CN103550157A - Preparation method of epidoxorubicin lipidosome and application of epidoxorubicin lipidosome in resisting tumors - Google Patents
Preparation method of epidoxorubicin lipidosome and application of epidoxorubicin lipidosome in resisting tumors Download PDFInfo
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- CN103550157A CN103550157A CN201310575936.2A CN201310575936A CN103550157A CN 103550157 A CN103550157 A CN 103550157A CN 201310575936 A CN201310575936 A CN 201310575936A CN 103550157 A CN103550157 A CN 103550157A
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- Prior art keywords
- liposome
- epidoxorubicin
- epi
- doxorubicine
- lipidosome
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- 231100000228 neurotoxicity Toxicity 0.000 description 1
- VVGIYYKRAMHVLU-UHFFFAOYSA-N newbouldiamide Natural products CCCCCCCCCCCCCCCCCCCC(O)C(O)C(O)C(CO)NC(=O)CCCCCCCCCCCCCCCCC VVGIYYKRAMHVLU-UHFFFAOYSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000008105 phosphatidylcholines Chemical class 0.000 description 1
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- 210000002706 plastid Anatomy 0.000 description 1
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- 238000005057 refrigeration Methods 0.000 description 1
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- 150000003839 salts Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- SRLOHQKOADWDBV-NRONOFSHSA-M sodium;[(2r)-2,3-di(octadecanoyloxy)propyl] 2-(2-methoxyethoxycarbonylamino)ethyl phosphate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCCNC(=O)OCCOC)OC(=O)CCCCCCCCCCCCCCCCC SRLOHQKOADWDBV-NRONOFSHSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
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- 230000001225 therapeutic effect Effects 0.000 description 1
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- 201000005112 urinary bladder cancer Diseases 0.000 description 1
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicines, and relates to a preparation method of epidoxorubicin lipidosome and application of the epidoxorubicin lipidosome in resisting tumors. The epidoxorubicin lipidosome is prepared from epidoxorubicin, at least one phospholipid, as well as at least one surfactant, cryoprotectant or cholesterol. Pharmacodynamic tests prove that the epidoxorubicin lipidosome has a remarkable anti-tumor effect, and can be used for treating diseases including but not limited to liver cancer, lung cancer and gastric cancer.
Description
Technical field
Present technique relates to a kind of preparation and anticancer usage thereof of epi-doxorubicine liposome, belongs to medical technical field.
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 direct intercalation of DNA base pair, disturb transcription, stop the formation of mRNA, thereby suppress the synthetic of DNA and RNA, therefore all there is effect in each stage of cell cycle, for cell cycle nonspecific agent (CCNSA), Main Function is in 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, during due to the intravenous injection of this medicine, can there is serious cellulitis, therefore unsuitable directly intravenous injection, also will avoid in little blood vessel duplicate injection in injection or same vein simultaneously.This has brought larger inconvenience to clinical practice, to patient, has brought very large misery.At present, epirubicin and salt thereof have many launch both at home and abroad, as: " Pharmorubicin RD " that Pharmacia & Upjohn (China) company limited produces, " Ida is raw " that Zhejiang Haizheng Pharmaceutical Co is produced etc., dosage form is generally freeze-dried powder, because drug molecule is not wrapped, directly contact with vascular tissue with skin, very easily cause 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 current pharmaceutics.Liposome is the focus of pharmaceutics research as a member of this system always, it can by drug selectivity be transported to target spot position, performance therapeutical effect, does not affect again the function of normal cell, tissue or organ simultaneously, thereby reaches the object 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.Meanwhile, preparation method of the present invention is applicable to Industry Promotion.
The storage stability of liposome is difficult to solve always, and existing freeze-drying method is having limitation aspect economy and industrial efficiency.Not only highly energy-consuming of freezing dry process, long consuming time, its dry run can impact the biology of liposome membrane, chemistry and physical property, 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.
There is patent (publication number: CN 1554354A) epi-doxorubicine liposome and preparation method thereof.With organic solvent injection method, prepared epi-doxorubicine liposome, but envelop rate is lower, can not solves local irritation problem.
There is patent (publication number: CN 101264056A) epirubicin hydrochloride liposome and preparation method thereof.Trial production problem and stability problem during liposome prepared by the method does not solve.
Above two patents giving full play to the drug effect of epirubicin, reduce aspect toxicity and industrialization and also have certain deficiency.
Summary of the invention
The present invention relates to preparation method and the anticancer usage of epi-doxorubicine liposome.Feature of the present invention is that epirubicin is prepared into liposome, and the pharmacodynamic study of being simultaneously correlated with finds that epi-doxorubicine liposome of the present invention is particularly suitable for preparation treatment including but not limited to the purposes of hepatocarcinoma, pulmonary carcinoma, gastric cancer medicine.
Epi-doxorubicine liposome in the present invention is by epirubicin and at least one phospholipid, can contains at least one surfactant or a kind of cryoprotective agent or cholesterol and form simultaneously.Storage method comprises that normal temperature storage, stored under refrigeration, stored frozen and lyophilization store.
Epi-doxorubicine 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%
Epi-doxorubicine 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 one phospholipid is selected from phosphatidylcholine class, phosphatidyl glycerol class, phosphatidyl-4 alcohols, cytoskeletal protein, sphingomyelin class, strand or double-stranded phospholipid (two Semen Myristicae acid phosphatidyl glycerols, two lauric acid phosphatidyl glycerols, two palmitic acid phosphatidyl glycerols, DSPG, two Semen Myristicae acid phosphatidic acid, two lauric acid phosphatidic acid, two palmitic acid phosphatidic acid, distearyl acid phosphatidic acid, two oleic acid Phosphatidylserine, dilinoleic acid phosphatidylinositols, DPPC (DPPC), two lauric acid phosphatidylcholines (DLPC), two myristic acid phosphatidylcholines (DMPC), distearoyl phosphatidylcholine (DSPC), single Semen Myristicae acid phosphatidyl glycerol, mono laurate phosphatidyl glycerol, single palmitic acid phosphatidyl glycerol, monostearate phosphatidyl glycerol, single Semen Myristicae acid phosphatidic acid, mono laurate phosphatidic acid, single palmitic acid phosphatidic acid, 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), MSPC (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--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 epi-doxorubicine liposome is to adopt one-step method to prepare blank nanometer liposome, with pH gradient method or ammonium sulphate gradient, carries out medicine loading, comprises the following steps:
Phospholipid, surfactant, the cholesterol of not getting recipe quantity are scattered in the buffer of pH2.0-5.0, the even attenuating particle diameter of Multiple through then out nanometer machine high pressure breast, the alkaline solution that adds pH9.0-12.0, regulate pH to 6.0-7.5, by blank liposome solution mix with the cryoprotection agent solution of epirubicin, at 30-70 ℃, hatch 10-60 minute, obtain; Or phospholipid, surfactant, the cholesterol of getting respectively recipe quantity are scattered in the ammonium sulfate of 100-300mM; the even attenuating particle diameter of Multiple through then out nanometer machine high pressure breast; obtain blank liposome; it is cryoprotection agent solution that blank liposome is replaced to concentrated outer water by ultrafilter; by blank liposome solution mix with the cryoprotection agent solution of epirubicin; at 30-70 ℃, hatch 10-60 minute, obtain.
Advantage of the present invention is: liposome can be avoided some toxic and side effects of normal injection, and tumor is had to certain targeting, can bring into play better drug effect, reduces toxicity; The present invention adopts one-step method to prepare liposome can industrialization, is applicable to suitability for industrialized production; The method of the liposome that keeps in cold storage adopting, the character of maintenance liposome that can be efficient, stable is unaffected.Pharmacodynamics test proves simultaneously, and epi-doxorubicine liposome of the present invention has significant antitumor action, can be used for treatment including but not limited to hepatocarcinoma, pulmonary carcinoma, gastric cancer.
the specific embodiment:
The specific embodiment of the present invention, illustrated, but protection scope of the present invention is not limited to this by following embodiment.
embodiment 1
By 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 the citric acid solution of 300mM pH4 of 70 ℃.After 1000bar high pressure breast is even, obtain 100mg/ml phospholipid concentration, the blank liposome that mean diameter is 50-300nm.The 0.4mM sodium carbonate liquor of the trehalose of 2.0ml epirubicin (5.0mg/ml) (1g/ml) aqueous solution and 1.5ml is added in the blank liposome of 2.0ml, at 60 ℃, hatch 30min.Then by 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.Result shows, adds the blank of cryoprotective agent and drug-loaded liposome after freeze/thaw, and particle diameter does not have significant change; And not adding the liposome of cryoprotective agent after freeze/thaw, particle diameter obviously increases.
The impact of table 1 freeze/thaw process on liposome particle size
embodiment 2
Press embodiment 1 method preparation table Evacet, sample is stored to 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 when pH value of percentage, the results are shown in Table 2.Result shows there is no significant change 6 months each character of lactone plastid, proves storage method reasonable.
The impact of table 2 freeze/thaw process on 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 |
embodiment 3
The inhibitory action of 1.1 pairs of animal transplanting tumors
Adopt 7402 people's Liver Cancer Bearing Nude Mices, MFC TCM23 people gastric cancer in nude mice and A549 people's pulmonary carcinoma nude mice model, the effect of investigation table Evacet anti-tumor in vivo.To inoculate respectively 7402 hepatocarcinoma, the nude mice of MFC TCM23 gastric cancer and A549 pulmonary carcinoma, aseptic taking-up tumor mass from people's cancer kind Corium Mus, with the clean blood of normal saline flushing, select well-grown tumor tissues to be cut into small pieces, about grain of rice size, small tissue blocks is inoculated in to nude mice right side axillary fossa subcutaneous, after inoculation, after Growth of Tumors Transplanted is to a certain size, (more than 100mm3) starts the administration of dividing into groups, by the grouping of tumor volume, be divided at random positive controls (epirubicin hydrochloride 10mg/kg), solvent control group (blank), epi-doxorubicine liposome of the present invention is high, in, low three dosage groups (10, 5, 2.5mg/kg), random packet posterior vein administration 1 time, after 14 days, put to death animal, separated oxter tumor is also weighed, calculate tumor control rate.Be calculated as follows tumour inhibiting rate: tumour inhibiting rate (%)=[(the average tumor weight of the average tumor weight-administration of blank group group) the average tumor weight of/blank group] * 100%.Experimental result is as follows:
Experimental result is as follows:
(1) impact on 7402 hepatocarcinoma: experimental result show Evacet (10,5,2.5mg/kg) can significantly suppress the tumor weight of nude mice, three dosage suppression ratio are respectively 99.93,90.18 and 83.09%.The results are shown in Table 1.
the impact of table 1 epi-doxorubicine liposome on 7402 Liver Cancer Bearing Nude Mices
* P<0.05, * * P<0.01 compares (lower with) with model control group
(2) impact on MFC TCM23 gastric cancer in nude mice: experimental result show Evacet (10,5,2.5mg/kg) can significantly suppress the tumor weight of nude mice, three dosage suppression ratio are respectively 100,98.47 and 81.31%.The results are shown in Table 2.
the impact of table 2 epi-doxorubicine liposome on MFC TCM23 gastric cancer in nude mice
(3) impact on A549 pulmonary carcinoma: experimental result show Evacet (10,5,2.5mg/kg) can significantly suppress the tumor weight of nude mice, three dosage suppression ratio are respectively 99.35,97.77 and 85.96%.The results are shown in Table 3.
table 3 epi-doxorubicine liposome is on the impact on mice A549 pulmonary carcinoma
Claims (3)
1. an epi-doxorubicine liposome, its feature by epi-doxorubicine liposome by epirubicin and at least one phospholipid, can contain at least one surfactant or a kind of cryoprotective agent or cholesterol form simultaneously.
2. epi-doxorubicine liposome claimed in claim 1, it is characterized in that, preparation method is as follows: by 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 the citrate buffer solution of 300mM pH=4 of 70 ℃; After 1000bar high pressure breast is even, 100mg/ml phospholipid concentration, the blank liposome that mean diameter is 50-300nm; The 0.4mM sodium carbonate liquor of the aqueous trehalose solution of 2.0mL epirubicin and 1.5mL is added in the blank liposome of 2.0mL, at 60 ℃, hatch 30min, in-20 ℃ of storages; Wherein, the concentration of epirubicin is 5.0mg/mL, and the concentration of trehalose is 1g/mL.
Described in claim 1 epi-doxorubicine liposome for the preparation for the treatment of including but not limited to hepatocarcinoma, pulmonary carcinoma, gastric cancer, purposes.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104958259A (en) * | 2015-07-10 | 2015-10-07 | 北京博恩特药业有限公司 | Epirubicin liposome injection and antineoplastic activity application |
| CN111588697A (en) * | 2020-05-26 | 2020-08-28 | 江西本草天工科技有限责任公司 | Preparation of long-circulating epirubicin liposome and industrialized production method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1554354A (en) * | 2003-12-23 | 2004-12-15 | 中国药科大学 | Epirubicin liposome and preparation method thereof |
| CN102552146A (en) * | 2012-02-13 | 2012-07-11 | 江西本草天工科技有限责任公司 | Epirubicin liposome as well as preparation method and preserving method thereof |
-
2013
- 2013-11-18 CN CN201310575936.2A patent/CN103550157A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1554354A (en) * | 2003-12-23 | 2004-12-15 | 中国药科大学 | Epirubicin liposome and preparation method thereof |
| CN102552146A (en) * | 2012-02-13 | 2012-07-11 | 江西本草天工科技有限责任公司 | Epirubicin liposome as well as preparation method and preserving method thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104958259A (en) * | 2015-07-10 | 2015-10-07 | 北京博恩特药业有限公司 | Epirubicin liposome injection and antineoplastic activity application |
| CN111588697A (en) * | 2020-05-26 | 2020-08-28 | 江西本草天工科技有限责任公司 | Preparation of long-circulating epirubicin liposome and industrialized production method thereof |
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