CN107137353A - A kind of injection Cabazitaxel Lipidosome and preparation method thereof - Google Patents
A kind of injection Cabazitaxel Lipidosome and preparation method thereof Download PDFInfo
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Abstract
The invention provides a kind of Cabazitaxel Lipidosome and preparation method thereof, the Cabazitaxel Lipidosome includes Cabazitaxel, phosphatide, cholesterol, lyophilized proppant, aqueous medium, stabilizer, can by Probe Ultrasonic Searching, scattered, high speed dispersor is scattered, high pressure homogenizer is scattered etc. that method is prepared from.The liposome not only reduces the allergy risk of solvent initiation, and the targeting of enhancing medicine in vivo improves vivo biodistribution availability, improves clinical compliance and the stability of medicine, and further increase Cabazitaxel liposome final product quality controllability and stability.
Description
Technical field
The present invention relates to a kind of Cabazitaxel liquid preparation and preparation method thereof, and in particular to a kind of Cabazitaxel liposome
Injection and preparation method thereof.
Background technology
Cabazitaxel (Cabazitaxol) belongs to taxane anti-tumor medicament, is the change extracted in the needle of Japanese yew
The semi-synthetic paclitaxel derivatives of compound, are developed and are listed by Sanofi-Aventis companies.Its mechanism of action and other Japanese yews
Alkanes medicine is similar, by promoting micro-pipe dimer to be assembled into micro-pipe, while preventing polymerisation process and making microtubule stabilization, hinders
Stagnant cell suppresses cell and further divided, so as to suppress mitosis and the propagation of cancer cell in G2 the and M phases.Cabazitaxel with
The affinity for the multi-efflux pumps P- glycoprotein (P-gp) that Mdr-p ATP is relied on is poor, therefore can overcome due to P-
Gp expression and the resistance of tumour cell caused.
In June, 2010, U.S. FDA approval Cabazitaxel is combined with metacortandracin for treating through swashing that docetaxel was treated
The intractable metastatic prostate cancer of element.Cabazitaxel antitumor spectra is wide, antitumor action is strong, to intractable breast cancer, non-small thin
The curative effect of born of the same parents' lung cancer, metastatic gastric carcinoma etc. is more prominent, and clinical practice potentiality are deep.
, there is following defect in the Cabazitaxel parenteral solution of Sanofi-Aventis companies exploitation：
(1) toxicity and sensitization of solvent：Cabazitaxel is water-soluble too poor, existing injection be using 100% tween-
80 make solvent.Research discovery, the fluid retention that the of short duration moderate hypersensitivity of Tween-80 induction and Tween-80 are likely to result in
It is relevant.Therefore, Loratadine and nonsteroidal anti-inflammatory drug must used to be pre-processed using preceding, even if after processing, suffering from
Person is it is possible to the different degrees of allergic reaction of appearance, need to be observed at any time.In addition, Tween-80 also has slight haemolysis
Property.
(2) stability is poor：The Cabazitaxel preparation of listing only has the Cabazitaxel note that match Norfin, Inc of France develops
Penetrate liquid (trade name Jevtan).Medicine is first dissolved in Tween-80 by the parenteral solution, before Clinical practice, dilute with 13% ethanol
Release to 10mg/ml, and before administration, further with 5% glucose or normal saline dilution to Clinical practice concentration, noted after dilution
Penetrating liquid need to use in 4 hours, otherwise will produce precipitation.In addition, Cabazitaxel Tween-80 solution below 15 DEG C of low temperature easily
Separate out.Need to carry out two step dilutions before this product Clinical practice, i.e., first diluted with 13% ethanol, then diluted with glucose, and need to filter,
Clinical practice complex steps, easily separate out, there is the potential safety hazard in terms of medication.
(3) clinical dosage accuracy is poor：Need to carry out two step dilutions before this product Clinical practice, and loading amount is smaller, exists
Different nurses dosage when making up a prescription is variant, exists and affects the treatment and security.
Patent CN201210394958.4 discloses a kind of Cabazitaxel lipidosome injection and preparation method thereof, the lipid
Body includes Cabazitaxel, phosphatide, cholesterol, mannitol or glucose, and the technical scheme solves original and grinds normal injection formula of liquid
In the allergy risk containing Tween-80, and improve the exposed amount of medicine in animal body.But liposome prepared by the composition
Final product quality controllability is poor, and stability is not good.
The present invention, there is provided a kind of injection Cabazitaxel liposome, solves original and grinds parenteral solution and deposit for drawbacks described above
The problem of：Reduce the allergy risk that solvent triggers；Strengthen the targeting of medicine in vivo, improve vivo biodistribution availability；Change
The stability of kind clinical compliance and medicine.Meanwhile, further increase Cabazitaxel liposome final product quality controllability and steady
It is qualitative.
The content of the invention
The invention provides a kind of preparation method of injection Cabazitaxel Lipidosome, including Cabazitaxel, phosphatide,
Cholesterol, lyophilized proppant, aqueous medium, stabilizer, six weight ratio for 1: 20~80: 0.2~4: 12~32: 200~
1000: 0.5~10；It is preferred that above-mentioned six weight ratio is 1: 30~60: 0.25~2.5: 16~28: 300~600: 1.0~6；
More preferably above-mentioned six weight ratio is 1: 40~50: 0.35~0.8: 18~24: 400~500: 1.5~3.0.
Described phosphatide can be selected from soybean lecithin, egg yolk lecithin, hydrogenated soya phosphatide, polyethylene glycol phosphatide, phosphatide
One or more in acyl glycerine etc..
Described lyophilized proppant can be selected from one in mannitol, glucose, sucrose, lactose, amino acid, trehalose etc.
Plant or several described aqueous mediums include the buffer solution of different pH value, can be buffered selected from phosphate buffer, citrate
Liquid, carbonate buffer solution, ammonium sulfate buffer salt, amphion organic chemistry buffer solution etc., pH value can be between 4.5~9.0.
Described stabilizer can be selected from EDTA-2Na, oleic acid, Crodaret, HYDROXYPROPYL BETA-CYCLODEXTRIN
Deng.
Cabazitaxel purity requirement of the present invention is between 95%~105%.
Injection Cabazitaxel liposome preparation technique vacuum available film concentration method of the present invention, rotary evaporation, high speed
Shearing method, high pressure homogenization method etc..
Organic solvent used can be selected from ethanol, dichloromethane, chloroform, methanol, ether, isopropyl in preparation process of the present invention
One or more in alcohol, acetone etc..
The invention provides a kind of method for preparing injection Cabazitaxel liposome：Phosphatide, the courage for weighing recipe quantity are solid
Alcohol, Cabazitaxel, are dissolved in after organic solvent and being evaporated, and make mixture film forming.Aqueous medium is added, the aquation at 30~70 DEG C takes
Go out after liposome cooling, stirred in ultrasonic disperse under the probe of cell crushing instrument or high speed dispersor, add lyophilized proppant,
Successively through 0.45 μm, 0.22 μm of membrane filtration, dispense, freeze-drying.
Injection Cabazitaxel liposomal particle size control range prepared by the present invention is 50nm~100nm；Envelop rate is more than
90%；Compatibility stability investigates 8h without Precipitation；Vitro release is less than 15% in 24h；Exposed amount increase in beasle dog body
About 0.85 times；Long-term place has good stability for 6 months.
The injection Cabazitaxel liposome of the present invention is cell toxicant series antineoplastic medicament, available for metastatic hormone refractory
The diseases such as property prostate cancer, the cancer of the brain, breast cancer, non-small cell lung cancer.
The injection Cabazitaxel liposome that the present invention is provided, adds aqueous medium and stabilizer, improves liposome
The surface tension of bilayer, reduces the mobility of liposome membrane, not only improves exposed amount in animal body, reduction solvent and causes
Allergy risk, improve clinical compliance, and improve the quality controllability and stability of liposome.Meanwhile, in liposome
Sustained drug release, extend circulation time in blood, improve the utilization rate of effective ingredient.Therefore, this product
Develop into injection Cabazitaxel novel liposome formulation significant.
Brief description of the drawings
Fig. 1 is Cabazitaxel liposomal particle size figure；
Fig. 2 is the Cabazitaxel liposomal particle size figure without aqueous medium and stabilizer；
Fig. 3 is Cabazitaxel liposome zeta potential diagrams；
Fig. 4 is the Cabazitaxel liposome zeta potential diagrams without aqueous medium and stabilizer；
Fig. 5 is Cabazitaxel canonical plotting；
Fig. 6 is that Cabazitaxel medicament contg detects collection of illustrative plates；
Fig. 7 is Cabazitaxel liposome In-vitro release curves comparison diagram；
Fig. 8 is Cabazitaxel Drug-time curve comparison diagram.
Embodiment
Embodiment 1
Prepare：The egg yolk lecithin 1000mg, cholesterol 10mg, Cabazitaxel 25mg of recipe quantity are weighed, absolute ethyl alcohol is used
500ml is in making dissolving under 55~60 DEG C of stirring in water bath, rear rotary evaporation, makes the ethanol of the phosphatide film forming on wall.55~60 DEG C
PBS solution (pH value 5.7) 100ml that synthermal aqueous medium 0.01mol/L is added after absolute ethyl alcohol, 60 DEG C of water-baths is removed under reduced pressure
Middle aquation (appropriate bead stirring can be added during aquation, untill aquation is uniform, notice that stirring can not be excessively violent during aquation), takes
Go out liposome to be put into beaker.Be cooled to after 40 DEG C, in ultrasonic disperse 5min under the probe of cell crushing instrument (450W × 5min,
Work 3s, interval 1s), add 5% lactose and freeze proppant, successively through 0.45 μm, 0.22 μm of membrane filtration, be sub-packed in cillin bottle
In, freeze-drying is produced.
Quality Control：Outward appearance is that white loose is block, and particle diameter is 79.16nm, and content is the 97.39% of labelled amount, and envelop rate is
94.31%.
Embodiment 2
Prepare：The soybean lecithin 1000mg, cholesterol 50mg, Cabazitaxel 28mg of recipe quantity are weighed, dichloromethane is used
550ml is in making dissolving under 30 DEG C of stirring in water bath, rear rotary evaporation, makes the dichloromethane solution of the phosphatide film forming on wall.30 DEG C subtract
Pressure removes citrate (pH value 6.6) the solution 100ml that synthermal aqueous medium 0.1mol/L is added after dichloromethane, 30 DEG C of water
Aquation (appropriate bead stirring can be added during aquation, untill aquation is uniform, notice that stirring can not be excessively violent during aquation) in bath,
Liposome is taken out to be put into beaker.It is cooled to after room temperature, 10000rpm disperses 5min in high speed dispersor, adds 4% grape
The lyophilized proppant of sugar, successively through 0.45 μm, 0.22 μm of membrane filtration, is sub-packed in cillin bottle, is freeze-dried, produces.
Quality Control：Outward appearance is that white loose is block, and particle diameter is 77.54nm, and content is the 99.01% of labelled amount, and envelop rate is
93.55%.
Embodiment 3
Prepare：Weigh egg yolk lecithin 800mg, DSPE-mPEG2000 200mg of recipe quantity, cholesterol 20mg, kappa
He matches 30mg, with absolute ethyl alcohol 400ml and dichloromethane 1OOml mixed solutions in making dissolving under 45~50 DEG C of stirring in water bath, after
Rotary evaporation, makes the mixed solution of the phosphatide film forming on wall.45~50 DEG C be removed under reduced pressure after mixed solvent add it is synthermal aqueous
Medium 0.02mol/L PBS solution (pH value 7.4, oleic acid containing 1.O%) 100ml, aquation (can be added during aquation in 50 DEG C of water-baths
Appropriate bead stirring, untill aquation is uniform, notices that stirring can not be excessively violent during aquation), take out liposome and be put into beaker.
It is cooled to after 40 DEG C, in ultrasonic disperse 5min under the probe of cell crushing instrument (450W × 5min, work 3s, interval 1s), adds
6% mannitol freezes proppant, successively through 0.45 μm, 0.22 μm of membrane filtration, is sub-packed in cillin bottle, freeze-drying, produces.
Quality Control：Outward appearance is that white loose is block, and particle diameter is 79.41nm, and content is the 98.63% of labelled amount, and envelop rate is
93.60%.
Embodiment 4
Prepare：Weigh soybean lecithin 700mg, DSPE-mPEG2000 300mg of recipe quantity, cholesterol 40mg, kappa
He matches 25mg, rear to rotate with methanol 350ml and dichloromethane 150ml mixed solutions in making dissolving under 40~45 DEG C of stirring in water bath
Evaporation, makes the mixed solution of the phosphatide film forming on wall.40~45 DEG C are removed under reduced pressure after mixed solvent and add synthermal aqueous medium
0.025mol/L PBS solution (pH value 8.0, containing 0.5%RH-40) 100ml, aquation (can be added suitable during aquation in 45 DEG C of water-baths
When bead stirring, untill aquation is uniform, notice that stirring can not be excessively violent during aquation), take out liposome and be put into beaker.It is cold
But to after room temperature, 10000rpm disperses 5min in high speed dispersor, adds 2% mannitol and 2% glucose freezes proppant,
Successively through 0.45 μm, 0.22 μm of membrane filtration, it is sub-packed in cillin bottle, is freeze-dried, produces.
Quality Control：Outward appearance is that white loose is block, and particle diameter is 80.78nm, and content is the 97.99% of labelled amount, and envelop rate is
94.05%.
Embodiment 5
Prepare：Weigh hydrogenated soy phosphatidyl choline 600mg, egg yolk lecithin 300mg, DSPE-mPEG2000 of recipe quantity
1OOmg, cholesterol 25mg, Cabazitaxel 25mg, it is rear to revolve with methanol 500ml solution in making dissolving under 45~50 DEG C of stirring in water bath
Turn evaporation, make the methanol solution of the phosphatide film forming on wall.45~50 DEG C be removed under reduced pressure after methanol solvate add it is synthermal it is aqueous be situated between
The NaHCO of matter 0.5%3Solution 100ml, aquation (can add appropriate bead stirring, aquation is uniformly in 50 DEG C of water-baths during aquation
Only, notice that stirring can not be excessively violent during aquation), take out liposome and be put into beaker.It is cooled to after room temperature, in high speed dispersor
Middle 10000rpm disperses 5min, adds 4% mannitol and 2% lactose freezes proppant, successively through 0.45 μm, 0.22 μm of filter membrane mistake
Filter, is sub-packed in cillin bottle, is freeze-dried, produces.
Quality Control：Outward appearance is that white loose is block, and particle diameter is 72.61nm, and content is the 97.58% of labelled amount, and envelop rate is
94.53%.
Embodiment 6
Prepare：Weigh hydrogenated soy phosphatidyl choline 200mg, the egg yolk lecithin 900mg of recipe quantity, cholesterol 20mg, kappa
He matches 30mg, rear to rotate with methanol 200ml and absolute ethyl alcohol 350ml mixed solutions in making dissolving under 50~55 DEG C of stirring in water bath
Evaporation, makes the mixed solution of the phosphatide film forming on wall.50~55 DEG C are removed under reduced pressure after mixed solvent and add synthermal aqueous medium
0.5% NaHCO3The mixed aqueous solution 1OOml of+0.1mol/L HYDROXYPROPYL BETA-CYCLODEXTRIN, aquation (aquation in 55 DEG C of water-baths
When can add the stirring of appropriate bead, untill aquation is uniform, notes that stirring can not be excessively violent during aquation), taking-up liposome is put
Enter in beaker.It is cooled to after room temperature, in ultrasonic disperse 5min under the probe of cell crushing instrument, (450W × 5min, work 3s, interval
1s), add 4.5% lactose and freeze proppant, successively through 0.45 μm, 0.22 μm of membrane filtration, be sub-packed in cillin bottle, freezing is dry
It is dry, produce.
Quality Control：Outward appearance is that white loose is block, and particle diameter is 78.16nm, and content is the 98.37% of labelled amount, and envelop rate is
93.84%.
Embodiment 7
Prepare：Weigh recipe quantity hydrogenated soy phosphatidyl choline 800mg, DSPE-mPEG2000 300mg, cholesterol 50mg,
Cabazitaxel 35mg, with absolute ethyl alcohol 500ml and dichloromethane 50ml mixed solutions in making dissolving under 45~50 DEG C of stirring in water bath,
Rotary evaporation afterwards, makes the mixed solution of the phosphatide film forming on wall.45~50 DEG C are removed under reduced pressure after mixed solvent and add synthermal water
Property medium 0.2mol/L ammonium sulfates (pH value 7.4) 100ml, aquation (can add appropriate bead in 50 DEG C of water-baths during aquation
Stirring, untill aquation is uniform, notices that stirring can not be excessively violent during aquation), take out liposome and be put into beaker.It is cooled to room temperature
Afterwards, in ultrasonic disperse 5min under the probe of cell crushing instrument (450W × 5min, work 3s, interval 1s), add 7% mannitol and freeze
Dry proppant, successively through 0.45 μm, 0.22 μm of membrane filtration, is sub-packed in cillin bottle, freeze-drying, produces.
Quality Control：Outward appearance is that white loose is block, and particle diameter is 79.41nm, and content is the 98.11% of labelled amount, and envelop rate is
93.26%.
Embodiment 8
Prepare：Soybean lecithin 100mg, egg yolk lecithin 900mg, DSPE-mPEG2000 50mg of recipe quantity are weighed,
Cholesterol 10mg, Cabazitaxel 25mg, with absolute ethyl alcohol 400ml and methanol 100ml and dichloromethane 50ml mixed solutions in
Make dissolving under 45~50 DEG C of stirring in water bath, rear rotary evaporation makes the mixed solution of the phosphatide film forming on wall.45~50 DEG C of decompressions are removed
Go after mixed solvent to add synthermal aqueous medium 0.1mol/LPBS solution (pH value 5.0, containing 0.2% oleic acid) 100ml, 50 DEG C
Aquation (can add appropriate bead stirring, untill aquation is uniform, notice that stirring can not be excessively acute during aquation in water-bath during aquation
It is strong), take out liposome and be put into beaker.It is cooled to after room temperature, 10000rpm disperses 5min in high speed dispersor, adds 2%
Mannitol and 3% sucrose freeze proppant, successively through 0.45 μm, 0.22 μm of membrane filtration, are sub-packed in cillin bottle, and freezing is dry
It is dry, produce.
Quality Control：Outward appearance is that white loose is block, and particle diameter is 77.70nm, and content is the 97.57% of labelled amount, and envelop rate is
93.08%.
Embodiment 9
Prepare：Hydrogenated soy phosphatidyl choline 125mg, DSPE-mPEG2000 50mg, DSPG-Na50mg of recipe quantity are weighed,
Cholesterol 10mg, Cabazitaxel 25mg, with absolute ethyl alcohol 400ml mixed solutions in making dissolving under 55~60 DEG C of stirring in water bath, after
Rotary evaporation, makes the mixed solution of the phosphatide film forming on wall.55~60 DEG C be removed under reduced pressure after mixed solvent add it is synthermal aqueous
Medium 0.01mol/LPBS solution (pH value 7.4, containing HEPES100mg) 100ml, aquation (can be added suitable during aquation in 50 DEG C of water-baths
When bead stirring, untill aquation is uniform, notice that stirring can not be excessively violent during aquation), take out liposome and be put into beaker.It is cold
But to after room temperature, 10000rpm disperses 5min in high speed dispersor, adds 4% sucrose and freezes proppant, successively through 0.45 μm,
0.22 μm of membrane filtration, is sub-packed in cillin bottle, freeze-drying, produces.
Quality Control：Outward appearance is that white loose is block, and particle diameter is 84.33nm, and content is the 98.70% of labelled amount, and envelop rate is
93.28%.
Test example 1：Injection Cabazitaxel liposome quality control
1. trial drug
Injection Cabazitaxel liposome (is prepared) according to embodiment 3
Cabazitaxel liposome (self-control, with reference to embodiment 3) without aqueous medium and stabilizer, is situated between aqueous in formula
Matter and stabilizer are deleted, and preparation is produced.
2. quality control
(1) outward appearance
This product is white loose block.
(2) particle diameter
Instrument：Zetasize dynamic light scattering particle size instrument, model：Nanozs types, producer：Malvern.
Sample preparation：Take injection Cabazitaxel liposome appropriate, plus PBS is diluted to 2.5ml, it is micro- through 0.22 μm
Hole membrane filtration, draws its 1ml in sample cell, is measured with Particle Size Analyzer, as a result such as table 1, shown in accompanying drawing 1 and Fig. 2.
The Cabazitaxel liposomal particle size testing result of table 1
| Sample | Injection Cabazitaxel liposome | Cabazitaxel liposome (without aqueous medium and stabilizer) |
| Average grain diameter | 79.41nm | 125.2nm |
Note：Liposome average grain diameter is smaller, and targeting is stronger, and the stability of film is better.
(3) zeta current potentials
Instrument：Zetasize dynamic light scattering particle size instrument, model：Nanozs types, producer：Malvern.
Sample preparation：Take injection Cabazitaxel liposome appropriate, plus PBS is diluted to 2.5ml, it is micro- through 0.22 μm
Hole membrane filtration, draws its 1ml in sample cell, is measured with potentiometric analyzer, as a result such as table 2, shown in accompanying drawing 3 and Fig. 4.
The Cabazitaxel liposome Zeta potential testing result of table 2
| Sample | Injection Cabazitaxel liposome | Cabazitaxel liposome (without aqueous medium and stabilizer) |
| Zeta Potential | -43.5mV | -12.5mV |
Note：Lipid volume charge can reduce mutual aggregation and fusion, increase stability, and Zeta potential absolute value exists
During 30-60mV, charged seat is more stable.
(4) content
Instrument：High performance liquid chromatograph, model：Agilent 1260.
Chromatographic column：ZORBAX EclipsePlus C18,150*4.6mm, 5um
Sample preparation：Take injection Cabazitaxel liposome appropriate, plus water for injection dissolves it, it is molten that precision measures sample
Liquid 0.2ml, is put in 10ml measuring bottles, with methanol dilution to scale, shakes up, and through 0.22 μm of filtering with microporous membrane, sample introduction, HPLC is surveyed
It is fixed, as shown in accompanying drawing 5 and Fig. 6.
As a result：This product content is the 98.63% of labelled amount.
(5) envelop rate
Dialysis：Precision measures Cabazitaxel liposome 2ml, puts in bag filter, bag filter is placed in beaker, adds water
Close medium 200ml, be put into stirrer, beaker is placed on magnetic stirring apparatus by good seal, start stirring, respectively at 0.5,1,2,
4th, 6,8,10,12,24h takes extracellular fluid dialysis 2ml, and supplement hydration medium 2ml simultaneously.Extracellular fluid dialysis take continuous through 0.22 μm of filtration
Filtrate presses above-mentioned chromatographic condition sample introduction.Each time point cumulative level is calculated, and is plotted against time, dialysis equilibrium point is found.
As a result：This product envelop rate is 93.60%.
(6) vitro release
Device：Model vivo environment carries out sterile working, and sample is put in bag filter, then puts in 37 DEG C of water-baths, takes dialysis
Outer liquid is measured.
Dissolution medium：With protein environment in bovine serum albumin(BSA) parody, tieed up with phosphate buffer (PBS, pH=7.4)
Premeabilisation of cells pressure is held, nutrient solution acid-base balance is adjusted, therefore select the PBS containing 5% calf serum to be used as vitro Release Medium.
Assay method：Take injection Cabazitaxel liposome appropriate, put in bag filter, bag filter is put into 50ml containing 5% N
In sero-abluminous PBS, then above-mentioned solution put in 37 DEG C of water-baths, magnetic agitation, respectively at 0.5h, 1.0h, 2.0h,
1ml diffusates are taken when 4.0h, 6.0h, 8.0h, 10.0h, 12.0h, 24.0h, while supplementing 1ml stostes.Determined by HPLC methods, meter
Release is calculated, as a result as shown in table 3, table 4 and accompanying drawing 7.
The injection Cabazitaxel liposome vitro release data of table 3
| Time (h) | 0.5 | 1.0 | 2.0 | 4.0 | 6.0 | 8.0 | 10.0 | 12.0 | 24.0 |
| Release (%) | 0.00 | 1.13 | 1.51 | 2.50 | 3.66 | 4.57 | 5.62 | 6.40 | 12.89 |
The Cabazitaxel liposome of table 4 (without aqueous medium and stability) release in vitro degrees of data
| Time (h) | 0.5 | 1.0 | 2.0 | 4.0 | 6.0 | 8.0 | 10.0 | 12.0 | 24.0 |
| Release (%) | 0.00 | 2.56 | 3.78 | 5.04 | 6.85 | 8.72 | 10.21 | 11.93 | 22.63 |
As a result show：The release of medicine has obvious slow release effect in liposome, and invented liposomes slow release effect is more
It is good.
(7) compatibility stability
Take injection Cabazitaxel liposome appropriate, plus 5% glucose or 0.9% sodium chloride injection are diluted to containing kappa
He matches 0.12mg/ml, investigates the stability placed 8 hours, as a result as shown in table 5.
The injection Cabazitaxel liposome compatibility stability data of table 5
| Time (h) | Outward appearance | Particle diameter (nm) | Content (%) | Envelop rate (%) |
| 0 | It is colourless to milky clear liquid, no Precipitation | 82.32 | 97.85 | 94.38 |
| 1 | It is colourless to milky clear liquid, no Precipitation | 81.56 | 97.96 | 94.26 |
| 3 | It is colourless to milky clear liquid, no Precipitation | 83.41 | 98.72 | 93.60 |
| 6 | It is colourless to milky clear liquid, no Precipitation | 83.89 | 98.26 | 92.96 |
| 8 | It is colourless to milky clear liquid, no Precipitation | 83.53 | 97.64 | 91.13 |
As a result show：This product compatibility stability is good.
Test example 2：Injection Cabazitaxel liposome is compared with Cabazitaxel parenteral solution pharmacokinetic parameters
1. trial drug
Injection Cabazitaxel liposome (is prepared) according to embodiment 3
Cabazitaxel parenteral solution (self-control, with reference to JEVTANA specifications)
Preparation method：Recipe quantity Tween-80 with 13% ethanol water with after the dissolving of Cabazitaxel Ultrasonic Heating, diluting fixed
Hold, then administration concentration is diluted to 5% D/W, through 0.22 μm of filtering with microporous membrane, produce.
2. experimental animal
SPF grades of Beagle dogs, hero female half and half, are purchased from：Beijing Marshall Biotechnology Co., Ltd, Changping District, Beijing stream village
Town tile kiln village, credit number：SCXK (capital) 2011-0003, licence issuing authority：Science and Technology Commission of Beijing.
3. test method
Injection Cabazitaxel liposome and Cabazitaxel parenteral solution are administered by beasle dog using forelimb lateral vein
(n=2), dosage 1.0mg/kg, is distributed in 0min, 2min, 5min, 15min, 30min, 1h, 2h, 4h, 6h before and after administration,
8h, 10h, 24h, 48h.Small saphenous vein takes blood 0.5ml into 1.5mlEP pipes on the outside of beasle dog hind leg, anticoagulant heparin.4 DEG C, condition
Lower 10000rpm centrifugal separation plasmas.Above-mentioned plasma containing drug determines plasma drug level after processing with HPLC/MS/MS, draws
Blood concentration-time curve.Pharmacokinetic data available is analyzed through DAS software kits, the pharmacokinetic parameters result such as He of table 6 of two preparations
Shown in accompanying drawing 8.
The injection Cabazitaxel liposome of table 6 is compared with Cabazitaxel parenteral solution pharmacokinetic parameters
As a result show：Liposome about 1 times of beasle dog prolonged half-life in vivo compared with parenteral solution, exposed amount increase about 0.85
Times.
Test example 3：Injection Cabazitaxel liposome stability test data compares
Placed 6 months under the conditions of being respectively placed in 4 DEG C and 25 DEG C by patent of the present invention (embodiment 3) finished product, investigate note
Penetrate and use Cabazitaxel liposome stability, as a result as shown in table 7.
The injection Cabazitaxel liposome stability test data of table 7
As a result show：This product is placed and had good stability for 6 months.
Claims (8)
1. a kind of injection Cabazitaxel Lipidosome, it is characterised in that including Cabazitaxel, phosphatide, cholesterol, lyophilized branch
Agent, aqueous medium, stabilizer are supportted, six weight ratio is 1: 20~80: 0.2~4: 12~32: 200~1000: 0.5~10.
2. injection Cabazitaxel Lipidosome according to claim 1, it is characterised in that including Cabazitaxel, phosphorus
Fat, cholesterol, lyophilized proppant, aqueous medium, stabilizer, six weight ratio is 1: 30~60: 0.25~2.5: 16~28:
300~600: 1.0~6.
3. injection Cabazitaxel Lipidosome according to claim 2, it is characterised in that including Cabazitaxel, phosphorus
Fat, cholesterol, lyophilized proppant, aqueous medium, stabilizer, six weight ratio is 1: 40~50: 0.35~0.8: 18~24:
400~500: 1.5~3.0.
4. according to any described injection Cabazitaxel Lipidosomes of claim 1-3, it is characterised in that：The phosphatide choosing
One or more from soybean lecithin, egg yolk lecithin, hydrogenated soya phosphatide, polyethylene glycol phosphatide, phosphatidyl glycerol.
5. the injection Cabazitaxel Lipidosome according to claim 1-3, it is characterised in that：The lyophilized proppant
One or more in mannitol, glucose, sucrose, lactose, amino acid, trehalose.
6. the injection Cabazitaxel Lipidosome according to claim 1-3, it is characterised in that：The aqueous medium bag
Include the buffer solution of different pH value, selected from phosphate buffer, citrate buffer, carbonate buffer solution, ammonium sulfate buffer salt,
One or more in amphion organic chemistry buffer solution, pH value is between 4.5~9.0.
7. the injection Cabazitaxel Lipidosome according to claim 1-3, it is characterised in that：The stabilizer is selected from
One or more in EDTA-2Na, oleic acid, Crodaret, HYDROXYPROPYL BETA-CYCLODEXTRIN.
8. according to the preparation method of any described injection Cabazitaxel liposomes of claim 1-7, it is characterised in that：Weigh
Phosphatide, cholesterol, the Cabazitaxel of recipe quantity, are dissolved in after organic solvent and being evaporated, and make mixture film forming.Aqueous medium is added,
Aquation at 30~70 DEG C, takes out after liposome cooling, is stirred in ultrasonic disperse or high speed dispersor under the probe of cell crushing instrument
Mix, add lyophilized proppant, successively through 0.45 μm, 0.22 μm of membrane filtration, dispense, freeze-drying.
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