CN106474057A - A kind of sucrose solution preparation of oxaliplatin thermosensitive long circulation liposome and preparation method thereof - Google Patents
A kind of sucrose solution preparation of oxaliplatin thermosensitive long circulation liposome and preparation method thereof Download PDFInfo
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- CN106474057A CN106474057A CN201611119508.9A CN201611119508A CN106474057A CN 106474057 A CN106474057 A CN 106474057A CN 201611119508 A CN201611119508 A CN 201611119508A CN 106474057 A CN106474057 A CN 106474057A
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- oxaliplatin
- liposome
- preparation
- sucrose solution
- thermal sensitive
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
Abstract
The present invention is a kind of sucrose solution preparation of oxaliplatin long circulating thermal sensitive liposome.Long circulating thermal sensitive liposome sucrose solution preparation is made up of oxaliplatin, DPPC, DSPE PEG2000, is prepared by blank liposome rear bearing medicine method, and is scattered in aqueous sucrose solution.By the addition of temperature-sensitive lipid DPPC so that said preparation has temperature sensitivity to the release of oxaliplatin.Said preparation has notable targeting to tumor.
Description
Technical field
The invention belongs to pharmaceutical technology field, it is related to a kind of drug-loaded liposome pharmaceutical solutionses and preparation method thereof, especially relates to
And a kind of thermosensitive long circulation liposome being loaded with oxaliplatin, preparation method and its sucrose solution preparation.
Background technology
Oxaliplatin is to the many animals such as colorectal cancer, ovarian cancer, nonsmall-cell lung cancer and breast carcinoma or human body cell
Strain, especially to having significant inhibitory action cisplatin and carboplatin drug-resistant tumor strain, can be used for the first-line treatment of advanced ovarian cancer more
Control again.Oxaliplatin substantially mitigates compared with cisplatin, carboplatin to gastrointestinal tract, liver, kidney and bone marrow toxicity, but still suffers from easily dividing
The shortcomings of solution and neurotoxicity.
Thermal sensitive liposome (thermosensitive liposomes) is one kind of liposome, and it is also known as temperature sensitivity fat
Plastid, nontoxic, preferably, DPPC is a kind of thermally sensitive lipid to biocompatibility, when liposome is heated to its phase alternating temperature
When more than spending, liposome membrane is converted to liquid crystal structure by " glue crystalline state ", and permeability increases, and so that medicine is discharged in a large number.Thus in spy
Fixed tumor targets discharge entrained medicine, and realize target administration.
Thermal sensitive liposome is easily removed by RES system in blood, and therefore in liposome, embedded DSPE-PEG2000 makes
Obtain PEG and form steric hindrance in surface of liposome, and the polar group of PEG increased the hydrophilic of surface of liposome, reduces RES
The identification to liposome for the system, extends liposome circulation time in blood, reaches the anticancer effect of passive target.Due to Austria
Husky profit platinum belongs to water soluble drug, and immobilized artificial membrane affinity little so that can discharge rapidly when liposome undergoes phase transition, be suitable for
Entrapped drug as thermal sensitive liposome.
It is contemplated that DPPC is combined with DSPE-PEG, prepare long circulating thermal sensitive liposome sucrose preparation, to tumor
Targeted therapy significant.
Content of the invention
An object of the present invention is to provide a kind of long circulating lipid carrier of the heat sensitivity of oxaliplatin pharmaceutical.This
Invention is used the DPPC with temperature-sensitive property as main body, is modified in lipid with the high DSPE-PEG2000 of biocompatibility simultaneously
The outside of body, oxaliplatin contains the hydrophilic intracavity in liposome.
The second object of the present invention is to provide a kind of preparation of the sucrose preparation of oxaliplatin thermosensitive long circulation liposome
Method.
The third object of the present invention is to provide a kind of sucrose preparation of oxaliplatin thermosensitive long circulation liposome in preparation
Purposes in antitumor drug.
The present invention provides following technical scheme：
A kind of oxaliplatin long circulating thermal sensitive liposome sucrose preparation it is characterised in that described preparation by oxaliplatin,
The liposome that DPPC, DSPE-PEG2000 are prepared into, and be scattered in sucrose solution, the wherein weight of oxaliplatin and DPPC
For 1: 3～30, for 1: 0.07～0.20, the concentration of sucrose solution is 4%-10% to the weight of DPPC, DSPE-mPEG ratio to ratio, fat
The particle diameter of plastid is 100-250nm, and current potential is -11～-30mV, and the particle diameter of more excellent liposome is 120-160nm；Described liposome
Current potential be -20～-30mV.
A kind of preparation method of oxaliplatin long circulating thermal sensitive liposome sucrose preparation is it is characterised in that weighed by recipe quantity
DPPC, DSPE-PEG2000, add organic solvent dissolving after uniformly mixing, put removal organic solvent film forming on Rotary Evaporators,
After adding aqueous sucrose solution aquation, liposome is prepared using Probe Ultrasonic Searching or high-speed shearing machine, in the liposome preparing
Middle addition oxaliplatin powder, heating lower dissolving stirring incubation, the oxaliplatin liposome preparing after letting cool, dialysis removes
Free oxaliplatin, and degerming through 0.22 μm of filtering with microporous membrane, and wherein incubation temperature is 50-60 DEG C, and described mixing speed is
80-250rpm, insulation incubation time is 2-4 hour；Wherein optimum heating-up temperature is 55 DEG C, and optimum mixing speed is 110rpm,
Optimum insulation incubation time is 3 hours.Finally by dialysis, polydextran gel column chromatography or ultrafiltration centrifuging by free Austria
Husky profit platinum removes.
Concentration after described oxaliplatin powder adds is 4mg/mL～12mg/mL, and is present in 4%～10% sucrose
In solution.
The feature of the present invention
It is an advantage of the current invention that being incubated from suitable blank liposome and carrying medicine method, water miscible oxaliplatin is stablized
Contain in liposome, and said preparation can when temperature is more than 42 DEG C quick and complete release medicine, and present in vivo
Go out to tumor preferably targeting.
The particle diameter of the oxaliplatin long circulating thermal sensitive liposome that the present invention prepares is 120-160nm, compares reverse steaming
The liposomal particle size of the method for sending out preparation is less, and Zeta potential is -11mV～-30mV, is not susceptible to assemble or precipitates, system in placement
There is good stability, and there is obvious passive targeting in vivo.Can keep in blood for a long time is effective
Anticancer concentration, prevents oxaliplatin removing in blood and degraded, reduces release in the normal tissue, thus effectively entering
Enter cancerous cell, effectively discharge medicine so that tumor locus drug level increases when tumor locus temperature raises, thus playing anti-
Cancer acts on.
Brief description
Fig. 1 is the grain size distribution of oxaliplatin long circulating thermal sensitive liposome in the present invention.
The release in vitro at a temperature of 37 DEG C and 42 DEG C is bent for the oxaliplatin long circulating thermal sensitive liposome in the present invention for Fig. 2
Line.
Fig. 3 is the oxaliplatin long circulating thermal sensitive liposome of variable concentrations and commercially available oxaliplatin injection in RKO cell
In suppression ratio.
Fig. 4 is the histofluorescence distribution of oxaliplatin long circulating thermal sensitive liposome different time points in tumor bearing nude mice body
Figure.
Specific embodiment
Embodiment 1：
(formula one)
DPPC 150mg
DSPE-PEG2000 26.9mg
Oxaliplatin 50mg
Weigh DPPC, DSPE-PEG2000 by recipe quantity, add organic solvent dissolving after uniformly mixing, put Rotary Evaporators
Upper removal organic solvent film forming, after adding 5% aqueous sucrose solution aquation, using Probe Ultrasonic Searching 300W, ultrasonic 2 minutes, prepares
Go out blank liposome, in the liposome preparing, add recipe quantity oxaliplatin powder, dissolving stirring incubation 2 at 55 DEG C
Hour, the oxaliplatin liposome preparing after letting cool, dialysis removes free oxaliplatin, and through 0.22 μm of microporous filter membrane mistake
Filter bacterium, be sub-packed in cillin bottle.
Embodiment 2：
(formula two)
DPPC 200mg
DSPE-PEG2000 13.92mg
Oxaliplatin 30mg
Weigh DPPC, DSPE-PEG2000 by recipe quantity, add organic solvent dissolving after uniformly mixing, put Rotary Evaporators
Upper removal organic solvent film forming, after adding 9% aqueous sucrose solution aquation, using Probe Ultrasonic Searching 300W, ultrasonic 5 minutes, prepares
Go out blank liposome, in the liposome preparing, add recipe quantity oxaliplatin powder, dissolving stirring incubation 3 at 50 DEG C
Hour, the oxaliplatin liposome preparing after letting cool, dialysis removes free oxaliplatin, and through 0.22 μm of microporous filter membrane mistake
Filter bacterium, be sub-packed in cillin bottle.
Embodiment 3：
(formula three)
DPPC 240mg
DSPE-PEG2000 18mg
Oxaliplatin 8mg
Weigh DPPC, DSPE-PEG2000 by recipe quantity, add organic solvent dissolving after uniformly mixing, put Rotary Evaporators
Upper removal organic solvent film forming, after adding 9% aqueous sucrose solution aquation, using Probe Ultrasonic Searching 300W, ultrasonic 5 minutes, prepares
Go out blank liposome, in the liposome preparing, add recipe quantity oxaliplatin powder, dissolving stirring incubation 4 at 60 DEG C
Hour, the oxaliplatin liposome preparing after letting cool, dialysis removes free oxaliplatin, and through 0.22 μm of microporous filter membrane mistake
Filter bacterium, be sub-packed in cillin bottle.
Embodiment 4：
The particle diameter distribution of oxaliplatin liposome and potential measurement：Oxaliplatin fat is measured by Malvern laser particle analyzer
The particle diameter of plastid and Zeta potential.Mean diameter 150nm, Zeta potential -15mV, grain size distribution is shown in Fig. 1.
Embodiment 5：
The release in vitro evaluation of oxaliplatin long circulating thermal sensitive liposome：Take the Thermo-sensitive liposome 0.5mL of oxaliplatin
In bag filter (molecular cut off=7000Da), two ends cotton thread tightens, and is placed in 25mL color comparison tube, respectively adds release medium
(pH6.8) 15mL, is respectively placed in 37 DEG C and 42 DEG C of thermostatic control oscillator vibrations, and rotating speed is 100r/min, respectively at 0.5h, 1h,
2h, 4h, 6h, 8h, 12h, 24h, take release medium 1mL in centrifuge tube, cross 0.22 μm of moisture film, abandon just filtrate, take subsequent filtrate in
Sample introduction bottle, in high performance liquid chromatograph sample introduction, calculates release amount of medicine, result is shown in Fig. 2.
Embodiment 6：
The Cytotoxic evaluation of oxaliplatin long circulating thermal sensitive liposome：RKO colon cancer cell is inoculated with 5000/hole
In 96 orifice plates, after incubation 24h, after long circulating thermal sensitive liposome is incubated 1 hour in 42 DEG C of water-baths, it is diluted to different dense
Degree adds in 96 orifice plates, simultaneously with the commercially available injection of oxaliplatin as matched group.Take 20 μ L Methyl thiazoly tetrazolium assay (MTT, 5mg/
ML) add each in the hole, continue incubation 4h, discard in the hole liquid, add DMSO 200 μ L, shaking, so that crystallization is fully dissolved,
Measure the light absorption value (ODsample) of each sample under 490nm wavelength with microplate reader, measure blank group OD value simultaneously
(ODcontrol), and calculate suppression ratio, result is shown in Fig. 3.
Embodiment 7：
The internal Evaluation on Its Targeting Performance of oxaliplatin long circulating thermal sensitive liposome：Preparation contains the long circulating temperature-sensitive lipid of Dir
Body, lotus RKO colon cancer nude mice (body weight 18～25g/ is only) is randomly assigned, every group 3, tail vein injection is administered, every mice
Dir dosed administration according to 1.5mg/kg.5% chloral hydrate anesthesia is used, respectively at 1h, 2h, 4h, 6h, 8h carry out glimmering after administration
Photoimaging shoots.Result is shown in Fig. 4.
Claims (9)
1. a kind of oxaliplatin long circulating thermal sensitive liposome sucrose solution preparation is it is characterised in that described preparation is by Ao Shali
The liposome that platinum, DPPC, DSPE-PEG2000 are prepared into, and be scattered in aqueous sucrose solution.
2. oxaliplatin long circulating thermal sensitive liposome according to claim 1 sucrose solution preparation it is characterised in that：
1) weight of described oxaliplatin and DPPC is than for 1: 3～30；
2) weight of described DPPC and DSPE-mPEG is than for 1: 0.07～0.2；
3) concentration of described sucrose solution is 4%-10%；
4) particle diameter of described liposome is 100-250nm；
5) current potential of described liposome is -11～-30mV.
3. oxaliplatin long circulating thermal sensitive liposome according to claim 1 sucrose solution preparation it is characterised in that：Institute
The particle diameter stating liposome is 120-200nm.
4. the sucrose solution preparation of the oxaliplatin long circulating thermal sensitive liposome according to any one of claim 1-3, it is special
Levy and be：The particle diameter of described liposome is 120-160nm；The current potential of described liposome is -20～-30mV.
5. a kind of preparation method of oxaliplatin long circulating thermal sensitive liposome sucrose preparation it is characterised in that：Weigh by recipe quantity
DPPC, DSPE-PEG2000, add organic solvent dissolving after uniformly mixing, put removal organic solvent film forming on Rotary Evaporators,
After adding aqueous sucrose solution aquation, liposome is prepared using Probe Ultrasonic Searching or high-speed shearing machine, in the liposome preparing
Middle addition oxaliplatin powder, heating, stirring and dissolving, and it is incubated incubation, remove free oxaliplatin after letting cool, and through 0.22 μm
Filtering with microporous membrane is degerming, obtains oxaliplatin long circulating thermal sensitive liposome sucrose solution preparation.
6. the preparation method of oxaliplatin long circulating thermal sensitive liposome sucrose solution preparation according to claim 5, it is special
Levy and be：
1) weight of the oxaliplatin described in and DPPC is than for 1: 3～30；
2) weight of DPPC, DSPE-mPEG described in is than for 1: 0.07～0.2；
3) concentration of described sucrose solution is 4%-10%；
4) described organic solvent is chloroform；
5) concentration after described oxaliplatin powder adds is 4mg/mL～12mg/mL；
6) described heating-up temperature is 50-60 DEG C；
7) described mixing speed is 80-250rpm；
8) described insulation incubation time is 2-4 hour.
7. the preparation method of oxaliplatin long circulating thermal sensitive liposome sucrose solution preparation according to claim 6, it is special
Levy and be：Described heating-up temperature is 55 DEG C；Described mixing speed is 110rpm；Described insulation incubation time is 3 hours.
8. the preparation method of oxaliplatin long circulating thermal sensitive liposome sucrose solution preparation according to claim 5, described
The method removing free oxaliplatin is dialysis, polydextran gel column chromatography or ultrafiltration centrifuging.
9. the preparation method of oxaliplatin long circulating thermal sensitive liposome sucrose solution preparation according to claim 9, it is special
Levy and be：The molecular cut off of the bag filter used in described dialysis is 2000-7000Da.
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Cited By (2)
| 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 |
| CN111544393A (en) * | 2020-06-11 | 2020-08-18 | 安徽医科大学 | Preparation method of drug-loaded liposome |
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| CN105232460A (en) * | 2015-09-24 | 2016-01-13 | 南京泛太化工医药研究所 | Preparation and application of oxaliplatin lipidosome freeze-dried powder injection |
| CN105412025A (en) * | 2015-12-31 | 2016-03-23 | 中国药科大学 | Preparation method for oxaliplatin lipidosome freeze-dried powder injection |
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| CN1413577A (en) * | 2002-10-18 | 2003-04-30 | 沈阳药科大学 | Thermosensitive long circulation liposome preparation |
| US20160338958A1 (en) * | 2011-10-31 | 2016-11-24 | Mallinckrodt Llc | Combinational Liposome Compositions for Cancer Therapy |
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Cited By (2)
| 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 |
| CN111544393A (en) * | 2020-06-11 | 2020-08-18 | 安徽医科大学 | Preparation method of drug-loaded liposome |
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Application publication date: 20170308 |