CN102552146B - Epirubicin liposome as well as preparation method and preserving method thereof - Google Patents
Epirubicin liposome as well as preparation method and preserving method thereof Download PDFInfo
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- CN102552146B CN102552146B CN 201210030179 CN201210030179A CN102552146B CN 102552146 B CN102552146 B CN 102552146B CN 201210030179 CN201210030179 CN 201210030179 CN 201210030179 A CN201210030179 A CN 201210030179A CN 102552146 B CN102552146 B CN 102552146B
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Abstract
The invention belongs to the field of pharmaceutical preparation and relates to an epirubicin liposome as well as a preparation method and a preserving method of the epirubicin liposome. The epirubicin liposome is formed by epirubicin and at least one phospholipid as, well as at least one surface active agent or one cryoprotectant or cholesterol which may be contained. The preserving method comprises the following types: preservation at normal temperature, refrigeration preservation, freezing preservation and freezing and drying preservation.
Description
Technical field:
The invention belongs to medical technical field, relate to the microparticle formulation in medicine administration field, more specifically refer to the liposome that a kind of epirubicin and suitable adjuvant are made, and preparation method thereof and storage method.
Background technology:
Epirubicin (Epirubicin, EPI) be Italian scholar Arcamone etc. in 1975 by the synthetic a kind of anthracene nucleus antineoplastic antibiotic of semi-synthetic approach, the mechanism of action is between the direct intercalation of DNA base pair, disturb transcription, stop the formation of mRNA, thereby suppress the synthetic of DNA and RNA, so all there is effect in each stage of cell cycle, be cell cycle nonspecific agent (CCNSA), mainly act on nucleus.At present, the clinical multiple solid tumors such as acute leukemia and malignant lymphoma, breast carcinoma, ovarian cancer, bladder cancer, carcinoma of testis, gastric cancer, hepatocarcinoma that are mainly used in of epirubicin.There is more untoward reaction in epirubicin, except the general untoward reaction of the antitumor drug that may occur, (comprise bone marrow depression, gastrointestinal reaction, neurotoxicity), also can cause serious local untoward reaction, drug extravasation can cause local pain, serious histologic lesion and kill, owing to during the intravenous injection of this medicine serious cellulitis can take place, so unsuitable directly intravenous injection also will be avoided in little blood vessel duplicate injection in injection or same the vein simultaneously.This has brought bigger inconvenience to clinical practice, has brought very big misery to the patient.At present, epirubicin and salt thereof have many launch both at home and abroad, as: " Pharmorubicin RD " that Pharmacia ﹠ Upjohn (China) company limited is produced, " Ida is given birth to " that the Zhejiang Haizheng Pharmaceutical Co is produced etc., dosage form is generally freeze-dried powder, because drug molecule is not wrapped up, and directly contacts with vascular tissue with skin, very easily causes above toxic and side effects.
Liposome is a kind of novel form of targeting drug delivery system, and this system is up-to-date, the most promising drug-supplying system of present pharmaceutics.Liposome is the focus of pharmaceutics research as a member of this system always, it can with drug selectivity be transported to the target spot position, the performance therapeutical effect does not influence the function of normal cell, tissue or organ again simultaneously, thereby reaches the purpose that improves curative effect, reduces toxic and side effects.The present invention adopts liposomal encapsulated epirubicin, has reduced toxic and side effects, has improved curative effect.Simultaneously, preparation method of the present invention is fit to Industry Promotion.
The storage stability of liposome is difficult to solve always, and existing freeze-drying method is having limitation aspect economy and the industrial efficiency.Not only highly energy-consuming of freezing dry process, long consuming time, its dry run can impact biology, chemistry and the physical property of liposome membrane, causes storing unstability.The final active component that liposome is sealed brings adverse effect.The present invention has adopted the storage method that adds cryoprotective agent, and the character of maintenance liposome that can be efficient, stable is unaffected.
Patent (publication number: epirubicin liposome and preparation method thereof CN 1554354A) is arranged.Prepared the epirubicin liposome with the organic solvent injection method, but envelop rate is lower, can not solves the local irritation problem.
Patent (publication number: epirubicin hydrochloride liposome and preparation method thereof CN 101264056A) is arranged.Trial production problem and stability problem during the liposome of this method preparation does not solve.
More than two patents giving full play to the drug effect of epirubicin, reducing and also have certain deficiency aspect toxicity and the industrialization.
Summary of the invention
The object of the present invention is to provide preparation and the storage method of epirubicin liposome.Characteristics of the present invention are that epirubicin is prepared into liposome, solve chemistry and the physical stability problem of liposome simultaneously with the method for stored frozen, improve the shelf life of liposome.
Epirubicin liposome among the present invention is by epirubicin and at least a phospholipid, can contains at least a surfactant or a kind of cryoprotective agent or cholesterol simultaneously and form.Storage method comprises that normal temperature storage, stored under refrigeration, stored frozen and lyophilization store.
The epirubicin liposome, it contains following component and percentage by weight:
Epirubicin 0.01% ~ 50.0%
Phosphatidase 10 .1% ~ 99.9%
Cholesterol 0% ~ 60.0%
Surfactant 0% ~ 60.0%
Cryoprotective agent 0% ~ 95%
The epirubicin liposome, can contain following component and percentage by weight:
Epirubicin 2.0% ~ 10.0%
Phosphatidase 14 0.0% ~ 80.0%
Cholesterol 5% ~ 30.0%
Surfactant 1% ~ 30.0%
Cryoprotective agent 0% ~ 60.0%
Described at least a phospholipid is selected from phosphatidylcholine class, the phosphatidyl glycerol class, the phosphatidyl-4 alcohols, the PHOSPHATIDYL ETHANOLAMINE class, the sphingomyelin class, strand or double-stranded phospholipid (two Semen Myristicaes acid phosphatidyl glycerol, two lauric acid phosphatidyl glycerols, two palmitic acid phosphatidyl glycerols, distearyl acid phosphatidyl glycerol, two Semen Myristicaes acid phosphatidic acid, two lauric acid phosphatidic acid, two palmitic acid phosphatidic acid, distearyl acid phosphatidic acid, two oleic acid Phosphatidylserine, the dilinoleic acid phosphatidylinositols, two Palmic acid phosphatidylcholines (DPPC), two lauric acid phosphatidylcholines (DLPC), two myristic acid phosphatidylcholines (DMPC), distearoyl phosphatidylcholine (DSPC), single Semen Myristicae acid phosphatidyl glycerol, the mono laurate phosphatidyl glycerol, single palmitic acid phosphatidyl glycerol, the monostearate phosphatidyl glycerol, single Semen Myristicae acid phosphatidic acid, the mono laurate phosphatidic acid, single palmitic acid phosphatidic acid, the monostearate phosphatidic acid, single oleic acid Phosphatidylserine, single linoleic acid phosphatidylinositols, single Palmic acid phosphatidylcholine (MPPC), mono laurate phosphatidylcholine (MLPC), single myristic acid phosphatidylcholine (MMPC), single stearoyl phosphatidylcholine (MSPC)) and composition thereof;
Described surfactant is selected from LYSO-PHOSPHATIDYLCHOLINE LYSOPC that bacteriolysin, bile acid, myristoyl surfactant, palmityl surfactant, stearoyl surfactant, glycerin mono-fatty acid ester, ceramide, Polyethylene Glycol esters surfactant, PEG-ceramide, C18-ether connect, polyethylene glycol-ethylene copolymer, block copolymer, fatty acid and composition thereof;
Described cryoprotective agent is selected from Polyethylene Glycol, polyaeryloyl morpholine, poly--the 2-ethyl-2-oxazoline, polyvinylpyrrolidone, methoxy poly (ethylene glycol) (mPEG), various saccharide (comprising: trehalose, mannitol, sucrose, glucose, sodium chloride, lactose, sorbitol, dextran, glycerol or glycine) and composition thereof.
The preparation method of epirubicin liposome is to adopt one-step method to prepare blank nanometer liposome, carries out medicine with pH gradient method or ammonium sulphate gradient and loads, and may further comprise the steps:
Phospholipid, surfactant, the cholesterol of not getting recipe quantity are scattered in the buffer of pH2.0-5.0, repeatedly by the even particle diameter that lowers of nanometer machine high pressure breast, the alkaline solution that adds pH9.0-12.0, regulate pH to 6.0-7.5, with blank liposome solution mix with the cryoprotection agent solution of epirubicin, hatched under 30-70 ℃ 10-60 minute, namely; Or phospholipid, surfactant, the cholesterol of getting recipe quantity respectively are scattered in the ammonium sulfate of 100-300mM; repeatedly by the even particle diameter that lowers of nanometer machine high pressure breast; obtain blank liposome; it is the cryoprotection agent solution that blank liposome is concentrated outer water by the ultrafilter displacement; with blank liposome solution mix with the cryoprotection agent solution of epirubicin; hatched under 30-70 ℃ 10-60 minute, namely.
Advantage of the present invention is: liposome can be avoided some toxic and side effects of normal injection, and tumor is had certain targeting, can bring into play drug effect better, reduces toxicity; The present invention adopts one-step method to prepare liposome can industrialization, is fit to suitability for industrialized production; The method of the liposome that keeps in cold storage that adopts, the character of maintenance liposome that can be efficient, stable is unaffected.
The specific embodiment:
The specific embodiment of the present invention, by following embodiment explanation, but protection scope of the present invention is not limited to this.
Embodiment 1
With hydrogenated soya phosphatide (HSPC) and N-(carbonyl-methoxy poly (ethylene glycol)-2000)-1,2-distearyl acyl group-sn-glycerol-3-phosphate ethanolamine (DSPE-mPEG2000) is scattered in mol ratio 90:10 in 70 ℃ the citric acid solution of 300mM pH4.After even through 1000bar high pressure breast, obtain the 100mg/ml phospholipid concentration, mean diameter is the blank liposome of 50-300nm.Trehalose (1g/ml) aqueous solution of 2.0ml epirubicin (5.0mg/ml) and the 0.4mM sodium carbonate liquor of 1.5ml are added in the blank liposome of 2.0ml, under 60 ℃, hatch 30min.Then with drug-loaded liposome and blank liposome in-20 ℃ of storages.The liposome that does not add cryoprotective agent mPEG and trehalose by identical method preparation.After-20 ℃ of storages, detect the variation of granularity, the results are shown in Table 1.The result shows that the blank of adding cryoprotective agent and drug-loaded liposome are through after the freeze/thaw, and particle diameter does not have significant change; And after not adding the liposome process freeze/thaw of cryoprotective agent, particle diameter obviously increases.
Table 1 freeze/thaw process is to the influence of liposome particle size
Embodiment 2
Prepare the epirubicin liposome by embodiment 1 method, sample is stored 6 months in-20 ℃, respectively at initial time, in the time of 1 month, 3 months, 6 months, the content of working sample, particle diameter, envelop rate, prominently release percentage pH value when, the results are shown in Table 2.The result shows do not have significant change 6 months each character of lactone plastid, proves that storage method is rationally feasible.
Table 2 freeze/thaw process is to the influence of liposome property
| Time | Content (epirubicin) (mg/ml) | Particle diameter (nm) | Envelop rate (%) | The prominent percentage (%) of releasing | PH value |
| Initially | 2.01 | 101 | 99.9 | 8 | 7.88 |
| 1 month | 1.99 | 103 | 99.8 | 7 | 7.91 |
| 3 months | 1.97 | 104 | 99.7 | 8 | 7.87 |
| 6 months | 1.98 | 107 | 99.8 | 9 | 7.92 |
Claims (2)
1. epirubicin liposome, it is characterized in that, preparation method is as follows: with hydrogenated soya phosphatide and N-(carbonyl-methoxy poly (ethylene glycol)-2000)-1,2-distearyl acyl group-sn-glycerol-3-phosphate ethanolamine is scattered in mol ratio 90:10 in 70 ℃ the citric acid solution of 300mM pH=4; After even through 1000bar high pressure breast, obtain the 100mg/mL phospholipid concentration, mean diameter is the blank liposome of 50-300nm; The aqueous trehalose solution of 2.0mL epirubicin and the 0.4mM sodium carbonate liquor of 1.5mL are added in the blank liposome of 2.0mL, under 60 ℃, hatch 30min, in-20 ℃ of storages; Wherein, the concentration of epirubicin is 5.0mg/mL, and the concentration of trehalose is 1g/mL.
2. the preparation method of an epirubicin liposome, it is characterized in that, comprise the steps: hydrogenated soya phosphatide and N-(carbonyl-methoxy poly (ethylene glycol)-2000)-1,2-distearyl acyl group-sn-glycerol-3-phosphate ethanolamine is scattered in mol ratio 90:10 in 70 ℃ the citric acid solution of 300mM pH=4; After even through 1000bar high pressure breast, obtain the 100mg/mL phospholipid concentration, mean diameter is the blank liposome of 50-300nm; The aqueous trehalose solution of 2.0mL epirubicin and the 0.4mM sodium carbonate liquor of 1.5mL are added in the blank liposome of 2.0mL, under 60 ℃, hatch 30min, in-20 ℃ of storages; Wherein, the concentration of epirubicin is 5.0mg/mL, and the concentration of trehalose is 1g/mL.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| DE102017002454A1 (en) | 2017-03-14 | 2018-09-20 | Friedrich-Schiller-Universität Jena | Organic polymer particles containing poly (oxazoline) stabilizers and use of poly (oxazolines) for the stabilization of organic polymer particles |
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| CN103550157A (en) * | 2013-11-18 | 2014-02-05 | 江西本草天工科技有限责任公司 | Preparation method of epidoxorubicin lipidosome and application of epidoxorubicin lipidosome in resisting tumors |
| CN105878260A (en) * | 2016-04-29 | 2016-08-24 | 陈西敬 | Composition liposome of ascorbyl palmitate and adriamycin |
| CN111821263B (en) * | 2019-04-19 | 2023-03-21 | 上海交通大学医学院附属第九人民医院 | Liposome, dispersion liquid containing liposome, preparation method and application of liposome and dispersion liquid |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1554354A (en) * | 2003-12-23 | 2004-12-15 | 中国药科大学 | Epi-doxorubicine liposome and its preparing method |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1554354A (en) * | 2003-12-23 | 2004-12-15 | 中国药科大学 | Epi-doxorubicine liposome and its preparing method |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102017002454A1 (en) | 2017-03-14 | 2018-09-20 | Friedrich-Schiller-Universität Jena | Organic polymer particles containing poly (oxazoline) stabilizers and use of poly (oxazolines) for the stabilization of organic polymer particles |
| WO2018166651A1 (en) | 2017-03-14 | 2018-09-20 | Friedrich-Schiller-Universität Jena | Organic polymer particles containing poly(oxazoline) stabilizers and use of poly(oxazolines) for stabilizing organic polymer particles |
| US11806355B2 (en) | 2017-03-14 | 2023-11-07 | Friedrich-Schiller-Universitaet Jena | Organic polymer particles containing poly(oxazoline) stabilizers and use of poly(oxazolines) for stabilizing organic polymer particles |
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