoxycholate 2000g
Preparation technology
(1) 200g rosuvastain calcium, 5000g soybean lecithin, 2000g cholesterol, 2400g Tween 80 and 2000g sodium deoxycholate are dissolved in the 40000ml methanol, mix homogeneously, the methanol that on rotary film evaporator, reduces pressure away makes immobilized artificial membrane;
(2) citric acid-sodium citrate buffer solution 20000ml of adding pH=6.0 stirs and makes the complete aquation of immobilized artificial membrane, the emulsifying 10min of reuse tissue mashing machine; Rotating speed 15000r/min; The solution mix homogeneously was incubated under 70 ℃ of states ultrasonic place 40 minutes, made liposome turbid liquor;
(3) with above-mentioned steps (2) gained suspension spray drying, make the rosuvastain calcium liposome.
Comparative Examples 2
The preparation of rosuvastain calcium liposome (preparation technology is different)
Prescription: rosuvastain calcium 200g
Soybean lecithin 5000g
Cholesterol 2000g
Tween 80 2400g
Sodium deoxycholate 2000g
Preparation technology
(1) 5000g soybean lecithin, 2000g cholesterol, 2000g NaGC are dissolved in the 20000ml methanol;
(2) 200g rosuvastain calcium and 2400g Tween 80 are dissolved in citric acid-sodium citrate buffer 6000ml of pH=6.0;
(3) both are mixed, stir, form w/o type Emulsion, the heated and stirred evaporation; When mixture reaches the thickness state, add pH=6.0 citric acid-sodium citrate buffer 4000ml again, continue the heated and stirred evaporation and remove methanol; Ultrasonic 15min is transferred in the tissue mashing machine jolting; At a high speed even matter emulsifying 10min, rotating speed 12000r/min makes liposome turbid liquor;
(4), make the rosuvastain calcium liposome with the suspension spray drying.
Embodiment 3
The preparation of rosuvastain calcium liposome particles
Prescription (1000 bags)
Rosuvastain calcium liposome (in rosuvastain calcium) 10g
Starch 80g
Dextrin 35g
Sucrose 50g
Aspartame 1.5g
Hypromellose 1.2g
Strawberry essence 1.5g
Preparation technology
The liposome that (1) will contain the 10g rosuvastain calcium is pulverized, and crosses 80 mesh sieves, and is subsequent use;
(2) take by weighing 80g starch, 35g dextrin, 50g sucrose and 1.5g aspartame, cross 80 mesh sieves, mix, subsequent use;
(3) with above-mentioned supplementary material mix homogeneously, again with 1.5g strawberry essence mix homogeneously, add 2% hypromellose, 20% alcoholic solution 60ml system soft material, cross 20 mesh sieves and granulate, 60 ℃ of oven dry, 18 mesh sieve granulate, subsequent use;
(4), make the agent of rosuvastain calcium liposome particles with the dried granules packing.
Embodiment 4
The preparation of Rosuvastatin calcium tablet
Prescription (1000)
Rosuvastain calcium liposome (in rosuvastain calcium) 10g
Pregelatinized Starch 45g
Lactose 50g
Polyvinylpolypyrrolidone 6g
30 POVIDONE K 30 BP/USP 30 3g
Pulvis Talci 2.4g
Magnesium stearate 1.2g
Preparation technology
The liposome that (1) will contain the 10g rosuvastain calcium is pulverized, and crosses 80 mesh sieves, and is subsequent use;
(2) take by weighing 45g starch, 50g lactose, 6g polyvinylpolypyrrolidone, cross 80 mesh sieves, mix, subsequent use;
(3) with above-mentioned supplementary material mix homogeneously, add the 50% alcoholic solution 60ml system soft material of 5% 30 POVIDONE K 30 BP/USP 30, to cross 20 mesh sieves and granulate, 55 ℃ of oven dry add 1.2g magnesium stearate and 2.4g Pulvis Talci mix homogeneously, and 18 mesh sieve granulate are subsequent use;
(4), promptly get the Rosuvastatin calcium tablet with the dried granules tabletting.
Embodiment 5
The capsular preparation of rosuvastain calcium
Prescription (1000)
Rosuvastain calcium liposome (in rosuvastain calcium) 10g
Starch 40g
Microcrystalline Cellulose 50g
Sodium carboxymethyl cellulose 1.2g
Magnesium stearate 1.5g
Preparation technology
The liposome that (1) will contain the 10g rosuvastain calcium is pulverized, and crosses 80 mesh sieves, and is subsequent use;
(2) take by weighing 40g starch, 50g microcrystalline Cellulose, cross 80 mesh sieves, mix, subsequent use;
(3) with above-mentioned supplementary material mix homogeneously, add 2% sodium carboxymethyl cellulose, 60% alcoholic solution 60ml system soft material, to cross 20 mesh sieves and granulate, 60 ℃ of oven dry add 1.5g magnesium stearate mix homogeneously, and 18 mesh sieve granulate are subsequent use;
(4) dried granules is filled in the capsule shells, makes the Rosuvastatin calcium capsule.
Test Example 1
The mensuration of envelop rate
Get the liposome of embodiment 1-2 and Comparative Examples 1-2 preparation, the total content of high effective liquid chromatography for measuring rosuvastain calcium is M, selects for use column chromatography to separate liposome.
Get 1.5g sephadex G-50, more than the phosphate buffer immersion swelling 12h with pH6.8, the chromatographic column interior (200 * 10mm) of packing into; With above-mentioned phosphate buffer flushing balance, get the rosuvastain calcium liposome that embodiment 1-2 and Comparative Examples 1-2 obtain respectively and be dissolved in water, process the solution that every 1ml contains the about 1.5mg of rosuvastain calcium; Get solution 1.5ml respectively and add the chromatographic column top; With phosphate buffer 50ml eluting, flow velocity 1.2ml/min, the eluent of collection add rupture of membranes agent (ethanol: 50ml benzyl alcohol=6: 1); Mixing, HPLC detects the content M1 of rosuvastain calcium.
Envelop rate %=M1/M * 100%
Table 1 entrapment efficiency determination result
Can know that by above result the liposome encapsulation that the present invention makes is very high, meet the actual production requirement basically; And the liposome encapsulation that the outer Comparative Examples prescription proportioning of the scope of the invention makes is very low, has compared tangible gap with embodiment, is not suitable for production requirement.
Test Example 2The detection of particle diameter
Get the liposome of embodiment 1-2 and Comparative Examples 1-2 preparation, adopt micro-image analyzer to measure the particle size distribution of liposome, the result sees table 2:
Table 2 particle diameter testing result
Can be known that by above result the liposome that enforcement row 1-2 makes shows spherical, particle diameter is average, and scope is 100-200nm; The liposome shape that Comparative Examples 1-2 makes is indefinite, disorderly and unsystematic, not of uniform size, and particle diameter is inhomogeneous, and scope is 400-800nm.
Test Example 3
Stability study
Sample and listing preparation Rosuvastatin calcium tablet (Shandong southern Shandong pharmacy Group Co.,Ltd with above embodiment 3-5; Lot number 20100318), under 40 ℃ of high temperature, relative humidity 75% ± 5% condition 6 months, carry out accelerated test and investigate; Compare dissolution and stability, the result is following:
Table 3 accelerated test is investigated
Can know that by above result the sample dissolution of embodiment of the invention 3-5 is higher than about 78% of listing tablet far away all more than 90%, explains that the rosuvastain calcium liposome that the present invention makes has improved its dissolubility, thereby has improved bioavailability accordingly.After the accelerated test 6 months; Significant change does not take place in sample dissolution, content and the related substance of embodiment of the invention 3-5; And listing formulation content and dissolution decline are bigger; Related substance raises obviously, explains that the rosuvastain calcium liposome that the present invention makes has improved its stability of formulation.
Test Example 4Bioavailability study
The liposome of Comparative Examples 1-2 preparation is processed the tablet of tablet and embodiment 4 preparations by the technology of embodiment 4, and listing preparation (conventional tablet, Shandong southern Shandong pharmacy Group Co.,Ltd, lot number 20100318) carries out the comparison of bioavailability, and the result is following:
The comparison of table 4 bioavailability
Can find out that by above result the tablet bioavailability of the embodiment of the invention 4 preparations is far longer than Comparative Examples 1-2 and listing preparation bioavailability; The synergism of the lipidosome solid preparation of the present invention's preparation owing to phospholipid and rosuvastain calcium is described, unexpected ground has improved the bioavailability of preparation of the present invention greatly.
Claims (4)
1. rosuvastain calcium liposome; It is characterized in that mainly processing, and count by weight: 1 part of rosuvastain calcium, soybean lecithin 8-20 part, cholesterol 3-10 part, Tween 80 0.5-10 part and sodium deoxycholate 1-6 part by rosuvastain calcium, soybean lecithin, cholesterol, Tween 80 and sodium deoxycholate;
Its preparation method may further comprise the steps:
(1) rosuvastain calcium, soybean lecithin, cholesterol, Tween 80, sodium deoxycholate are dissolved in the methanol, placing reduces pressure on the rotating thin film evaporimeter eliminates methanol, has obtained immobilized artificial membrane;
(2) add buffer solution and make the complete aquation of immobilized artificial membrane, reuse tissue mashing machine spares matter emulsifying, and the solution mix homogeneously is incubated under 50～70 ℃ of states supersound process 40-60 minute, makes liposome turbid liquor;
(3) above-mentioned steps (2) gained solution is carried out spray drying, make rosuvastain calcium liposome powder;
Described buffer solution is that pH value is the pharmaceutically acceptable buffer solution of 4-7.5, is selected from phosphate buffer, citrate buffer, carbonate buffer solution, the acetate buffer one or more, and the amount that adds buffer solution is the 10-40 weight portion.
2. a rosuvastain calcium lipidosome solid preparation is characterized in that mainly being processed by following component by weight: 1 part of the described rosuvastain calcium liposome of claim 1, filler 9-11.5 part, disintegrating agent 0-0.6 part, binding agent 0.12-0.3 part, correctives 0-5.15 part, aromatic 0-0.15 part and lubricant 0-0.36 part;
Its preparation method comprises the steps:
(1) the rosuvastain calcium liposome is pulverized, crossed 80 mesh sieves, subsequent use;
(2) filler, disintegrating agent, correctives are pulverized, crossed 80 mesh sieves, mix, subsequent use;
(3) with above-mentioned supplementary material mix homogeneously, add binding agent, aromatic system soft material, the granulation of sieving, oven dry, the adding mix lubricant is even, granulate;
(4) dried granules is carried out packing or tabletting, make the rosuvastain calcium solid preparation.
3. the application of the described rosuvastain calcium liposome of claim 1 in the medicine of preparation treatment or prevention cardiovascular and cerebrovascular disease.
4. the application of the described rosuvastain calcium lipidosome solid preparation of claim 2 in the medicine of preparation treatment or prevention cardiovascular and cerebrovascular disease.
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| CN101804029A (en) * | 2010-05-15 | 2010-08-18 | 王丽燕 | Atorvastatin liposome and preparation method thereof, and medicine composition containing atorvastatin |
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2010
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101804029A (en) * | 2010-05-15 | 2010-08-18 | 王丽燕 | Atorvastatin liposome and preparation method thereof, and medicine composition containing atorvastatin |
Non-Patent Citations (2)
| Title |
|---|
| 李玉霞 等.《瑞舒伐他汀的研究进展》.《心血管病学进展》.2010,第31卷(第4期),第585-588页. |
| 李玉霞 等.《瑞舒伐他汀的研究进展》.《心血管病学进展》.2010,第31卷(第4期),第585-588页. * |
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| CN102028658A (en) | 2011-04-27 |
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