CN103169659A - Oxaliplatin long-circulating liposome and application thereof - Google Patents
Oxaliplatin long-circulating liposome and application thereof Download PDFInfo
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- CN103169659A CN103169659A CN2012104855847A CN201210485584A CN103169659A CN 103169659 A CN103169659 A CN 103169659A CN 2012104855847 A CN2012104855847 A CN 2012104855847A CN 201210485584 A CN201210485584 A CN 201210485584A CN 103169659 A CN103169659 A CN 103169659A
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Abstract
The invention discloses an oxaliplatin long-circulating liposome and an application thereof. The oxaliplatin long-circulating liposome includes oxaliplatin, phospholipid, cholesterol acid, poloxamer F68 and polyethylene glycol monostearate, wherein the weight ratio of the phospholipid to the cholesterol is (3-8):1; the weight ratio of the oxaliplatin to the phospholipid is 1:(30-60); the weight ratio of the poloxamer F68 to the phospholipid is 1:(5-15); and the molar ratio of the polyethylene glycol monostearate to the phospholipid is (2-15):100. The oxaliplatin long-circulating liposome disclosed by the invention is small in grain size, high in encapsulation efficiency, long-circulating, cheap in materials, simpler in process and suitable for large-scale industrial production.
Description
(1) technical field
The present invention relates to the medicinal liposome field, relate in particular to a kind of oxaliplatin long circulating liposomes and application thereof.
(2) background technology
Oxaliplatin is third generation platinum-containing anticancer drug.FDA in 2004 approval Oxaliplatin for Injection and 5-fluorouracil and folinic acid are united the first-line treatment for progressive stage colon rectal cancer.The oxaliplatin formulations that has now gone on the market has aqueous injection and freeze-dried powder.Oxaliplatin centering advanced colorectal cancer is evident in efficacy, also can treat other digestive tract tumor such as gastric cancer.But along with oxaliplatin extensive application clinically, its untoward reaction is also constantly found and is reported.Neurotoxicity, gastrointestinal reaction, bone marrow depression are its common untoward reaction.
Liposome is a kind of drug-supplying system of good biocompatibility, as the delivery vehicles of antitumor drug, can improve the tumor-targeting of medicine, reduces drug toxicity, therefore receives people's concern.Oxaliplatin is made liposome be delivered in body, medicine better can be delivered to tumor locus, improve the antitumor action of medicine, reduce its toxic reaction.Oxaliplatin is water soluble drug, and after being prepared into liposome, envelop rate is not high and seepage easily occurs.Should keep the higher envelop rate of liposome, can not therefore reduce again the drug level in liposome, this is a Major Difficulties of preparation oxaliplatin long circulating liposomes.
The oxaliplatin long circulating liposomes is disclosed in Chinese patent 200310124776.6 and WO/2007/099377, but they otherwise the raw material that adopts is expensive, or technological requirement is very high, or envelop rate is lower, and is more difficult for industrialized great production.In Chinese patent 200710025130.0, Chen Xiang peak etc. adopts the Filter column separation and purification, improve envelop rate, but this method is more difficult for industrialized great production.The freeze-thaw cycle technique that adopts the thesis for the doctorate of Yang Meiyan " the long circulation thermal sensitive liposome research of oxaliplatin " improves the envelop rate of liposome, but result only is increased to 30% with envelop rate, and envelop rate is still lower.
Therefore, this area in the urgent need to provide a kind of inexpensive, technique is simple, the method for preparing the oxaliplatin long circulating liposomes of the large production of suitability for industrialized, and requires that the liposome particle diameter obtain is little, envelop rate is high, have long recursive nature.
(3) summary of the invention
The object of the invention is to provide a kind of oxaliplatin long circulating liposomes, to improve the envelop rate of oxaliplatin long circulating liposomes, reduces particle diameter, and technique is simple, is suitable for industrialized great production.
For achieving the above object, the present invention adopts following technical scheme:
A kind of oxaliplatin long circulating liposomes, its raw materials comprise oxaliplatin, phospholipid, the solid acid of gallbladder, poloxamer F68 and polyethylene glycol mono stearate.
Oxaliplatin long circulating liposomes of the present invention can be prepared by the conventional method of this area, and concrete recommendation of the present invention is prepared by anti-phase evaporation-high pressure homogenization method.
In raw material components of the present invention, described phospholipid is to choose any one kind of them in natural phosphatidyl choline, soybean phospholipid, synthetic phospholipid or several mixing.
In raw material components of the present invention, in described polyethylene glycol mono stearate, molecular weight polyethylene glycol is 2000～6000, is preferably 4000.
In each raw material components of the present invention, the mass ratio of phospholipid and cholesterol is 3～8:1, is preferably 6:1.The mass ratio of oxaliplatin and phospholipid is 1:30～60, is preferably 1:50.The mass ratio of poloxamer F68 and phospholipid is 1:5～15, is preferably 1:10.The mol ratio of polyethylene glycol mono stearate and phospholipid is 2～15:100, is preferably 5.
Concrete, the preparation of described oxaliplatin long circulating liposomes comprises the steps:
Get phospholipid, cholesterol is dissolved in organic solvent, then adds the aqueous solution of oxaliplatin, stir, ultrasonic, rotary evaporation is removed organic solvent, after gel subsides, add the aqueous solution that contains polyethylene glycol mono stearate, poloxamer F68, continue evaporation, high pressure homogenize, water standardize solution, carry out ultrafiltration with slipstream film bag, water repeats ultrafiltration as replacement fluid, adjusts suspension volume and namely gets the oxaliplatin long circulating liposomes.
Organic solvent can be chloroform, dichloromethane, ether, is preferably dichloromethane.The volume ratio of organic solvent and oxaliplatin aqueous solution is 2～4:1, is preferably 3:1.Described high pressure homogenize condition is: pressure 200～800 bar, times 2～8 min; Preferred high pressure homogenize condition is: pressure 400 bar, times 5 min.Ultrafilter membrane bag molecular weight is 3K～50K, is preferably 10K.
The preferred described oxaliplatin long circulating liposomes of the present invention prepares in accordance with the following steps:
Proportioning raw materials is: preferred proportion is that the mass ratio of lecithin and cholesterol is 6:1, and the mass ratio of oxaliplatin and phospholipid is 1:50, and the mass ratio of poloxamer F68 and phospholipid is 1:10.Get lecithin, cholesterol is dissolved in dichloromethane, then adds the aqueous solution of oxaliplatin, the volume ratio of dichloromethane and oxaliplatin aqueous solution is 3:1.Stir, ultrasonic, rotary evaporation is removed organic solvent, after gel subsides, add the aqueous solution that contains poloxamer F68, polyethylene glycol mono stearate, continue evaporation, high pressure homogenize 5 min under 400 bar conditions, water standardize solution, carry out ultrafiltration with slipstream film bag, water repeats ultrafiltration as replacement fluid, adjusts suspension volume and namely gets the oxaliplatin long circulating liposomes.
The oxaliplatin long circulating liposomes that the present invention makes can be applicable to prepare the application for the treatment of in digestive tract tumor's medicine, and for example the form with ejection preparation is used for the treatment of digestive tract tumor.
Compared with prior art, the oxaliplatin long circulating liposomes particle diameter that the present invention obtains is little, envelop rate is high, has long cyclicity, and raw material is inexpensive, and technique is simpler, the large production of suitability for industrialized.
(4) description of drawings
Fig. 1 is the particle size distribution figure of embodiment 1 gained oxaliplatin long circulating liposomes.
(5) specific embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used for explanation the present invention and be not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example is usually according to normal condition or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise all percent, ratio, ratio or umber by weight.Unless otherwise defined, the same meaning that all specialties and scientific words and the one skilled in the art who uses in literary composition is familiar with.
get lecithin 4 g, cholesterol 667 mg are dissolved in dichloromethane 60 mL, add 20 mL to contain the aqueous solution of 80 mg oxaliplatins, stir 30 min, ultrasonic 20 min, 40 ℃ of rotary evaporations are removed organic solvent, after gel subsides, add by component and contain Polyethylene Glycol (4000) monostearate 1.14 g, aqueous solution 50 mL of F68 400mg, continue evaporation 30 min, high pressure homogenize 400 bar, 5min, water is settled to 100 mL, then adopt cross-flow ultrafiltration method separated free oxaliplatin, the slipstream film bag that is 10K with the molecular retention amount carries out ultrafiltration, water is as replacement fluid, repeat ultrafiltration 3 times, survey its envelop rate and the last drug level of high effective liquid chromatography for measuring with the ultra-filtration centrifuge tube method, envelop rate is 95.12%, particle diameter is (124 ± 42) nm.Add water and adjust liposome turbid liquor Chinese medicine concentration to 500 μ gmL
-1And get final product.Its particle size distribution figure sees accompanying drawing 1.
Claims (10)
1. an oxaliplatin long circulating liposomes, is characterized in that the raw materials of described oxaliplatin long circulating liposomes comprises oxaliplatin, phospholipid, the solid acid of gallbladder, poloxamer F68 and polyethylene glycol mono stearate.
2. oxaliplatin long circulating liposomes as claimed in claim 1, it is characterized in that: the mass ratio of phospholipid and cholesterol is 3～8:1, the mass ratio of oxaliplatin and phospholipid is 1:30～60, the mass ratio of poloxamer F68 and phospholipid is 1:5～15, and the mol ratio of polyethylene glycol mono stearate and phospholipid is 2～15:100.
3. oxaliplatin long circulating liposomes as claimed in claim 2, is characterized in that the preparation of described oxaliplatin long circulating liposomes comprises the steps:
Get phospholipid, cholesterol is dissolved in organic solvent, then adds the aqueous solution of oxaliplatin, stir, ultrasonic, rotary evaporation is removed organic solvent, after gel subsides, add the aqueous solution that contains poloxamer F68, polyethylene glycol mono stearate, continue evaporation, high pressure homogenize, water standardize solution, carry out ultrafiltration with slipstream film bag, water repeats ultrafiltration as replacement fluid, adjusts suspension volume and get final product.
4. oxaliplatin long circulating liposomes as described in one of claim 1～3, it is characterized in that: described phospholipid is to choose any one kind of them in natural phosphatidyl choline, soybean phospholipid, synthetic phospholipid or several mixing.
5. oxaliplatin long circulating liposomes as described in one of claim 1～3, it is characterized in that: in described polyethylene glycol mono stearate, molecular weight polyethylene glycol is 2000～6000.
6. oxaliplatin long circulating liposomes as described in one of claim 1～3, it is characterized in that: described organic solvent is chloroform, dichloromethane or ether.
7. oxaliplatin long circulating liposomes as claimed in claim 3, it is characterized in that: the volume ratio of organic solvent and oxaliplatin aqueous solution is 2～4:1.
8. oxaliplatin long circulating liposomes as claimed in claim 3, is characterized in that described high pressure homogenize condition is: pressure 200～800 bar, times 2～8 min.
9. oxaliplatin long circulating liposomes as claimed in claim 1, the mass ratio that it is characterized in that phospholipid and cholesterol is 6:1, the mass ratio of oxaliplatin and phospholipid is 1:50, the mass ratio of poloxamer F68 and phospholipid is 1:10, the mol ratio of polyethylene glycol mono stearate and phospholipid is 5:100, and described oxaliplatin long circulating liposomes prepares in accordance with the following steps:
Get lecithin, cholesterol is dissolved in dichloromethane, then the aqueous solution that adds oxaliplatin, the volume ratio of dichloromethane and oxaliplatin aqueous solution is 3:1, stir, ultrasonic, rotary evaporation is removed organic solvent, after gel subsides, add the aqueous solution that contains poloxamer F68, polyethylene glycol mono stearate, continue evaporation, high pressure homogenize 5min under the 400bar condition, the water standardize solution carries out ultrafiltration with slipstream film bag, and water is as replacement fluid, repeat ultrafiltration 3 times, adjust suspension volume and namely get the oxaliplatin long circulating liposomes.
10. oxaliplatin long circulating liposomes as claimed in claim 1 is in the application for preparing in treating digestive tract tumor's medicine.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110200918A (en) * | 2019-06-12 | 2019-09-06 | 东南大学 | Prussian blue-oxaliplatin liposome of one kind and preparation method thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040022842A1 (en) * | 2002-06-03 | 2004-02-05 | Mebiopharm Co., Ltd. | Liposome preparations containing oxaliplatin |
| CN1628638A (en) * | 2003-12-17 | 2005-06-22 | 梅比欧法姆股份有限公司 | Liposome preparation containing Oxaliplatin |
| CN1775216A (en) * | 2004-11-15 | 2006-05-24 | 胡才忠 | New formulation oxaliplatin liposome |
| CN101897668A (en) * | 2009-05-27 | 2010-12-01 | 上海医药工业研究院 | Oxaliplatin liposome, preparation method and application thereof |
| CN102065840A (en) * | 2008-05-23 | 2011-05-18 | 微脂体医药有限责任公司 | Liposomes for drug delivery and methods for preparation thereof |
-
2012
- 2012-11-23 CN CN2012104855847A patent/CN103169659A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040022842A1 (en) * | 2002-06-03 | 2004-02-05 | Mebiopharm Co., Ltd. | Liposome preparations containing oxaliplatin |
| CN1628638A (en) * | 2003-12-17 | 2005-06-22 | 梅比欧法姆股份有限公司 | Liposome preparation containing Oxaliplatin |
| CN1775216A (en) * | 2004-11-15 | 2006-05-24 | 胡才忠 | New formulation oxaliplatin liposome |
| CN102065840A (en) * | 2008-05-23 | 2011-05-18 | 微脂体医药有限责任公司 | Liposomes for drug delivery and methods for preparation thereof |
| CN101897668A (en) * | 2009-05-27 | 2010-12-01 | 上海医药工业研究院 | Oxaliplatin liposome, preparation method and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| HOWARD ET AL: "PEGylation of Nanocarrier Drug Delivery Systems: State of the Art", 《JOURNAL OF BIOMEDICAL NANOTECHNOLOGY》 * |
| XIULING LU ET AL: "Nanoparticles Containing Anti-inflammatory Agents as Chemotherapy Adjuvants: Optimization and In Vitro Characterization", 《THE AAPS JOURNAL》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110200918A (en) * | 2019-06-12 | 2019-09-06 | 东南大学 | Prussian blue-oxaliplatin liposome of one kind and preparation method thereof |
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Application publication date: 20130626 |