CN101317816A - Docetaxel long-circulation formulation - Google Patents
Docetaxel long-circulation formulation Download PDFInfo
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Abstract
The invention provides a long-circulating preparation which is an invisible nano particle, a stealth lipidosome, or an invisible micelle containing docetaxle, carrier materials and additive. The long-circulating preparation is prepared by wrapping the docetaxle with the carrier materials that are modified by polyethylene glycol, a hydrotropic substance. The long-circulating preparation of the docetaxel can avoid being captured or swallowed by the hepatolienal reticular endothelial system in the body, thus prolonging circulation time in blood. Compared with the common injection of the docetaxel or the non-stealth lipidosome of the docetaxel, the long-circulating preparation of the docetaxel provided by the invention has stronger inhibit function on a tumor.
Description
Technical field
The present invention relates to the long-circulation formulation of antitumor drug docetaxel, said preparation can be invisible nano particle, hidden liposome and stealthy micelle, relates in particular to the main carrier material of described preparation use, the preparation method and the purposes of said preparation.
Background technology
Docetaxel (docetaxel/Taxotere) is a kind of new type antineoplastic medicine.Molecular formula is C
43H
53NO
14, structural formula is:
It is by the former Rhone-Poulenc Rorer of France, the i.e. a kind of semi-synthetic antitumor drug of Sanofi-Aventis company exploitation now, April nineteen ninety-five is in Mexico's Initial Public Offering, and is present then get permission sale in more or less a hundred country, the world that comprises China and Europe, the United States, day etc.JIUYUE 27 good days, ten thousand spies (China) Investment Co., Ltd at first carried out the imported product registration in 2003, and injection docetaxel was listed China's medical insurance catalogue Class B kind in 2004 in.
Docetaxel belongs to taxone, and it can suppress the tumor cell differentiation by " freezing " the inherent skeleton of cell in fact.Cytoskeleton is made up of microtubule, and microtubule in cell cycle assembling and partition phenomenon can take place in good time.Docetaxel can impel the microtubule assembling and stop the microtubule partition, suppresses the tumor cell differentiation thus, finally causes death of neoplastic cells.Docetaxel is a mitotic inhibitor, multiple solid tumor had stronger anti-tumor activity, experiment in vitro is the result show, docetaxel can suppress the growth of lung adenocarcinoma cell, and along with the increase inhibitory action of dosage strengthens, this effect is relevant with this drug-induced cell generation retarded growth.The mechanism of action of docetaxel and taxanes seemingly, but anti-tumor activity is 1.3～12 times of paclitaxel.Docetaxel has at present obtained to be used for the treatment of now in each major country of the whole world that three kinds of the most common tumors of the world are the multiple indication of breast carcinoma, nonsmall-cell lung cancer and carcinoma of prostate, and is becoming one of the most frequently used or standard treatment of these cancer kinds treatments.Docetaxel also is widely used in the later stage clinical research of treatment gastric cancer, tumor of head and neck, the esophageal carcinoma, ovarian cancer etc., the treatment of these indications is expected to can obtain the America and Europe in the future ratifies.Being used for the treatment of gastric cancer, tumor of head and neck, the esophageal carcinoma, ovarian cancer and carcinoma of endometrium at Japanese docetaxel at present gets the Green Light.
But the docetaxel poorly water-soluble, at present commercially available docetaxel is gone on the market with the liquor type to concentrate infusion, and its concrete preparation specification has two kinds of 20mg/0.5ml and 80mg/2ml, and conventional recommended dose scheme is per 3 all 1 time 1 hour venoclysis 75mg/m
2Injection docetaxel is that to adopt tween 80 (tween-80) to make the dissolution with solvents docetaxel be 1 medicinal liquid, is furnished with simultaneously in addition to contain 1 of 13% alcoholic acid diluent again.Because tween 80 has hemolytic, can cause allergic reaction when being used for intravenous injection, comprise shock, dyspnea, hypotension, angioedema, rubella etc., these untoward reaction cause very serious consequence in people's clinical experiment, and dead report is arranged.So the conventional enforcement of clinical application pretreatment.Some patients (12.2%) still can be irritated although after chemoprophylaxis.15% patient can have to stop using because of allergy.6.5% patient can produce irritated edema.In order to remind doctor and patient to recognize the seriousness of this poison of drug side reaction, the allergy shock side reaction to this product in the drug products description of the U.S. is added with the grave warning term; And the tween 80 stickiness is big, also makes troubles for clinical application.
Based on the consideration of the problems referred to above, the invention provides a kind of docetaxel long-circulation formulation, it is invisible nano particle, hidden liposome or stealthy micelle.Said preparation does not need other solvent and diluent with direct intravenously administrable after the normal saline dilution, so just can avoid side effect such as anaphylaxis.What is more important since in dosage surface by physical absorption or covalent bond hydrophilic polymer, form the hydrophilic clothing film of one or more layers protectiveness, can hinder opsonic action, make stealthy preparation.Most important character with polymer of stealthy effect is hydrophilic and pliability.Hydrophilic is strong, and hydrogen bonded large quantity of moisture seems just more as water; Have pliability, macromolecular chain can freely swing, and can stop the opsonic action of opsonin to dosage surface better, can avoid engulfing of liver Kupffer again, makes the docetaxel Transshipment Permitted to its hetero-organization and organ or be present in for a long time in the body circulation.Through after the circulation repeatedly, hetero-organization of its outside the liver or the organ in body that can concentrate significantly reaches the purpose of targeting.Therefore, the invisible nano particle of docetaxel or hidden liposome or stealthy micelle have bigger AUC area than common docetaxel injecta (taxotere) and the nanoparticle, liposome, the micelle that do not have a stealthy effect, and tumor is had stronger inhibitory action.
Summary of the invention
The long-circulation formulation that the purpose of this invention is to provide a kind of antitumor drug docetaxel, it can be invisible nano particle, hidden liposome or stealthy micelle.The long-circulation formulation of described docetaxel comprises:
Docetaxel 0.1%～5wt%
Carrier material 0.01%～48wt%
Additives 50%～99.8wt%.
Described carrier material is one or more of the polyethyleneglycol modified DSPE of hydroaropic substance, poly-cetyl cyanoacrylate, polylactic acid, poly (lactic acid-glycolic acid) copolymer, polycaprolactone copolymer, PHOSPHATIDYL ETHANOLAMINE, poly benzyl glutamate.Be specially Polyethylene Glycol-DSPE (PEG-DSPE), Pegylation gathers cetyl cyanoacrylate (PEG-PHDCA), Polyethylene Glycol copolymer of poly lactic acid (PEG-PLA), Polyethylene Glycol poly (lactic acid-glycolic acid) copolymer (PEG-PLGA), Polyethylene Glycol polycaprolactone copolymer (PEG-PCL), the mixture of Polyethylene Glycol polylactic acid (PEG-PLA) and polylactic acid (PLA), Pegylation PHOSPHATIDYL ETHANOLAMINE (PEG-PE), Pegylation poly benzyl glutamate amphiphilic block copolymers such as (PEG-PBLG).
Described Polyethylene Glycol is the mixture that is selected among PEG1000, PEG2000, PEG4000, the PEG6000 any one or a few.
Described additives are any one in the poly-azoles quinoline of lecithin, cholesterol, vitamin E, polyvinyl alcohol (PVA), poloxamer, polyvidon, methyl that can help long-circulation formulation to form, Polysorbate, triethylamine, the polyoxyethylene.
According to the particle diameter of invisible nano particle, hidden liposome and the stealthy micellar preparation of docetaxel long-circulation formulation of the present invention in the scope of 20～500nm.Preferred particle size range is 100～300nm.
Another object of the present invention provides the preparation method of docetaxel long-circulation formulation:
(a) get docetaxel, carrier material and additives and be dissolved in the organic solvent, organic solvent is removed in water-bath decompression, form thin film after, add aqueous solution and make the films swell hydration, ultra-sonic dispersion forms the docetaxel hidden liposome; Or
(b) get docetaxel and be dissolved in the dehydrated alcohol, add the organic solvent that contains carrier material, ultrasonic emulsification gets the W/O colostrum; Again this colostrum is added and contain in the aqueous solution of additives the ultrasonic W/O/W emulsion that gets; Add in the aqueous solution, reduction vaporization is removed organic solvent and is promptly got invisible nano particle colloid solution, and centrifugal, washing of precipitate promptly gets the docetaxel invisible nano particle; Or
(c) get docetaxel and be dissolved in ethanol, add the organic solvent that contains carrier material and additives, remove organic solvent with gyroscope and form the pastille adipose membrane, vacuum drying eliminates residual organic solvent again, add aquation in the buffer solution water-bath, place under the room temperature promptly to get and wrap the stealthy micelle that carries docetaxel.
Described organic solvent be in dehydrated alcohol, dichloromethane, the chloroform any one or multiple.
In addition, docetaxel long-circulation formulation of the present invention can be made into injection, is used for intravenous injection, and also further freeze-dried powder is made in lyophilization.
The proppant of described freeze-dried powder is one or more a mixture of glucose, sucrose, lactose, mannitol.
A further object of the present invention provides described docetaxel long-circulation formulation in the application that is used for preparing the medicine for the treatment of malignant tumor.
Beneficial effect
Docetaxel long-circulation formulation of the present invention since in dosage surface by physical absorption or covalent bond hydrophilic polymer, form the hydrophilic clothing film of one or more layers protectiveness, can hinder opsonic action, the seizure that escapes liver spleen reticuloendothelial system is engulfed; Most important character with polymer of stealthy effect is hydrophilic and pliability, hydrophilic is strong, hydrogen bonded large quantity of moisture, can stop the opsonic action of opsonin better to dosage surface, can avoid engulfing of liver Kupffer again, make the docetaxel Transshipment Permitted to its hetero-organization and organ or be present in for a long time in the body circulation.Through after the circulation repeatedly, hetero-organization of its outside the liver or the organ in body that can concentrate significantly reaches the purpose of targeting.Therefore, docetaxel long-circulation formulation of the present invention has stronger inhibitory action to tumor.
With common docetaxel injection (trade name: taxotere), after the non-hidden liposome of docetaxel and the administration of docetaxel hidden liposome, get blood, measure the pharmacokinetic data available of rat in different time sections.Measure and contrast the tumour inhibiting rate of three groups of medicines behind the inoculated tumour simultaneously.In vivo test the results are shown in Table 1, the AUC area of digital proof long-circulation formulation of the present invention is 3.01 times of AUC area of common injection docetaxel, tumour inhibiting rate is 2.69 times of common injection docetaxel, compare with non-cryptomorphic preparation, docetaxel long-circulation formulation of the present invention also has better effect.
Table 1: common docetaxel injection, the non-hidden liposome of docetaxel and docetaxel hidden liposome effect are relatively
| Preparation | AUC (h*μg/mL) | Contrast | Tumour inhibiting rate (%) | Contrast |
| The normal injection agent | 98.54 | 1 | 18.45 | 1 |
| Non-hidden liposome | 125.81 | 1.28 | 27.45 | 1.49 |
| Hidden liposome | 296.65 | 3.01 | 49.54 | 2.69 |
Description of drawings
The measurement result of the docetaxel hidden liposome particle diameter of Fig. 1 embodiment 1 preparation.
The specific embodiment
To further specify the present invention by specific embodiment below, but below be described as nonrestrictively, do not limit the claimed scope of claim of the present invention.
Reagent and instrument:
Lecithin (German Degussa); Cholesterol (Shanghai Ru Ji biotechnology Development Co., Ltd); PEG series (Shanghai Gaoqiao chemical plant); Docetaxel raw material (Shanghai Sunve Pharmaceutical Co., Ltd.); PEG2000-DSPE, PEG4000-DSPE (German Lipoid company and U.S. Avanti company);
HPLC instrument (Aglient 1100); Particle size determination instrument (NICOMP 380 ZLS); Freezer dryer (Labconco 6L).
Embodiment 1
Accurately take by weighing lecithin 15.8mg, cholesterol 7.8mg and PEG2000-DSPE 0.6mg, vitamin E 0.1mg, docetaxel 2mg are dissolved in the 5ml chloroform jointly, gained solution places the 50ml eggplant type flask, chloroform is removed in 37 ℃ of water-bath decompressions, after forming the thin film of homogeneous transparent on the eggplant type flask wall, the pH6.8 phosphate buffered solution 6ml that adds 0.02mol/L, continuation is rotated 30min under 37 ℃ of water-bath normal pressures, make the films swell hydration, the suspension whirlpool concussion 10min of gained.Behind ultra-sonic dispersion 1min, promptly get docetaxel stealthy liposome liquid solution under the room temperature, the dialysis desalination.Add 20ml water dilution, with mannitol 1.0g as proppant lyophilization make freeze-dried powder.With the deionized water is the mean diameter of disperse medium working sample, and recording particle diameter is 20～500nm, mean diameter 120nm.The results are shown in Figure 1.
Common docetaxel injection (trade name: taxotere), the non-hidden liposome of docetaxel (self-control, promptly replace PEG2000-DSPE to prepare with above-mentioned same procedure with DSPE) and above-mentioned docetaxel hidden liposome all be diluted to docetaxel dosage 0.65mg/mL with normal saline, dosage 5mg/kg, the rat tail vein injection.After the administration in 1,3,6,12,24 and 48h get blood, use anticoagulant heparin, centrifugal separation plasma.Add internal standard substance, with moving to centrifuge tube behind the methanol mixed 5min, the centrifugal 5min of 4000rpm extracts.Nitrogen dries up.Add the dissolving of 1ml mobile phase, get 20 μ L sample introductions, carry out RP-HPLC and measure.Chromatographic condition: Discovery post (25cm * 4.6mm, 5 μ m), mobile phase: methanol: acetonitrile (25: 75), flow velocity 1.0mL/min detects wavelength 227nm.Data processing method: the blood drug level data are handled with the 3P87 pharmacokinetics program of Chinese Pharmacological Society's establishment.The AUC area of three kinds of preparations that the result records is respectively 98.54h μ g/mL (taxotere injection), 125.81h μ g/mL (the non-hidden liposome of docetaxel) and 257.65h μ g/mL (docetaxel hidden liposome).
In order to estimate the antitumous effect of docetaxel hidden liposome, measure the propagation situation that its suppresses human breast cancer cell (MCF-7) with mtt assay, and be contrast with the docetaxel raw material.Calculate the IC of two kinds of preparations respectively with the Logit method
50Value, IC
50Value is respectively 0.057 ± 0.001nmol/L (docetaxel hidden liposome) and 4.24 ± 0.24nmol/L (docetaxel raw material), show that hidden liposome has strengthened the inhibitory action of docetaxel to the breast cancer cell growth, compare with the docetaxel raw material, the docetaxel hidden liposome shows stronger anti-tumor activity.
Embodiment 2
Accurately take by weighing lecithin 20mg, cholesterol 5.6mg and PEG4000-DSPE 1.0mg, docetaxel 5mg is dissolved in the 10ml dichloromethane jointly, gained solution places the 50ml eggplant type flask, dichloromethane is removed in 37 ℃ of water-bath decompressions, after forming the thin film of homogeneous transparent on the eggplant type flask wall, the pH6.8 phosphate buffered solution 10ml that adds 0.01mol/L, continuation is rotated 30min under 37 ℃ of water-bath normal pressures, make the films swell hydration, the suspension whirlpool concussion 10min of gained.Behind ultra-sonic dispersion 1min, promptly get docetaxel stealthy liposome liquid solution under the room temperature, the dialysis desalination.Add the dilution of 20ml water, add mannitol 0.5g and glucose 0.4g as proppant, freeze-dried powder is made in lyophilization.With the deionized water is the mean diameter of disperse medium working sample, and recording particle diameter is 100～400nm, mean diameter 220nm.
Taxotere the injection, (self-control of the non-hidden liposome of docetaxel, promptly replace PEG4000-DSPE to prepare with above-mentioned same procedure with DSPE) and the docetaxel hidden liposome all be diluted to docetaxel dosage 0.65mg/mL with normal saline, dosage 5mg/kg, the rat tail vein injection.After the administration in 1,3,6,12,24 and 48h get blood, use anticoagulant heparin, centrifugal separation plasma.Add internal standard substance, with moving to centrifuge tube behind the methanol mixed 5min, the centrifugal 5min of 4000rpm extracts.Nitrogen dries up.Add the dissolving of 1ml mobile phase, get 20 μ L sample introductions, carry out RP-HPLC and measure.Chromatographic condition: Discovery post (25cm * 4.6mm, 5 μ m), mobile phase: methanol: acetonitrile (25: 75), flow velocity 1.0mL/min detects wavelength 227nm.Data processing method: the blood drug level data are handled with the 3P87 pharmacokinetics program of Chinese Pharmacological Society's establishment.The AUC area of three kinds of preparations that the result records is respectively 98.54h μ g/mL (taxotere injection), 125.81h μ g/mL (the non-hidden liposome of docetaxel) and 296.65h μ g/mL (docetaxel hidden liposome).
With forelimb axil subcutaneous vaccination H
22Tumor-bearing mice when about 10d, tumor entity grow to heavily about 1g after the tumor is divided into blank administration matched group, taxotere injection group, the non-hidden liposome group of docetaxel and docetaxel hidden liposome group at random, tail vein injection dosage is respectively the docetaxel of 4mg/kg, 1 time/d, continuous 5d.4h puts to death simultaneously after the last administration, cuts open and gets solid tumor, claims tumor heavy, calculates tumour inhibiting rate.Pressing tumour inhibiting rate=(the average tumor of the average tumor weight/blank of mice group mice is heavy after the 1-administration) * 100% calculates.Tumour inhibiting rate is respectively 49.54% (docetaxel hidden liposome), 27.45% (the non-hidden liposome of docetaxel), 18.45% (taxotere injection group).Above-mentioned data show that hidden liposome can strengthen the inhibitory action of docetaxel to tumor cell.
Embodiment 3
Get docetaxel 10mg, be dissolved in the 25ml dehydrated alcohol, inject 30mg and contain the poly-cetyl cyanoacrylate (PEG6000-PHDCA of Pegylation, its method for making is a conventional method of the prior art, specific as follows: with PHDCA20mg, N, N-dicyclohexyl carbimide 10mg, N-maloyl imines 10mg is dissolved in dimethyl sulfoxine 25ml, stirred 3 hours, and crossed leaching filtrate, PEG600020mg adds wherein after being dissolved in dichloromethane 15ml, continue to stir 4 hours, cross leaching filtrate, place 24 hours recrystallization for 0 ℃, filter, lyophilization, promptly.) dichloromethane solution 30ml in, after ultrasonic cell disruptor (60W, 30 minutes) the continuous ultrasound emulsifying, obtain the W/O colostrum.Again this colostrum is joined 50ml, in 4% the PVA solution, under the ice bath, reuse ultrasonic cell disruptor impulse ultrasound 5 minutes obtains the W/O/W emulsion.The gained emulsion is joined 120mL contain in the solution of 1wt%PVA, the room temperature reduction vaporization is removed dichloromethane, promptly get invisible nano particle colloid solution, the centrifugal 40min of 14000rpm, abandoning supernatant, precipitation promptly gets the docetaxel invisible nano particle with distillation washing 3 times.Add the dilution of 50ml water, as proppant, freeze-dried powder is made in lyophilization with sucrose 5.4g.With the deionized water is the mean diameter of disperse medium working sample, and recording particle diameter is 20～150nm, mean diameter 80nm.
Substitute PEG-PHDCA with poly-cetyl cyanoacrylate (PHDCA), prepare the non-invisible nano particle that does not have stealthy effect, measure envelop rate with above-mentioned identical method.The measurement result of envelop rate is: 12.14% (non-invisible nano particle of docetaxel) and 54.17% (docetaxel invisible nano particle).
Taxotere injection, the non-invisible nano particle of docetaxel and docetaxel invisible nano particle all are diluted to docetaxel dosage 0.65mg/mL with normal saline, dosage 5mg/kg, rat tail vein injection.After the administration in 1,3,6,12,24 and 48h get blood, use anticoagulant heparin, centrifugal separation plasma.Add internal standard substance, with moving to centrifuge tube behind the methanol mixed 5min, the centrifugal 5min of 4000rpm extracts.Nitrogen dries up.Add the dissolving of 1ml mobile phase, get 20 μ L sample introductions, carry out RP-HPLC and measure.Chromatographic condition: Discovery post (25cm * 4.6mm, 5 μ m), mobile phase: methanol: acetonitrile (25: 75), flow velocity 1.0mL/min detects wavelength 227nm.Data processing method: the blood drug level data are handled with the 3P87 pharmacokinetics program of Chinese Pharmacological Society's establishment.The AUC area of three kinds of preparations that the result records is respectively 98.54h μ g/mL (taxotere injection), 128.46h μ g/mL (the non-invisible nano particle of docetaxel) and 350.42h μ g/mL (docetaxel invisible nano particle).
Measure the propagation situation that the docetaxel invisible nano particle suppresses human breast cancer cell (MCF-7) with mtt assay, and be contrast with the docetaxel raw material.Calculate the IC of two kinds of preparations respectively with the Logit method
50Value, IC
50Value is respectively 0.042 ± 0.036nmol/L (docetaxel invisible nano particle) and 4.24 ± 0.24nmol/L (docetaxel raw material), and experimental data shows that invisible nano particle has strengthened the inhibitory action of docetaxel to the breast cancer cell growth.Compare with the docetaxel raw material, the docetaxel invisible nano particle shows stronger anti-tumor activity.
Embodiment 4
Get docetaxel 15mg, be dissolved in the 30ml dehydrated alcohol, inject 30mg and contain Polyethylene Glycol copolymer of poly lactic acid (PEG6000-PLA, self-control, method for making is as follows: with PLA15mg, N, N-dicyclohexyl carbimide 15mg, N-maloyl imines 15mg are dissolved in dimethyl sulfoxine 30ml, stir 5 hours, cross leaching filtrate, PEG6000 20mg adds wherein after being dissolved in dichloromethane 15ml, continues to stir 4 hours, is 5000 bag filter dialysis with molecular weight, lyophilization, promptly.) dichloromethane solution 25ml in, with after ultrasonic cell disruptor (60W, 10 minutes) the continuous ultrasound emulsifying, obtain the W/O colostrum.Again this colostrum is joined 50ml, in 5% the PVA solution, under the ice bath, reuse ultrasonic cell disruptor impulse ultrasound 5 minutes obtains the W/O/W emulsion.The gained emulsion is joined 120mL contain in the solution of 1%PVA, the room temperature reduction vaporization is removed dichloromethane, promptly get invisible nano particle colloid solution, the centrifugal 40min of 14000rpm, abandoning supernatant, precipitation adds the dilution of 50ml water with distillation washing 3 times, promptly gets docetaxel invisible nano particle solution.With the deionized water is the mean diameter of disperse medium working sample, and recording particle diameter is 50～200nm, mean diameter 100nm.
Substitute PEG6000-PLA with PLA and prepare the non-invisible nano particle of docetaxel with above-mentioned identical method.
Taxotere injection, the non-invisible nano particle of docetaxel and docetaxel invisible nano particle all are diluted to docetaxel dosage 0.65mg/mL with normal saline, dosage 5mg/kg, rat tail vein injection.After the administration in 1,3,6,12,24 and 48h get blood, use anticoagulant heparin, centrifugal separation plasma.Add internal standard substance, with moving to centrifuge tube behind the methanol mixed 5min, the centrifugal 5min of 4000rpm extracts.Nitrogen dries up.Add the dissolving of 1ml mobile phase, get 20 μ L sample introductions, carry out RP-HPLC and measure.Chromatographic condition: Discovery post (25cm * 4.6mm, 5 μ m), mobile phase: methanol: acetonitrile (25: 75), flow velocity 1.0mL/min detects wavelength 227nm.Data processing method: the blood drug level data are handled with the 3P87 pharmacokinetics program of Chinese Pharmacological Society's establishment.The AUC area of three kinds of preparations that the result records is respectively 98.54h μ g/mL (taxotere injection), 125.46h μ g/mL (the non-invisible nano particle of docetaxel) and 298.47h μ g/mL (docetaxel invisible nano particle).
Embodiment 5
Get docetaxel 15mg, be dissolved in the 30ml dehydrated alcohol, inject 30mg and contain Polyethylene Glycol poly (lactic acid-glycolic acid) copolymer (PEG2000-PLGA, method for making is as follows: with PLGA15mg, N, N-dicyclohexyl carbimide 15mg, N-maloyl imines 15mg are dissolved in dimethyl sulfoxine 35ml, stirred 5 hours, cross leaching filtrate, PEG2000 20mg adds wherein after being dissolved in dichloromethane 25ml, continue stirring 4 hours, is that 1500 bag filter is dialysed with molecular weight, removes small-molecule substance, lyophilization, promptly.) dichloromethane solution 55ml in, add the 25mg polyvidon, after ultrasonic cell disruptor (60W, 10 minutes) continuous ultrasound emulsifying, obtain the W/O colostrum.Again this colostrum is joined 50ml, in 4% the PVA solution, under the ice bath, reuse ultrasonic cell disruptor impulse ultrasound 10 minutes obtains the W/O/W emulsion.The gained emulsion is joined 120mL contain in the solution of 1%PVA, the room temperature reduction vaporization is removed dichloromethane, promptly get invisible nano particle colloid solution, the centrifugal 40min of 14000rpm, abandoning supernatant, precipitation promptly gets the docetaxel invisible nano particle with distillation washing 3 times.Add the dilution of 50ml water, add glucose 1.5g as proppant, freeze-dried powder is made in lyophilization.With the deionized water is the mean diameter of disperse medium working sample, and recording particle diameter is 120～350nm, mean diameter 210nm.
Substitute PEG2000-PLGA with PLGA and prepare the non-invisible nano particle of docetaxel with above-mentioned identical method.
Taxotere injection, the non-invisible nano particle of docetaxel and docetaxel invisible nano particle all are diluted to docetaxel dosage 0.65mg/mL with normal saline, dosage 5mg/kg, rat tail vein injection.After the administration in 1,3,6,12,24 and 48h get blood, use anticoagulant heparin, centrifugal separation plasma.Add internal standard substance, with moving to centrifuge tube behind the methanol mixed 5min, the centrifugal 5min of 4000rpm extracts.Nitrogen dries up.Add the dissolving of 1ml mobile phase, get 20 μ L sample introductions, carry out RP-HPLC and measure.Chromatographic condition: Discovery post (25cm * 4.6mm, 5 μ m), mobile phase: methanol: acetonitrile (25: 75), flow velocity 1.0mL/min detects wavelength 227nm.Data processing method: the blood drug level data are handled with the 3P87 pharmacokinetics program of Chinese Pharmacological Society's establishment.The AUC area of three kinds of preparations that the result records is respectively 98.54h μ g/mL (taxotere injection), 159.82h μ g/mL (the non-invisible nano particle of docetaxel) and 328.47h μ g/mL (docetaxel invisible nano particle).
Embodiment 6
6g lecithin, 5g Polyethylene Glycol polycaprolactone copolymer (PEG4000-PCL, method for making is as follows: with PCL15mg, N, N-dicyclohexyl carbimide 10mg, N-maloyl imines 10mg are dissolved in dimethyl sulfoxine 25ml, stirred 4 hours, and crossed leaching filtrate, PEG4000 20mg adds wherein after being dissolved in dichloromethane 15ml, continue to stir 5 hours, with molecular weight is the dialysis of 3500 bag filter, lyophilization, promptly.) and the 110mg docetaxel be dissolved in the 100ml alcoholic solution, add then and contain among the aqueous solution 150ml of 1g poloxamer, high speed shear power stirs disperses to form dispersion just down.Ethanol is removed in decompression, more first dispersion is handled 2～3 times through the high pressure dispersing emulsification machine under 200～500 atmospheric pressure, can obtain required docetaxel invisible nano particle.As proppant, freeze-dried powder is made in lyophilization with sucrose 1.5g.With the deionized water is the mean diameter of disperse medium working sample, and recording particle diameter is 40～240nm, mean diameter 100nm.
Replace PEG4000-PCL with PCL, prepare the non-invisible nano particle of docetaxel with above-mentioned identical method.
Taxotere injection, the non-invisible nano particle of docetaxel and docetaxel invisible nano particle all are diluted to docetaxel dosage 0.65mg/mL with normal saline, dosage 5mg/kg, rat tail vein injection.After the administration in 1,3,6,12,24 and 48h get blood, use anticoagulant heparin, centrifugal separation plasma.Add internal standard substance, with moving to centrifuge tube behind the methanol mixed 5min, the centrifugal 5min of 4000rpm extracts.Nitrogen dries up.Add the dissolving of 1ml mobile phase, get 20 μ L sample introductions, carry out RP-HPLC and measure.Chromatographic condition: Discovery post (25cm * 4.6mm, 5 μ m), mobile phase: methanol: acetonitrile (25: 75), flow velocity 1.0mL/min detects wavelength 227nm.Data processing method: the blood drug level data are handled with the 3P87 pharmacokinetics program of Chinese Pharmacological Society's establishment.The AUC area of three kinds of preparations that the result records is respectively 98.54h μ g/mL (taxotere injection), 168.41h μ g/mL (the non-invisible nano particle of docetaxel) and 528.45h μ g/mL (docetaxel invisible nano particle).
Embodiment 7
1g lecithin, 3g PEG6000-PLA: PLA (50: 50) mixture (PEG6000-PLA for the treatment of excess syndrome example 4 preparations mixes with 1: 1 with PLA) and 100mg docetaxel are dissolved in the 80ml alcoholic solution, add then and contain among the aqueous solution 140ml of 1g poloxamer, high speed shear power stirs disperses to form dispersion just down.Ethanol is removed in decompression, more first dispersion is handled 2～3 times through the high pressure dispersing emulsification machine under 200～500 atmospheric pressure, can obtain required docetaxel invisible nano particle.The dilution of 50ml water, as proppant, freeze-dried powder is made in lyophilization with sucrose 1.5g.With the deionized water is the mean diameter of disperse medium working sample, and recording particle diameter is 50～460nm, mean diameter 190nm.
Replace PEG6000-PLA: PLA to prepare the non-invisible nano particle of docetaxel with PLA with above-mentioned identical method.
Taxotere injection, the non-invisible nano particle of docetaxel and docetaxel invisible nano particle all are diluted to docetaxel dosage 0.65mg/mL with normal saline, dosage 5mg/kg, rat tail vein injection.After the administration in 1,3,6,12,24 and 48h get blood, use anticoagulant heparin, centrifugal separation plasma.Add internal standard substance, with moving to centrifuge tube behind the methanol mixed 5min, the centrifugal 5min of 4000rpm extracts.Nitrogen dries up.Add the dissolving of 1ml mobile phase, get 20 μ L sample introductions, carry out RP-HPLC and measure.Chromatographic condition: Discovery post (25cm * 4.6mm, 5 μ m), mobile phase: methanol: acetonitrile (25: 75), flow velocity 1.0mL/min detects wavelength 227nm.Data processing method: the blood drug level data are handled with the 3P87 pharmacokinetics program of Chinese Pharmacological Society's establishment.The AUC area of three kinds of preparations that the result records is respectively 98.54h μ g/mL (taxotere injection), 168.57h μ g/mL (the non-invisible nano particle of docetaxel) and 485.24h μ g/mL (docetaxel invisible nano particle).
Embodiment 8
Get the 20mg docetaxel and be dissolved in 50ml ethanol, Pegylation PHOSPHATIDYL ETHANOLAMINE (the PEG2000-PE that adds 20g/L, method for making is as follows: with PE20mg, N, N-dicyclohexyl carbimide 10mg, N-maloyl imines 10mg are dissolved in dimethyl sulfoxine 25ml, stirred 3 hours, and crossed leaching filtrate, PEG2000 20mg adds wherein after being dissolved in dichloromethane 25ml, continue to stir 4 hours, cross the lyophilization of leaching filtrate promptly.) chloroform soln 50ml, place to revolve and steam bottle, add the poly-azoles quinoline of 10mg methyl again, mix homogeneously.Remove organic solvent with gyroscope and form the pastille adipose membrane in 40 ℃ of waters bath with thermostatic control, vacuum drying eliminates residual organic solvent again.In above-mentioned adipose membrane, add pH6.8 phosphate buffered solution 100ml, inflated with nitrogen, sealing, aquation 30min in 40 ℃ of waters bath with thermostatic control promptly gets behind the placement 2h under the room temperature and wraps the stealthy micelle that carries docetaxel, the dilution of 50ml water, as proppant, freeze-dried powder is made in lyophilization with sucrose 1.5g.
Replace PEG2000-PE with PE, prepare the non-stealthy micelle of docetaxel with above-mentioned identical method.
With the deionized water is the mean diameter of disperse medium working sample, and recording particle diameter is 20～400nm, mean diameter 210nm.Measure envelop rate: envelop rate=(1-dissociate the docetaxel of docetaxel/always) * 100%; The pharmaceutical pack carrying capacity is to estimate an important indicator of medicament nano delivery vehicles, and the nano-carrier that de-luxe compartment carries efficient not only can reduce the consumption of nano material, the more important thing is the untoward reaction that reduces nano material itself and to the influence of medicine.The stealthy micellar envelop rate of the docetaxel that records is 85%, and the micellar envelop rate of the non-stealth of docetaxel is 38%.
The stealthy micelle of taxotere injection, the non-stealthy micelle of docetaxel and docetaxel all is diluted to docetaxel dosage 0.65mg/mL with normal saline, dosage 5mg/kg, rat tail vein injection.After the administration in 1,3,6,12,24 and 48h get blood, use anticoagulant heparin, centrifugal separation plasma.Add internal standard substance, with moving to centrifuge tube behind the methanol mixed 5min, the centrifugal 5min of 4000rpm extracts.Nitrogen dries up.Add the dissolving of 1ml mobile phase, get 20 μ L sample introductions, carry out RP-HPLC and measure.Chromatographic condition: Discovery post (25cm * 4.6mm, 5 μ m), mobile phase: methanol: acetonitrile (25: 75), flow velocity 1.0mL/min detects wavelength 227nm.Data processing method: the blood drug level data are handled with the 3P87 pharmacokinetics program of Chinese Pharmacological Society's establishment.The AUC area of three kinds of preparations that the result records is respectively 98.54h μ g/mL (taxotere injection), 246.19h μ g/mL (the non-stealthy micelle of docetaxel) and 489.25h μ g/mL (the stealthy micelle of docetaxel).
Embodiment 9
Get the 20mg docetaxel and be dissolved in 50ml ethanol, (method for making is as follows: with PBLG 20mg, N for Pegylation poly benzyl glutamate (PEG4000-PBLG) amphiphilic block copolymer of adding 20g/L, N-dicyclohexyl carbimide 10mg, N-maloyl imines 10mg are dissolved in dimethyl sulfoxine 25ml, stirred 3 hours, cross leaching filtrate, PEG4000 20mg adds wherein after being dissolved in dichloromethane 30ml, continue to stir 4 hours, cross leaching filtrate, place 24 hours recrystallization for 0 ℃, filter, lyophilization, promptly.) chloroform soln 50ml, place to revolve and steam bottle, add the 20mg polyoxyethylene sorbitan monoleate again, mix homogeneously. remove organic solvent with gyroscope and form the pastille adipose membrane in 40 ℃ of waters bath with thermostatic control, vacuum drying eliminates residual organic solvent again.In above-mentioned adipose membrane, add pH6.8 phosphate buffered solution 100ml, inflated with nitrogen, sealing, aquation 30min in 40 ℃ of waters bath with thermostatic control places the stealthy micelle that promptly get docetaxel behind the 2h under the room temperature, 50ml water dilutes, as proppant, freeze-dried powder is made in lyophilization with sucrose 1.5g.
Replace PEG4000-PBLG to prepare the non-stealthy micelle of docetaxel with PBLG with above-mentioned identical method.
With the deionized water is the mean diameter of disperse medium working sample, and recording particle diameter is 60～360nm, mean diameter 190nm.Measure envelop rate: envelop rate=(1-dissociate the docetaxel of docetaxel/always) * 100%; The stealthy micellar envelop rate of the docetaxel that records is 85.6%.
The stealthy micelle of taxotere injection, the non-stealthy micelle of docetaxel and docetaxel all is diluted to docetaxel dosage 0.65mg/mL with normal saline, dosage 5mg/kg, rat tail vein injection.After the administration in 1,3,6,12,24 and 48h get blood, use anticoagulant heparin, centrifugal separation plasma.Add internal standard substance, with moving to centrifuge tube behind the methanol mixed 5min, the centrifugal 5min of 4000rpm extracts.Nitrogen dries up.Add the dissolving of 1ml mobile phase, get 20 μ L sample introductions, carry out RP-HPLC and measure.Chromatographic condition: Discovery post (25cm * 4.6mm, 5 μ m), mobile phase: methanol: acetonitrile (25: 75), flow velocity 1.0mL/min detects wavelength 227nm.Data processing method: the blood drug level data are handled with the 3P87 pharmacokinetics program of Chinese Pharmacological Society's establishment.The AUC area of three kinds of preparations that the result records is respectively 98.54h μ g/mL (taxotere injection), 175.58h μ g/mL (the non-stealthy micelle of docetaxel) and 404.58h μ g/mL (the stealthy micelle of docetaxel).
Embodiment 10
Get the 15mg docetaxel and be dissolved in 80ml ethanol, Pegylation poly benzyl glutamate (PEG4000-PBLG) amphiphilic block copolymer (method for making is with embodiment 9) the chloroform soln 60ml and the polyoxyethylene 25mg that add 20g/L, place to revolve and steam bottle, add the 0.5mg triethylamine again, mix homogeneously.Remove organic solvent with gyroscope and form the pastille adipose membrane in 40 ℃ of waters bath with thermostatic control, vacuum drying eliminates residual organic solvent again.In above-mentioned adipose membrane, add pH6.8 phosphate buffered solution 100ml, inflated with nitrogen, sealing, aquation 30min in 40 ℃ of waters bath with thermostatic control promptly gets behind the placement 2h under the room temperature and wraps the stealthy micelle that carries docetaxel, the dilution of 50ml water, as proppant, freeze-dried powder is made in lyophilization with sucrose 1.5g.
Replace PEG4000-PBLG to use above-mentioned identical method to prepare the non-stealthy micelle of docetaxel with PBLG.
With the deionized water is the mean diameter of disperse medium working sample, and recording particle diameter is 70～420nm, mean diameter 220nm.The stealthy micellar envelop rate of the docetaxel that records is 80.56%.
The stealthy micelle of taxotere injection, the non-stealthy micelle of docetaxel and docetaxel all is diluted to docetaxel dosage 0.65mg/mL with normal saline, dosage 5mg/kg, rat tail vein injection.After the administration in 1,3,6,12,24 and 48h get blood, use anticoagulant heparin, centrifugal separation plasma.Add internal standard substance, with moving to centrifuge tube behind the methanol mixed 5min, the centrifugal 5min of 4000rpm extracts.Nitrogen dries up.Add the dissolving of 1ml mobile phase, get 20 μ L sample introductions, carry out RP-HPLC and measure.Chromatographic condition: Discovery post (25cm * 4.6mm, 5 μ m), mobile phase: methanol: acetonitrile (25: 75), flow velocity 1.0mL/min detects wavelength 227nm.Data processing method: the blood drug level data are handled with the 3P87 pharmacokinetics program of Chinese Pharmacological Society's establishment.The AUC area of three kinds of preparations that the result records is respectively 98.54h μ g/mL (taxotere injection), 168.79h μ g/mL (the non-stealthy micelle of docetaxel) and 325.59h μ g/mL (the stealthy micelle of docetaxel).
Claims (10)
1, a kind of long-circulation formulation, said preparation are invisible nano particle, hidden liposome or stealthy micelle, it is characterized in that, described preparation comprises:
Docetaxel 0.1%～5wt%
Carrier material 0.01%～48wt%
Additives 50%～99.8wt%.
2, long-circulation formulation as claimed in claim 1, described carrier material are one or more of the polyethyleneglycol modified DSPE of hydroaropic substance, poly-cetyl cyanoacrylate, polylactic acid, poly (lactic acid-glycolic acid) copolymer, polycaprolactone copolymer, PHOSPHATIDYL ETHANOLAMINE, poly benzyl glutamate.
3, long-circulation formulation as claimed in claim 2, described Polyethylene Glycol are selected among PEG1000, PEG2000, PEG4000, the PEG6000 any one or a few mixture.
4, long-circulation formulation as claimed in claim 1, described additives are selected from any one in lecithin, cholesterol, vitamin E, polyvinyl alcohol, polyvidon, poloxamer, the poly-azoles quinoline of methyl, Polysorbate, triethylamine, the polyoxyethylene.
5, long-circulation formulation as claimed in claim 1, its particle diameter is in the scope of 20～500nm.
6, a kind of method for preparing the described long-circulation formulation of claim 1 is characterized in that,
(a) get docetaxel, carrier material and additives and be dissolved in the organic solvent, organic solvent is removed in water-bath decompression, form thin film after, add aqueous solution, make the films swell hydration, ultra-sonic dispersion forms the docetaxel hidden liposome; Or
(b) get docetaxel and be dissolved in the dehydrated alcohol, add the organic solvent that contains carrier material, ultrasonic emulsification gets the W/O colostrum; Again this colostrum is added and contain in the aqueous solution of additives the ultrasonic W/O/W emulsion that gets; Add in the aqueous solution, reduction vaporization is removed organic solvent and is promptly got invisible nano particle colloid solution, and centrifugal, washing of precipitate promptly gets the docetaxel invisible nano particle; Or
(c) get docetaxel and be dissolved in ethanol, add the organic solvent that contains carrier material and additives, remove organic solvent with gyroscope and form the pastille adipose membrane, vacuum drying eliminates residual organic solvent again, add aquation in the buffer solution water-bath, place under the room temperature promptly to get and wrap the stealthy micelle that carries docetaxel;
Described organic solvent be in dehydrated alcohol, dichloromethane, the chloroform any one or multiple.
7, long-circulation formulation as claimed in claim 1 is characterized in that, can be made into injection.
8, long-circulation formulation as claimed in claim 1 is characterized in that, also can make freeze-dried powder through lyophilization.
9, long-circulation formulation as claimed in claim 8, the proppant of described freeze-dried powder are one or more mixture of glucose, sucrose, lactose, mannitol.
10, as each described long-circulation formulation of above-mentioned claim 1～9 in the application that is used for preparing the medicine for the treatment of malignant tumor.
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| CN101822642B (en) * | 2009-03-04 | 2012-02-15 | 上海交通大学医学院 | Peptide modified invisible nano particle loaded with anti-tumor angiogenesis drug and application thereof |
| CN102357075A (en) * | 2011-09-30 | 2012-02-22 | 武汉平华生物医药科技有限公司 | Docetaxel nano preparation and preparation method thereof |
| CN101822641B (en) * | 2009-03-04 | 2012-04-11 | 上海交通大学医学院 | K237 polypeptide-modified invisible nanoparticles and application thereof |
| CN102579337A (en) * | 2012-03-07 | 2012-07-18 | 山东大学 | Long circulation lipid nano-suspension containing docetaxel and preparation method thereof |
| CN102836437A (en) * | 2011-06-22 | 2012-12-26 | 中国科学院上海药物研究所 | Docetaxelpolyoxyethelene-polyoxypropylene-polyoxyethelene compound capable of self-assembling into micelle |
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| CN102836437B (en) * | 2011-06-22 | 2014-09-10 | 中国科学院上海药物研究所 | Docetaxelpolyoxyethelene-polyoxypropylene-polyoxyethelene compound capable of self-assembling into micelle |
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| CN102357075A (en) * | 2011-09-30 | 2012-02-22 | 武汉平华生物医药科技有限公司 | Docetaxel nano preparation and preparation method thereof |
| CN102579337A (en) * | 2012-03-07 | 2012-07-18 | 山东大学 | Long circulation lipid nano-suspension containing docetaxel and preparation method thereof |
| CN102579337B (en) * | 2012-03-07 | 2013-11-06 | 山东大学 | Long circulation lipid nano-suspension containing docetaxel and preparation method thereof |
| CN102885786A (en) * | 2012-09-26 | 2013-01-23 | 山东大学 | Mixed micelle freeze-dried preparation loaded with docetaxel and preparation method thereof |
| CN102885786B (en) * | 2012-09-26 | 2014-04-02 | 山东大学 | Mixed micelle freeze-dried preparation loaded with docetaxel and preparation method thereof |
| CN109589419A (en) * | 2019-01-17 | 2019-04-09 | 中国人民解放军第四军医大学 | It targets temperature control and carries polysaccharide long circulating liposome-microvesicle compound delivery system and preparation method thereof |
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