CN102008440B - Solid preparation of atorvastatin calcium liposome - Google Patents
Solid preparation of atorvastatin calcium liposome Download PDFInfo
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- CN102008440B CN102008440B CN2010105781447A CN201010578144A CN102008440B CN 102008440 B CN102008440 B CN 102008440B CN 2010105781447 A CN2010105781447 A CN 2010105781447A CN 201010578144 A CN201010578144 A CN 201010578144A CN 102008440 B CN102008440 B CN 102008440B
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Abstract
The invention discloses a solid preparation of atorvastatin calcium liposome. The preparation is prepared from the atorvastatin calcium liposome and other pharmaceutically common auxiliary materials, wherein the atorvastatin liposome is prepared from the following components in parts by weight: 1 part of atorvastatin calcium, 2-5 parts of phospholipid and 0.8-3 parts of additive. The atorvastatin solid preparation prepared from the liposome has the advantages that the dissolution rate is increased, the stability and bioavailability are greatly improved, the product quality of the preparation is improved and the toxic and side effect is reduced.
Description
Technical field
The present invention relates to a kind of Atorvastatin calcium Liposomal formulation, particularly keep the amorphous atorvastatin calcium Liposomal formulation of high bioavailability, further relate to Atorvastatin calcium lipidosome solid preparation and method for making thereof, belong to medical technical field.
Background technology
Cardiovascular disease is one of common, the most serious disease of harm humans health; Characteristics with " four is high by more than one " of " sickness rate is high, disability rate is high, mortality rate is high, relapse rate is high; complication is many ", at present, China cardiovascular and cerebrovascular disease patient has surpassed 2.7 hundred million people.In recent years; Hypertension prevention and control guide both domestic and external shows; Strengthen the blood pressure lowering dynamics, make hyperpietic's blood pressure reduce to (the best should be reduced to below 130/80 millimetres of mercury) below 140/90 millimetres of mercury actively, enduringly, effectively the target organ damages such as heart and brain kidney that cause of alleviating hypertension.Further can treat all kinds hypertension, angina pectoris, atherosclerosis effectively; And prevention or cardiovascular and cerebrovascular diseases such as treatment diabetes, diabetic complication, apoplexy, myocardial infarction, cardiac insufficiency, renal function injury, ventricular hypertrophy, aneurysm, myocardial ischemia and glaucoma; Reduce incident rate, mortality rate and the disability rate of cardiovascular and cerebrovascular disease; Improve patients ' life quality, prolong patient's life-span.
Atorvastatin or its pharmaceutically acceptable salt are Statins blood lipid regulation medicine, belong to the HMG-CoA reductase inhibitor.Non-activity own; Hydrolyzate after the oral absorption suppresses the rate-limiting enzyme hydroxyl first glutaryl CoA reductase in the cholesterol building-up process in vivo competitively; Make the synthetic minimizing of cholesterol; Also make the synthetic increase of low density lipoprotein receptor, main site of action is at liver, and the result reduces cholesterolemia and low-density lipoprotein cholesterol level; Moderate reduces serum triglyceride level and increases the blood hdl level, is mainly used in treatment or prevention hypercholesterolemia, combined hyperlipidemia familial, coronary heart disease or apoplexy.
Atorvastatin calcium, chemical being called [R-(R, R)]-2-(4-fluorophenyl)-b, d-dihydroxy-5-(1-Methylethyl)-3-phenyl-4-[(anilino-) carbonyl]-1 hydrogen-pyrroles-1-Calcium salt enanthate trihydrate, molecular formula is (C
33H
34FN
2O
5)
2Ca3H
2O, molecular weight are 1209.42, and chemical structural formula is:
Atorvastatin calcium has highly lipophilic, and poorly water-soluble is prone in the methanol dissolve; Slightly soluble in ethanol or acetone, atomic dissolve in water, almost insoluble and have a stronger bitterness in chloroform, ether; All responsive to humidity, light, heat and low pH etc., under low pH situation, can be degraded to lactone especially.
What use clinically at present all is ordinary tablet basically, has problems such as prolonged disintegration, stripping be slow sometimes.Compare with homemade conventional tablet; Its external stripping of the commercially available conventional tablet lipitor of import is very fast; But its in prescription, also added the surfactant Tween 80 (Wang Jing, Lin Yang, Chen Yan etc. the external dissolution of homemade and import Atorvastatin calcium sheet is investigated [J]. Chinese Pharmaceutical Journal; 2002,37 (8): 632.).
In addition, behind the extensive first pass metabolism, absolute bioavailability is lower, is merely 12% in liver for atorvastatin calcium, and oral dose is bigger, has brought inconvenience for the patient of child, old man and dysphagia.
Even more important ground, Atorvastatin calcium generally is that amorphous form or a kind of crystal form (form I, form II, form III and form IV) exist (WO 97/3958A and WO 97/3959A).Its amorphous form compare with crystal form show different dissolving characteristics and bioavailability pattern (Konno T., Chem.Pharm.Bull., 1990,38:2003-2007).For some treatment indication, bioavailability is a key parameter of used material form in the decision pharmaceutical formulation, and depends on the form of used material in the pharmaceutical formulation.
Because the dissolubility of various atorvastatin forms is different, and is ben like patent application WO 97/3960, and its bioavailability of remote-effects, guarantee that therefore the homogeneity of used material in the pharmaceutical formulation is extremely important with stability.
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; Continuous progress along with biotechnology; Liposome preparation technology is progressively perfect, and the liposome mechanism of action is further illustrated, and liposome is fit to vivo degradation, avirulence and non-immunogenicity in addition; Particularly great number tested data proof liposome can keep medicine stability, improves the Drug therapy index, reduces drug toxicity and reduce drug side effect as pharmaceutical carrier, and reduces advantage such as drug dose.
CN101804029A discloses a kind of atorvastatin liposome; For overcome the dosage form that exists in the prior art adopt the simple atorvastatin calcium raw material drug that does not add any modification add pH greater than 5 alkalizing agent that make and stability said preparation and bioavailability poor; Can not effectively bring into play the defective of the pharmacological activity of atorvastatin; Be made into pharmaceutically liposome of salt of atorvastatin or its, the liposome of above-mentioned acquisition and fixedly the Atorvastatin calcium in the preparation all do not overcome crystal formation and cause the bioavailability problem.
In sum; In view of Atorvastatin calcium in the prior art and the problem that fixedly exists in the pharmacodynamics aspect of the physico-chemical property that exists of preparation and bioavailability thereof; The inventor is through research chronically; After paying creative work, obtained to have Atorvastatin calcium Liposomal formulation and solid preparation thereof far above the bioavailability of prior art.
Summary of the invention
The technical problem that the present invention will solve be not only to overcome in the prior art the character such as bitterness, slightly solubility and unstability of known Atorvastatin calcium, can also improve the bioavailability of the preparation that contains Atorvastatin calcium.Further, Atorvastatin calcium liposome of the present invention has stronger antiplatelet aggregation, activatory effect owing to adopted particular excipient, has produced synergism for the therapeutic activity of Atorvastatin calcium.
One of the object of the invention provides a kind of Atorvastatin calcium Liposomal formulation, is mainly processed by Atorvastatin calcium, phospholipid, additives, and its ratio of weight and number is: 1 part of Atorvastatin calcium, phosphatidase 12-5 part, additives 0.8-3 part.
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.
The preferred phospholipid of the present invention is the combination of soybean lecithin and two myristoyl PHOSPHATIDYL ETHANOLAMINEs, further preferably 2: 1 combination of weight portion.
The preferred additives of the present invention are the combination of cholesterol and 18-amine., further preferably 1: 1 combination of weight portion.
Atorvastatin calcium Liposomal formulation of the present invention can also comprise pharmaceutically acceptable other excipient, so that promote the stability of liposome better and keep having the crystal formation of the Atorvastatin calcium of better bioavailability.
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.
One of the object of the invention provides a kind of method for preparing above-mentioned Atorvastatin calcium Liposomal formulation, it is characterized in that may further comprise the steps:
1) phospholipid, additives are dissolved in the organic solvent, mix homogeneously makes immobilized artificial membrane except that after desolvating;
2) add the buffer salt that is dissolved with Atorvastatin calcium and make the complete aquation of immobilized artificial membrane, become liposome turbid liquor;
Further, adopt the conventional spray-dired technology of this area to be prepared into the liposome powder, lyophilization destroys its crystal form.
The present invention also further provides a kind of method of above-mentioned Atorvastatin calcium liposome, and concrete steps comprise:
(1) soybean lecithin and two myristoyl PHOSPHATIDYL ETHANOLAMINEs and cholesterol and 18-amine. are dissolved in the organic solvent, place that decompression eliminates organic solvent on the rotating thin film evaporimeter, obtained immobilized artificial membrane;
(2) add the buffer salt be dissolved with Atorvastatin calcium and make the complete aquation of immobilized artificial membrane, the solution mix homogeneously is incubated under 50～70 ℃ of states supersound process 40-60 minute;
(3) above-mentioned steps (2) gained solution is carried out spray drying, promptly get Atorvastatin calcium liposome powder.
In the above-mentioned described method for preparing; Organic solvent is selected from one or more in ethanol, isopropyl alcohol, methanol, butanone, acetone, ethyl acetate, chloroform, dichloromethane or the ethyl acetate, is preferably volume ratio and is 3: 2 ethyl acetate and ethanol mixed solvent.
In the above-mentioned described method for preparing, what buffer salt solution can be in phosphate buffer, citrate buffer, carbonate buffer solution, the borate buffer solution is a kind of, is preferably pH value and is citric acid-sodium citrate buffer of 5.6.
One of the object of the invention provides a kind of Atorvastatin calcium lipidosome solid preparation, has more outstanding bioavailability.
Said Atorvastatin calcium lipidosome solid preparation comprises the dosage form that granule, tablet, capsule etc. are commonly used clinically.
Said Atorvastatin calcium lipidosome solid preparation; Comprise Atorvastatin calcium liposome of the present invention and pharmaceutically acceptable excipient thereof, said excipient comprises filler, disintegrating agent, binding agent, lubricant, aromatic, correctives and their combination.The amount of various excipient in pharmaceutical composition can change in the normal ranges of this area.
Further preferably; Based on the weight portion meter, Atorvastatin calcium lipidosome solid preparation of the present invention comprises: 1 part of Atorvastatin calcium liposome, filler 1.6-3 part, disintegrating agent 0-0.2 part, binding agent 0.04-0.2 part, correctives 0-17 part, aromatic 0-0.6 part and lubricant 0-0.06 part.
Said filler can be selected from starch, pregelatinized Starch, microcrystalline Cellulose, optimization microcrystalline Cellulose, Powderd cellulose, saccharide, sugar derivatives, calsium supplement and their combination; Calsium supplement is selected from calcium carbonate, calcium phosphate, calcium hydrogen phosphate, Malic acid citric acid calcium, Citric acid calcium, calcium malate, calcium lactate or calcium acetate.
Said disintegrating agent can be selected from carboxymethylstach sodium, polyvinylpolypyrrolidone, primojel, L-hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose and their combination.
Said binding agent can be selected from polyvidone, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, starch and their combination; Polyvidone is preferably 30 POVIDONE K 30 BP/USP
30
Said lubricant can be selected from micropowder silica gel, magnesium stearate, calcium stearate, zinc stearate, calcium silicates, Pulvis Talci and their combination.
Described correctives is selected from sucrose, Aspartane, saccharin sodium, sucralose, stevioside, the steviosin and their combination.
Described aromatic is selected from flavoring orange essence, oleum Citri sinensis, strawberry essence, Mentholum, cream flavour and their combination.
One of the object of the invention has provided a kind of method for preparing above-mentioned Atorvastatin calcium lipidosome solid preparation, it is characterized in that may further comprise the steps:
(1) the Atorvastatin 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, make the Atorvastatin calcium solid preparation.
Atorvastatin calcium lipidosome solid preparation of the present invention, advantage be:
Atorvastatin calcium content in the unit volume of the Atorvastatin calcium liposome that (1) makes is high, has shown that prescription of the present invention and technology both can guarantee that liposome reached high envelop rate, had stable drug loading again.In addition, can increase the stability of Atorvastatin calcium, guarantee its drug effect, prove this point through stability test and acceleration time.
(2) because the therapeutic activity of Atorvastatin calcium has been worked in coordination with in the absorption of phospholipid, it is high further to have improved bioavailability.
(3) the Atorvastatin calcium lipidosome solid preparation that makes of the present invention meets the requirement of industrialized great production, and preparation technology is simple, and cost is low.
(4) lipidosome solid preparation that makes has improved the product quality of preparation, has reduced toxic and side effects.
The specific embodiment
Embodiment 1
The preparation of Atorvastatin calcium liposome
Prescription:
Atorvastatin calcium 100g
Soybean lecithin 133.3g
Two myristoyl PHOSPHATIDYL ETHANOLAMINE 66.7g
Cholesterol 40g
18-amine. 40g
Preparation technology:
(1) 133.3g soybean lecithin and 66.7g two myristoyl PHOSPHATIDYL ETHANOLAMINEs and 40g cholesterol and 40g 18-amine. being dissolved in the 2000ml volume ratio is in 3: 2 the ethyl acetate and ethanol mixed solvent; Placing reduces pressure on the rotating thin film evaporimeter eliminates organic solvent, has obtained immobilized artificial membrane;
(2) adding the pH value be dissolved with the 100g Atorvastatin calcium is that citric acid-sodium citrate buffer 800ml of 5.6 makes the complete aquation of immobilized artificial membrane, and the solution mix homogeneously was incubated under 70 ℃ of states supersound process 40 minutes;
(3) above-mentioned steps (2) gained solution is carried out spray drying, promptly get Atorvastatin calcium liposome powder.
Comparative Examples 1
The preparation of Atorvastatin calcium liposome (usage ratio of each component is different)
Prescription:
Atorvastatin calcium 100g
Soybean lecithin 100g
Two myristoyl PHOSPHATIDYL ETHANOLAMINE 100g
Cholesterol 50g
18-amine. 30g
Preparation technology makes the Atorvastatin calcium liposome with embodiment 1.
Comparative Examples 2
The preparation of Atorvastatin calcium liposome (adopting the lyophilizing mode to process)
Prescription:
Atorvastatin calcium 100g
Soybean lecithin 133.3g
Two myristoyl PHOSPHATIDYL ETHANOLAMINE 66.7g
Cholesterol 40g
18-amine. 40g
Preparation technology:
(1) 133.3g soybean lecithin and 66.7g two myristoyl PHOSPHATIDYL ETHANOLAMINEs and 40g cholesterol and 40g 18-amine. being dissolved in the 2000ml volume ratio is in 3: 2 the ethyl acetate and ethanol mixed solvent; Placing reduces pressure on the rotating thin film evaporimeter eliminates organic solvent, has obtained immobilized artificial membrane;
(2) adding the pH value be dissolved with the 100g Atorvastatin calcium is that citric acid-sodium citrate buffer 800ml of 5.6 makes the complete aquation of immobilized artificial membrane, and the solution mix homogeneously was incubated under 70 ℃ of states supersound process 40 minutes;
(3) above-mentioned steps (2) gained solution is sub-packed in the stainless steel disc, places and carry out lyophilizing in the freezer dryer:
A, pre-freeze: the medicinal liquid that branch is installed is cooled to-40 ℃ by 2 ℃ of/minute speed, is incubated freezing 3 hours;
B, distillation: the medicinal liquid evacuation that pre-freeze is good, to 15Pa, in 8 hours, at the uniform velocity slowly be warming up to-20 ℃ then, be incubated 2 hours, in 5 hours, at the uniform velocity be warming up to 10 ℃ again;
C, drying: the distillation medicinal liquid of stage after finishing that finish at the uniform velocity was warming up to 30 ℃ in 4 hours, heat preservation and dryness 3 hours makes the Atorvastatin calcium liposome.
Embodiment 2
The preparation of Atorvastatin calcium liposome
Prescription:
Atorvastatin calcium 100g
Soybean lecithin 333.3g
Two myristoyl PHOSPHATIDYL ETHANOLAMINE 166.7g
Cholesterol 150g
18-amine. 150g
Preparation technology:
(1) 333.3g soybean lecithin and 166.7g two myristoyl PHOSPHATIDYL ETHANOLAMINEs and 150g cholesterol and 150g 18-amine. being dissolved in the 6000ml volume ratio is in 3: 2 the ethyl acetate and ethanol mixed solvent; Placing reduces pressure on the rotating thin film evaporimeter eliminates organic solvent, has obtained immobilized artificial membrane;
(2) adding the pH value be dissolved with the 100g Atorvastatin calcium is that citric acid-sodium citrate buffer 3000ml of 5.6 makes the complete aquation of immobilized artificial membrane, and the solution mix homogeneously was incubated under 50 ℃ of states supersound process 60 minutes;
(3) above-mentioned steps (2) gained solution is carried out spray drying, promptly get Atorvastatin calcium liposome powder.
Comparative Examples 3
The preparation of Atorvastatin calcium liposome (component is different)
Prescription:
Atorvastatin calcium 100g
Two myristoyl PHOSPHATIDYL ETHANOLAMINE 166.7g
Cholesterol 150g
Tween 80 150g
Preparation technology makes the Atorvastatin calcium liposome with embodiment 2.
Embodiment 3
The preparation of Atorvastatin calcium liposome particles
Place's shell (1000 bags):
Atorvastatin calcium liposome (in Atorvastatin calcium) 50g
Starch 150g
Sucrose 850g
30 POVIDONE K 30 BP/USP
3010g
Fructus Citri tangerinae essence 30g
Preparation technology:
The liposome that (1) will contain the 50g Atorvastatin calcium is pulverized, and crosses 80 mesh sieves, and is subsequent use;
(2) take by weighing 150g starch, 850g sucrose and cross 80 mesh sieves and mix, subsequent use;
(3), with 30g Fructus Citri tangerinae essence mix homogeneously, add 3% 30 POVIDONE K 30 BP/USP again with above-mentioned supplementary material mix homogeneously
3080% alcoholic solution 330ml makes soft material, and cross 20 mesh sieves and granulate, 60 ℃ of oven dry, 18 mesh sieve granulate, subsequent use;
(4), make the agent of Atorvastatin calcium liposome particles with the dried granules packing.
Embodiment 4
The preparation of Atorvastatin calcium liposome tablet
Prescription (1000):
Atorvastatin calcium liposome (in Atorvastatin calcium) 50g
Starch 100g
Microcrystalline Cellulose 50g
Carboxymethylstach sodium 10g
30 POVIDONE K 30 BP/USP
305g
Magnesium stearate 3g
Preparation technology:
The liposome that (1) will contain the 50g Atorvastatin calcium is pulverized, and crosses 80 mesh sieves, and is subsequent use;
(2) take by weighing 100g starch, 50g microcrystalline Cellulose, 10g carboxymethylstach sodium and cross 80 mesh sieves and mix, subsequent use;
(3) with above-mentioned supplementary material mix homogeneously, add 5% 30 POVIDONE K 30 BP/USP
3080% alcoholic solution 100ml makes soft material, crosses 20 mesh sieves and granulates, and 55 ℃ of oven dry add 3g magnesium stearate mix homogeneously, and 18 mesh sieve granulate are subsequent use;
(4), make Atorvastatin calcium liposome sheet with the dried granules tabletting.
Embodiment 5
The preparation of Atorvastatin calcium liposome methods
Prescription (1000):
Atorvastatin calcium liposome (in Atorvastatin calcium) 50g
Starch 30g
Microcrystalline Cellulose 50g
Hypromellose 2g
Pulvis Talci 3g
Preparation technology:
The liposome that (1) will contain the 50g Atorvastatin calcium is pulverized, and crosses 80 mesh sieves, and is subsequent use;
(2) take by weighing 30g starch, 50g microcrystalline Cellulose and cross 80 mesh sieves and mix, subsequent use;
(3) with above-mentioned supplementary material mix homogeneously, add 2% hypromellose, 60% alcoholic solution 100ml system soft material, cross 20 mesh sieves and granulate, 60 ℃ of oven dry, again with 3g Pulvis Talci mix homogeneously, 18 mesh sieve granulate, subsequent use;
(4), make the Atorvastatin calcium lipidosome capsule with the dried granules filled capsules.
Test Example 1
The mensuration of envelop rate
Get the liposome turbid liquor 10ml that embodiment 1-2 and Comparative Examples 1-3 make and place the bag filter of having handled; Bag filter is immersed among dialysis solution (the aquation medium that promptly the prepares liposome) 100ml; Put on the magnetic stirring apparatus and stir, regularly change dialysis solution, behind the 12h content taking-up in the dialysis solution is put in the 100ml measuring bottle; Add the alcoholic solution 10ml breakdown of emulsion of 5% polyoxyethylene nonylphenol ether, water is settled to scale.Get each 20 μ l of solution of the embodiment 1-2 that states and Comparative Examples 1-3 respectively, the sample introduction analysis calculates the amount W of parcel Atorvastatin calcium in the Atorvastatin calcium liposome
Bag, according to formula: envelop rate=(W
Bag/ W
Always) * 100% computational envelope rate.
Table 1 entrapment efficiency determination result
Can know that by above result it is very high that the A Shu that the present invention makes cuts down his spit of fland calcium liposome encapsulation, meets 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 2
Stability study
Sample and listing preparation atorvastatin calcium tablet (Beijing Hong Hui bio-pharmaceuticals limited company with above embodiment 3-5; Lot number 20100428), 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 2 accelerated test is investigated
Can know by above result; The sample dissolution of embodiment of the invention 3-5 is all more than 90%; Be higher than listing preparation about 78% far away, explain that the Atorvastatin calcium lipidosome solid preparation that the present invention makes has improved its dissolubility, thereby improved bioavailability accordingly.After the accelerated test 6 months; Sample dissolution, content and the related substance of embodiment of the invention 3-5 do not have significant change; And listing formulation content and dissolution decline are bigger; Related substance raises obviously, explains that the stability of the Atorvastatin calcium lipidosome solid preparation that the present invention makes increases.
Test Example 3Bioavailability study
The liposome of Comparative Examples 1-3 preparation is processed tablet by the technology of embodiment 4; Step by the embodiment among the patent documentation CN101804029A 1 and 6 prepares the atorvastatin calcium tablet again; Tablet with embodiment 4 preparations; Listing preparation (Beijing Hong Hui bio-pharmaceuticals limited company, lot number 20100428) carries out the comparison of bioavailability, and the result is following:
The comparison of table 3 bioavailability
Can find out that by above result the prescription that the tablet bioavailability of the embodiment of the invention 4 preparations is far longer than among Comparative Examples 1-3 and the patent documentation CN101804029A prepares the atorvastatin calcium tablet; Also greater than listing preparation bioavailability; The lipidosome solid preparation that the present invention's preparation is described has obtained unexpected technical effect because the synergism of specific phospholipid combination improves bioavailability widely.
Claims (4)
1. an Atorvastatin calcium lipidosome solid preparation is characterized in that mainly being processed by Atorvastatin calcium, phospholipid, additives, based on the weight portion meter, and 1 part of Atorvastatin calcium, phosphatidase 12-5 part, additives 0.8-3 part; Said phospholipid is 2: 1 the combination of weight portion of soybean lecithin and two myristoyl PHOSPHATIDYL ETHANOLAMINEs; Said additives are 1: 1 the combination of weight portion of cholesterol and 18-amine.;
Its preparation method may further comprise the steps:
(1) soybean lecithin and two myristoyl PHOSPHATIDYL ETHANOLAMINEs and cholesterol and 18-amine. are dissolved in the organic solvent, place that decompression eliminates organic solvent on the rotating thin film evaporimeter, obtained immobilized artificial membrane;
(2) add the buffer salt be dissolved with Atorvastatin calcium and make the complete aquation of immobilized artificial membrane, the solution mix homogeneously is incubated under 50～70 ℃ of states supersound process 40-60 minute;
(3) above-mentioned steps (2) gained solution is carried out spray drying, promptly get Atorvastatin calcium liposome powder;
Said organic solvent is that volume ratio is 3: 2 ethyl acetate and an ethanol mixed solvent;
Said buffer salt solution is that pH value is citric acid-sodium citrate buffer of 5.6.
2. an Atorvastatin calcium lipidosome solid preparation is characterized in that said solid preparation comprises 1 part of the described Atorvastatin calcium liposome of claim 1, filler 1.6-3 part, disintegrating agent 0-0.2 part, binding agent 0.04-0.2 part, correctives 0-17 part, aromatic 0-0.6 part and lubricant 0-0.06 part;
Its preparation method may further comprise the steps:
(1) the Atorvastatin 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 Atorvastatin calcium solid preparation.
3. the application of the described Atorvastatin calcium lipidosome solid preparation of claim 1 in the medicine of preparation treatment or prevention hypercholesterolemia, combined hyperlipidemia familial, coronary heart disease or apoplexy.
4. the application of the described Atorvastatin calcium lipidosome solid preparation of claim 2 in the medicine of preparation treatment or prevention hypercholesterolemia, combined hyperlipidemia familial, coronary heart disease or apoplexy.
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