CN101416943A - Ozagrel liposomes and preparation method thereof - Google Patents
Ozagrel liposomes and preparation method thereof Download PDFInfo
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- CN101416943A CN101416943A CNA2008102287674A CN200810228767A CN101416943A CN 101416943 A CN101416943 A CN 101416943A CN A2008102287674 A CNA2008102287674 A CN A2008102287674A CN 200810228767 A CN200810228767 A CN 200810228767A CN 101416943 A CN101416943 A CN 101416943A
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- Prior art keywords
- ozagrel
- liposomes
- liposome
- preparation
- lipid
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Abstract
The invention provides an ozagrel liposome and a preparation method thereof. The Ozagrel liposome consists of ozagrel which is an active substance, lipid used for preparing the liposome, a buffer solution and a propping agent. The preparation method can improve the stability of the ozagrel and is characterized by high drug-load rate and good stability. Experiments prove that the ozagrel liposome prepared by the preparation method of the invention can prolong the in-vivo retention time of the ozagrel which is the active substance, avoid first pass effect, enhance the targeting performance of the ozagrel liposome to blood platelets and endothelial cells in blood vessels, improve curative effect and increase the adaptability of patients, has simple preparation process and low cost and is suitable for industrialized large scale production.
Description
Technical field
The present invention relates to medical technical field, specifically relate to a kind of Ozagrel liposomes and preparation method thereof.
Background technology
Ozagrel is first specificity thromboxane (TXA2) synthetase inhibitors in the world, and its site of action is platelet and vascular endothelial cell.Pharmacological research shows, the potent inhibition TXA2 synthase activity of this product energy, thereby anticoagulant, improve prostacyclin PGI2 concentration simultaneously, blood vessel dilating, blood flow increasing effectively suppresses cerebral thrombosis, and the thrombosis that has formed is dissolved voluntarily by breaking of blood equilibrium relation, reach the effect of treatment cerebral infarction.The ozagrel common form has three kinds, is respectively: free carboxy acid's form, sodium-salt form and hydrochloride form.Wherein both dissolution properties of back are close, belong to the water soluble drug, and free carboxy acid's form is fat, water indissoluble all then.Clinically bronchial asthma and other type asthma of being used for the treatment of of the hydrochlorate of ozagrel more.Its sodium salt is mainly used in mobility's obstacle that the acute or progressivity cerebral infarction of treatment and cerebral infarction are followed clinically.Prevention and treatment postoperative cerebral vasospasm of subarachnoid hemorrhage and concurrent symptoms of cerebral ischemia.Along with deepening continuously of pharmacology and clinical research, find it to Liver and kidney ischemia injury, angina pectoris, coronary heart disease, acute coronary artery syndrome, chronic pulmonary heart disease, pulmonary function imbalance and acute lung injury, pulmonary hypertension, vasculitis, acute necrotizing pancreatitis, diabetic peripheral neuropathy, embolism of retinal artery, transplant organ survival etc. all has better curative effect.The sodium ozagrel clinical practice is evident in efficacy in the treatment cerebral infarction, its domestic and international clinical common formulations has only injection at present, pharmacokinetic study shows: have significant liver first-pass effect during the sodium ozagrel oral administration, cause area (AUC) under the drug-time curve of its oral administration to be significantly less than the AUC of quiet notes administration, simultaneously the AUC of its metabolite is obviously greater than the AUC of quiet notes administration, therefore, the pharmacokinetics of sodium ozagrel and metabolite thereof depends on its route of administration.After human vein instiled, this product blood drug level-time graph met two chambers model, and plasma half-life is very short, and (t1/2 (β)=0.764h), blood drug level only can measure 3h after the drug withdrawal, and behind the drug withdrawal 24h, almost all medicines excrete through urine.Because medicine is eliminated very fast from blood after the administration of ozagrel sodium injection, therefore this product can only adopt the continuous intravenous infusion administration clinically, causes patient's medication poor compliance, in addition this product aqueous solution instability, meet light and easily decompose, its clinical practice further is restricted.Publication number is that the patent of CN101019994A turns to the prodrug Ozagrel ester with Ozagrel ester, has solved ozagrel aqueous solution problem of unstable, and has made it be easy to be prepared into multiple form of medication; Publication number is that two patents of CN1847228A and CN1872840A are prepared into ozagrel ornithine salt and lysinate respectively, thereby increases its dissolubility in water and improve stability.There is the existence form that has formed new salt or derivant isoreactivity material jointly in above-mentioned three patents, and these new existence forms are not seen relevant pharmacokinetics and pharmacodynamic experiment data, and its safety and effectiveness is without the problem of fully verifying.Patent CN1546021A discloses a kind of ozagrel sodium oral solution, though increased partial adaptation disease, unresolved ozagrel sodium water solution instability and the low problem of oral administration biaavailability.Patent CN1568977A discloses a kind of injection ozagrel sodium freeze-drying powder, has solved ozagrel sodium water solution problem of unstable, but fails to prolong after its administration the holdup time in the body.Patent JP2001316265A, JP2004339172A, JP2005120016A, JP2005154415A, JP2006131624A adopt respectively and add multi-form stabilizing agent, means such as preparation premix have improved the stability of ozagrel sodium water solution to a certain extent, but still plasma half-life is short after having administration, continuously the problem of quiet administration patient poor compliance.Therefore, how to prepare a kind of high ozagrel preparation of sodium of compliance that does not have first pass effect, administration time weak point, good stability and patient's medication, make it bring into play therapeutical effect more fully and be still present problem demanding prompt solution.Liposome is made of one or more double-layer of lipoid vesicles that separated by water or buffer solution layer, because similar biomembrane on the structure, so be otherwise known as artificial membrane or artificial cell.Liposome is as pharmaceutical carrier the time, drug molecule both can be encapsulated in the aqueous layer, also can embed in the lipid bilayer, can also be present in the interfacial film place, therefore in theory its both can water soluble medicament-entrapping in the interior aqueous phase of liposome interior, can wrap again and carry in fat-soluble medicine or the hydrophobic microenvironment of double type medicine in lipid bilayer.In view of liposome have height biocompatibility, can change institute's entrapped drug the moving parameter of medicine, improve targeting, reduce toxic and side effects, improve plurality of advantages such as bioavailability of medicament and stability, it is paid close attention to day by day widely and is used in field of pharmaceutical preparations.For solving the problem that the existing preparation of ozagrel exists holdup time weak point in first pass effect, poor stability, the body, administration time length, patient's poor compliance, the present invention is prepared into liposome with ozagrel, by controlling suitable size, make liposome escape the picked-up that monokaryon is engulfed system, improve the body circulation holdup time, so that medicine is kept the valid density of long period in blood, and concentrate to greatest extent, reduce administration time in target site.Solid preparation is made in the spray-dried or lyophilization of liposome, has further solved ozagrel aqueous solution problem of unstable.
Summary of the invention
The objective of the invention is to development and provide a kind of safe to clinical, stable in properties, evident in efficacy, clinical practice is simple relatively, and the Ozagrel liposomes of suitable suitability for industrialized production.It is material that the present invention adopts preparation liposome lipid, the water ease of solubility form bag of ozagrel is stated from interior water, to get in the hydrophobic microenvironment in its water-insoluble form insertion or the embedding lipid bilayer, it can improve or improve the envelop rate of medicine, has control drug release, the release of targeting location, advantages such as holdup time and good stability in the extension body.Can overcome the defective and the deficiency of existing preparation, the preparation of a kind of drug loading height, good stability is provided, can improve the bioavailability and the therapeutic index thereof of ozagrel again.Another object of the present invention provides a kind of preparation method of Ozagrel liposomes, and this method all adopts conventional process equipment, high efficiency production on a large scale.
Ozagrel liposomes of the present invention, each compositions in weight percentage consists of:
Ozagrel 0.1%～2%
Preparation liposome lipid 0.5%～50%
Buffer system is regulated pH4.0～9.0 with salt
Protective agent 1.0%～30%
Water for injection is an amount of
Ozagrel of the present invention comprises one or more compositionss in free carboxy acid's form, sodium-salt form and the hydrochloride form of ozagrel.
Preparation liposome lipid of the present invention is the compatible biodegradable natural or synthetic lipid of physiology, comprise soybean lecithin, Ovum Gallus domesticus Flavus lecithin, hydrolecithin, ceramide, distearoyl phosphatidylcholine, two Semen Myristicae phosphatidylcholines, dipalmitoyl phosphatidyl choline, two palmityl PHOSPHATIDYL ETHANOLAMINE, two palmityl Phosphatidylserine, two palmityl phosphatidyl glycerols, the dioleoyl phospholipid phatidylcholine, DOPG, DOPE, poloxamer, Polyethylene Glycol 660-12-hydroxy stearic acid ester and brejs nonionic surfactant, one or more compositionss in the cholesterol.Protective agent of the present invention is selected from trehalose, sucrose, glucose, mannitol, sorbitol, lactose, sodium chloride, maltose, cottonseed sugar, fructose, hexose, xylitol, one or more compositionss in aminoacid and the polyvinylpyrrolidone etc.Buffer system of the present invention comprises phosphatebuffer buffer system, citrate buffer system, carbonate buffer system system.Ozagrel liposomes of the present invention, the envelop rate of its ozagrel are 60%～100%, and be preferred more than 85%, satisfies the entrapment efficiency requirement of clinical use.
Ozagrel liposomes of the present invention, particle diameter are preferably 50-250nm at 20～1000nm, and are evenly distributed.Ozagrel liposomes of the present invention can prepare by the following method:
Method one: (1) will prepare liposome with lipid and ozagrel mixed melting or with suitable organic solvent dissolution, make lipid soln; (2) lipid soln and buffer are made Ozagrel liposomes by film dispersion method or fusion method or injection method or reverse evaporation; (3) with the liposome that makes with ultrasonic dispersing or use high pressure homogenization; (4) in the Ozagrel liposomes solution for preparing, add an amount of protective agent, obtain solid preparation by vacuum lyophilization or spray drying process.
Method two: (1) will prepare liposome with the lipid fusion or with suitable organic solvent dissolution, make lipid soln; (2) ozagrel sodium salt or hydrochlorate are dissolved in appropriate amount of buffer solution, make ozagrel solution; (3) lipid soln and ozagrel solution are made Ozagrel liposomes by pH gradient method or ammonium sulphate gradient or calcium acetate gradient method or film dispersion method or fusion method or injection method or reverse evaporation; (4) with the liposome that makes with ultrasonic dispersing or use high pressure homogenization; (5) in the Ozagrel liposomes solution for preparing, add an amount of protective agent, obtain solid preparation by vacuum lyophilization or spray drying process.In the preparation method of Ozagrel liposomes of the present invention, the organic solvent in the step (1) is dichloromethane, chloroform, ether and ethanol.
In the preparation method of Ozagrel liposomes of the present invention, the even pressure of high pressure breast is 100～2500bar, and the even number of times of breast is more than 1 time.Ultra-sonic dispersion power is 100～1000W, and the accumulation ultrasonic time is more than 1 minute.
Ozagrel liposomes of the present invention obtains solid preparation through lyophilization or spray drying, and this solid preparation is used normal saline before use, after glucose solution or Ringer's solution dilute, is solubilized in 100 seconds.
The Ozagrel liposomes body of the present invention's development has the following advantages:
1. this Ozagrel liposomes injectable administration, serious first pass effect when having avoided the ozagrel oral administration.
2. ozagrel is combined with liposome, make Ozagrel liposomes of the present invention have the drug release of improvement character, the holdup time in the may command drug release, extension body, have targeting, can improve advantages such as bioavailability of medicament and therapeutic index.
3. this Ozagrel liposomes obtains solid product by lyophilization or drying process with atomizing, solved ozagrel problem of unstable in aqueous solution, what also overcome simultaneously conventional liposome be easy to defectives such as gathering, sedimentation, fusion and seepage, guaranteed product store and transportation in stability.
4. this Ozagrel liposomes preparation technology is simple, and maturation is convenient to suitability for industrialized production.
Description of drawings
Fig. 1 is Ozagrel liposomes granulometry figure
Fig. 2 is the granulometry figure after the Ozagrel liposomes lyophilized formulations redissolves
Fig. 3 is the particle size determination figure after the Ozagrel liposomes spray dried formulations redissolves
Fig. 4 is that positive dynamic dialysis method is measured Ozagrel liposomes and the outer release profiles of commercially available ozagrel injecting fluid
Fig. 5 is that anti-phase dynamic dialysis method is measured Ozagrel liposomes and the outer release profiles of commercially available ozagrel injecting fluid
The specific embodiment
The present invention is not subjected to the restriction of following embodiment.
Embodiment 1:
Get ozagrel 5g, soybean lecithin 30g, cholesterol 30g, chloroform 200mL, the pH7.4 phosphate buffer adds to 1000mL.Place round-bottomed flask fully to dissolve in above-mentioned ozagrel, soybean lecithin, cholesterol, put vacuum rotary steam in the 20-40 ℃ of water bath with thermostatic control, make lipid in the even film forming of drag with chloroform.In the above-mentioned flask of pH7.4 phosphate buffer impouring, hydration, vibration is settled to 1000mL with the pH7.4 phosphate buffer again, spares 6 times through 750bar high pressure breast, obtains liposome turbid liquor; Or in above-mentioned Ozagrel liposomes suspension, add glucose 200g, promptly get the Ozagrel liposomes pressed powder through lyophilization.
Embodiment 2:
Get ozagrel 10g, Ovum Gallus domesticus Flavus lecithin 50g, cholesterol 50g, the pH7.4 phosphate buffer adds to 1000mL.
Above-mentioned ozagrel, Ovum Gallus domesticus Flavus lecithin, cholesterol are added an amount of dissolve with ethanol, slowly inject the phosphate buffer of 800mL pH7.4, residual ethanol is removed in decompression, is settled to 1000mL with buffer, spare 7 times through 700bar high pressure breast, promptly get the Ozagrel liposomes suspension; Or in above-mentioned Ozagrel liposomes suspension, add lactose 200g, promptly get the Ozagrel liposomes pressed powder through lyophilization.
Embodiment 3:
Get ozagrel 7.5g, dipalmitoyl phosphatidyl choline 60g, poloxamer F6850g, cholesterol 50g, the pH7.4 phosphate buffer adds to 1000mL.
Get ozagrel, dipalmitoyl phosphatidyl choline, poloxamer F68, cholesterol fusion mixing to clear and bright, splash in the pH7.4 phosphate buffer that is heated to 65 ℃ under stirring, insulation is through 500w, 5 minutes ultra-sonic dispersion of accumulative total make the Ozagrel liposomes suspension; Or trehalose 100g, the spray-dried Ozagrel liposomes pressed powder that promptly gets will be added in the above-mentioned Ozagrel liposomes suspension.Spray drying condition: 160 ℃ of inlet temperatures, 91 ℃ of outlet temperatures, air quantity 100%, flow velocity 0.01%, productive rate 40.8%.
Embodiment 4:
Get sodium ozagrel 15g, ceramide 50g, Ovum Gallus domesticus Flavus lecithin 40g, cholesterol 60g, poloxamer F6840g, the pH7.4 phosphate buffer adds to 1000mL.
With above-mentioned ceramide, Ovum Gallus domesticus Flavus lecithin, cholesterol, poloxamer with 200mL ether dissolution and mix homogeneously, as organic facies; Sodium ozagrel is dissolved in an amount of pH7.4 phosphate buffer, as water; Stir down water added in the organic facies, under the ice-water bath ultrasonic 20 minutes, inverse micellar solution; This inverse micellar solution is revolved steaming remove ether, be settled to 1000mL, spare 7 times, promptly get the Ozagrel liposomes suspension through 1200bar high pressure breast with the pH7.4 phosphate buffer; Or in above-mentioned Ozagrel liposomes suspension, add mannitol 200g, promptly get the Ozagrel liposomes pressed powder through lyophilization.
Embodiment 5:
Get ozagrel hydrochloride 10g, soybean lecithin 50g, cholesterol 5g, calcium acetate 22g, water for injection adds to 1000mL.
The 4/5th page of description
Above-mentioned soybean lecithin, cholesterol with an amount of dissolve with ethanol, are placed round-bottomed flask, flask is put vacuum rotary steam in the 20-40 ℃ of water bath with thermostatic control, make lipid in the even film forming of drag; Calcium acetate is mixed with the solution of 120mmol/L with water for injection, this solution is added in the above-mentioned flask, hydration, vibration, through 400w, 5 minutes ultra-sonic dispersion of accumulative total, blank liposome; With dialysis under an amount of 5% aqueous sucrose solution room temperature 3 times, amount to 24 hours; To wherein adding the ozagrel hydrochloride aqueous solution, hatched 15 minutes under 55 ℃ of tepidariums, be cooled to room temperature and promptly get the Ozagrel liposomes suspension; Or in above-mentioned Ozagrel liposomes suspension, add sorbitol 200g, the spray-dried Ozagrel liposomes pressed powder that promptly gets.Spray drying condition: 170 ℃ of inlet temperatures, 100 ℃ of outlet temperatures, air quantity 100%, flow velocity 0.01%, productive rate 36.4%.
Embodiment 6:
Get Ozagrel liposomes suspension or its lyophilization, spray dried formulations, measure medicament contg and envelop rate.
Medicine assay: after Ozagrel liposomes suspension or its pressed powder lyophilized formulations added water and redissolve, precision is measured Ozagrel liposomes suspension 0.5mL, place the 10mL volumetric flask, add methanol-1% glacial acetic acid (10:90) and be settled to scale, shake up, ultrasonic after, the centrifugal 3min of 3500rmin-1, get supernatant, advance the high performance liquid chromatograph analysis, the results are shown in Table shown in 1.Entrapment efficiency determination: will pack in the syringe of 3mL solid-phase extraction column with the good Sephadex G-50 of distilled water balance (5.2cm * 0.9cm), a circular sieve plate that is slightly less than its internal diameter is put in the bottom, the centrifugal 1min of 1000rmin-1 removes redundant moisture, makes the micro-column of Sephadex G-50.The accurate Ozagrel liposomes suspension 0.5mL that draws slowly is added on the column top, the centrifugal 1min of 1000rmin-1.By the water for injection of column top adding 1.0mL, the centrifugal 1min of 1000rmin-1 collects filtered solution, add equal volume water for injection again in the column top, repeat above operation, merge 1～9 pipe filtered solution, add the injection dilute with water and be settled to 10mL, shake up, the accurate 20 μ L solution of drawing, sample introduction is measured peak area, content with one point external standard method calculating ozagrel is designated as M1; Other draws 0.5mL Ozagrel liposomes suspension, presses content assaying method and handles sample introduction, counts M0; Envelop rate (%)=(M1/M0) * 100%, M1 are the amount of the ozagrel sealed in the liposome; M0 is the total amount of the ozagrel sealed in the liposome, the results are shown in Table shown in 1.
The content of ozagrel in the Ozagrel liposomes suspension among table 1 embodiment 1～5
Embodiment 7:
Get Ozagrel liposomes suspension or its lyophilization, spray dried formulations, measure its release in vitro curve, and the release in vitro curve under itself and ozagrel injection the same terms is compared.Adopting positive dynamic dialysis method, is release medium with pH7.4 phosphate buffer 200mL, rotating speed 50rmin-1, temperature (37 ± 0.5) ℃.With the bag filter and the bag filter (molecular cut off 12000～14000) that 2mL ozagrel injection is housed of 2mL Ozagrel liposomes suspension are housed, immerse in the release medium respectively.In 0.5,1.0,2.0,4.0,8.0,12.0,24.0 draw release medium 2mL, mend equivalent equality of temperature release medium, the laggard high performance liquid chromatograph analysis of sample filtering simultaneously.The result shows that under this release conditions, rate of release was very fast in preceding 8 hours, and rate of release slows down subsequently, and the release in vitro persistent period prolongs about 16 hours than injection.The result as shown in Figure 4.
Embodiment 8:
Get Ozagrel liposomes suspension or its lyophilization, spray dried formulations, measure its release in vitro curve, and the release in vitro curve under itself and ozagrel injection the same terms is compared.Adopting anti-phase dynamic dialysis method, is release medium with pH7.4 phosphate buffer 200mL, rotating speed 50rmin-1, temperature (37 ± 0.5) ℃.With 12 size unanimities, the bag filter (molecular cut off 12000～14000) of 2mL release medium is housed respectively, immerses in Ozagrel liposomes suspension or the ozagrel injection.Respectively at 0.5,1.0,2.0,4.0,8.0,12.0,24.0 respectively take out a bag filter, draw an amount of solution in the bag, mend equivalent equality of temperature release medium, sample introduction behind the sample filtering simultaneously.The result shows that under release conditions, rate of release was very fast in preceding 8 hours, and rate of release slows down subsequently, and the release in vitro persistent period prolongs about 16 hours than injection.The result as shown in Figure 5.
Embodiment 9:
Ozagrel liposomes suspension or its lyophilization, spray drying gained pressed powder are diluted to suitable multiple with buffer, adopt the laser particle size distribution instrument to measure the size and the distribution of liposome, the results are shown in Figure shown in 1～3.
Safety experiment
The Ozagrel liposomes lumbar injection gives Cavia porcellus 8.0mg/kg, the next day once, totally three times, the 14th day and the 21st day this medicine of vena femoralis injection 16.0mg/kg respectively after the administration, the result there is no Cavia porcellus anaphylaxis.The Cavia porcellus that gives 1% Ovum Gallus domesticus album anaphylaxis all occurred behind the vena femoralis injection Ovum Gallus domesticus album respectively in the 14th day and the 21st day after giving Ovum Gallus domesticus album, and all dead in 15min.Ozagrel liposomes does not have haemolysis and red cell agglutination to tame rabbit erythrocyte at application of sample in 0.25～4.0 hour under the in vitro tests condition.Place and also do not have haemolysis and hemagglutination after 24 hours.The injection Ozagrel liposomes is dissolved in 0.9% sodium chloride injection, makes the need testing solution of 160g/mL.To this solution of mouse mainline, dosage is 0.5mL/, observes 48 hours, and mice does not have death in 48 hours as a result, and its undue toxicity checks up to specification.
Injection Ozagrel liposomes man rabbit ear vein drug administration by injection, dosage is 3.5mg/kg, once a day, continuous three days.The result: the perusal of tame rabbit ear vein medicine-feeding part does not have significant change; The pathological section microscope inspection shows apart from injection site 1cm place blood vessel, 5cm place blood vessel endothelium tissue and surrounding tissue no abnormality seen.
Above-mentioned result of the test shows that the safety of injection Ozagrel liposomes is good, can be used for intravenous administration.
Claims (10)
1. Ozagrel liposomes is characterized in that making with following method, and each compositions in weight percentage forms:
Ozagrel 0.1%～2%
Preparation liposome lipid 0.5%～50%
Buffer system is regulated pH4.0～9.0 with salt
Protective agent 1.0%～30%
Water for injection is an amount of.
2. Ozagrel liposomes according to claim 1 is characterized in that described protective agent is selected from trehalose, sucrose; glucose; mannitol, sorbitol, lactose; sodium chloride, maltose; cottonseed sugar, fructose, hexose; xylitol, one or more compositionss in aminoacid and the polyvinylpyrrolidone etc.
3. Ozagrel liposomes according to claim 1 is characterized in that described buffer system comprises phosphatebuffer buffer system, lemon hydrochlorate buffer system, carbonate buffer system system.
4. Ozagrel liposomes according to claim 1, it is characterized in that described preparation liposome lipid is the compatible biodegradable natural or synthetic lipid of physiology, comprise soybean lecithin, Ovum Gallus domesticus Flavus lecithin, hydrolecithin, ceramide, distearoyl phosphatidylcholine, two Semen Myristicae phosphatidylcholines, dipalmitoyl phosphatidyl choline, two palmityl PHOSPHATIDYL ETHANOLAMINE, two palmityl Phosphatidylserine, two palmityl phosphatidyl glycerols, the dioleoyl phospholipid phatidylcholine, DOPG, DOPE, poloxamer, Polyethylene Glycol 660-12-hydroxy stearic acid ester and brejs nonionic surfactant, one or more compositionss in the cholesterol.
5. Ozagrel liposomes according to claim 1 is characterized in that one or more compositionss in free carboxy acid's form, sodium-salt form and the hydrochloride form that described active substance ozagrel is an ozagrel.
6. the preparation method of an Ozagrel liposomes is characterized in that may further comprise the steps:
(1) will prepare liposome with lipid and ozagrel mixed melting or with suitable organic solvent dissolution, make lipid soln;
(2) lipid soln and buffer are made Ozagrel liposomes by film dispersion method or fusion method or injection method or reverse evaporation;
(3) with the liposome that makes with ultrasonic dispersing or use high pressure homogenization;
(4) in the Ozagrel liposomes for preparing, add an amount of protective agent, obtain solid preparation by vacuum lyophilization or spray drying process.
7. the preparation method of an Ozagrel liposomes is characterized in that comprising following steps:
(1) will prepare liposome with the lipid fusion or with suitable organic solvent dissolution, make lipid soln;
(2) ozagrel is dissolved in appropriate amount of buffer solution, makes ozagrel solution;
(3) lipid soln and ozagrel solution are made Ozagrel liposomes by pH gradient method or ammonium sulphate gradient or calcium acetate gradient method or film dispersion method or fusion method or injection method or reverse evaporation;
(4) with the liposome that makes with ultrasonic dispersing or use high pressure homogenization;
(5) in the Ozagrel liposomes for preparing, add an amount of protective agent, obtain solid preparation by vacuum lyophilization or spray drying process.
8. Ozagrel liposomes according to claim 1 is characterized in that described particle diameter at 20～1000nm, is preferably 50-250nm, and is evenly distributed.
9. Ozagrel liposomes according to claim 1, the envelop rate that it is characterized in that ozagrel is 60%～100%, and is preferred more than 85%, satisfies the entrapment efficiency requirement of clinical use.
10. Ozagrel liposomes according to claim 1 is characterized in that administering mode including but not limited to venoclysis, the lumbar injection intramuscular injection, and subcutaneous injection, atomizing sucks or oral administration.
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| CN101642431B (en) * | 2009-08-28 | 2011-02-02 | 海南永田药物研究院有限公司 | Ozagrel sodium liposome injection |
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| CN102626388A (en) * | 2012-04-19 | 2012-08-08 | 海南永田药物研究院有限公司 | Liposome solid preparation of ozagrel |
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| CN113384705A (en) * | 2021-06-28 | 2021-09-14 | 西南大学 | Preparation of poloxamer modified liposome and application of poloxamer modified liposome in oral drug delivery |
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