CN105287377A - Taxol polymer micelle drug-loading system and preparation method and application thereof - Google Patents
Taxol polymer micelle drug-loading system and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a taxol polymer micelle drug-loading system and a preparation method thereof, as well as application of the taxol polymer micelle drug-loading system to treatment of tumor diseases. The taxol polymer micelle drug-loading system consists of the following ingredients by mass percent: 80-99.9 percent of an amphipathic segmented copolymer and 0.1-20 percent of taxol, wherein the amphipathic segmented copolymer comprises a hydrophilic segment and a hydrophobic segment; the hydrophilic segment is polyethylene glycol with the molecular weight of 100-6,000 or methoxy polyethylene glycol with the molecular weight of 300-6,000 and the hydrophobic segment is polylactide with the molecular weight of 200-6,000; the hydrophobic segment is end-sealed by a group containing fluorenylmethoxy carbony and/or amino acid containing a benzene ring structure; and the weight ratio of polyethylene glycol or methoxy polyethylene glycol to polylactide is (0.1-30): 1. The invention also provides application of the taxol polymer micelle drug-loading system to preparation of tumor treatment medicines.
Description
Technical field
The invention provides a kind of paclitaxel micelle medicine carrying system and preparation method thereof, and the application of its treatment tumor aspect disease, belong to drug world.
Background technology
Paclitaxel is the natural product with active anticancer.Taxane family extracts or semisynthetic effective ingredient from the trunk of Ramulus et folium taxi cuspidatae, bark or needle.Namely find to have anti-tumor activity by the crude extract of US West's Ramulus et folium taxi cuspidatae (Taxusbrevifolia) trunk as far back as the sixties, Wall in 1971 etc. are separated to paclitaxel, and nineteen eighty-three enters clinical research, within 1994, goes on the market in China.It is one of anticancer medicine using the widest in the world at present.
The molecular formula of paclitaxel: C
47h
51nO
14, molecular weight is 853.92, and structural formula is as follows:
Polymer micelle is a kind of stable colloidal dispersion system that development in recent years is got up.Micelle is formed by self assembly by amphiphilic block macromolecular polymer usually, and its hydrophobic segment is inside, and hydrophilic chain is outside, presents typical " core-shell structure copolymer " structure.Polymer micelle can significantly improve the dissolubility of insoluble drug; Hydrophobic pharmaceutical pack is wrapped in the core of micelle, can reduce the toxicity of medicine; In addition, micelle passs release system as a kind of Nano medication, reaches the object of tumor tissues passive target by strengthening osmotic effect (EnhancedPermeabilityandRetentionEffect, EPR effect).
In order to effectively play the EPR effect of nano-carrier, improving the tumor tissue targeting of medicine, just requiring that carrier can keep stable in blood, by nano-carrier in blood for a long time circulation improve the probability entering tumor tissues.But, for self-assembling polymers micelle, research in recent years finds: in the very short time of micelle after entering blood, medicine just discharges, and the medicine of release completes the transhipment (JournalofControlledRelease164 (2012): 108-114) of tissue and tumor essentially by the mode of random diffusion.Occur that the main cause of this situation is that hydrophobic segment in block macromolecular and the active force between medicine are more weak, micelle is through the dilution of blood after entering blood, and medicine is easy to diffuse out from the core of micelle.As can be seen here, the stability of micelle be improved, thus the effect of more effective performance passive target, the problem of core increases the active force between hydrophobic segment and drug molecule.
For above-mentioned technical problem, inventor is by feasibility in theory demonstration and the collection of many experimental results, provide a kind of paclitaxel micelle medicine carrying system, except the paclitaxel containing effective dose, this system further comprises a kind of novel amphipathic sex-mosaicism copolymer, this copolymer is made up of jointly hydrophilic section and hydrophobic section, hydrophilic section has selected Polyethylene Glycol (PEG) or methoxy poly (ethylene glycol) (mPEG), these two kinds have polymer and have good biocompatibility and biodegradability, hydrophobic section then needs with polylactide, thus construct PEG-PLA or mPEG-PLA polymer, and on the terminal hydroxyl of PEG-PLA or mPEG-PLA, introduce fluorenylmethyloxycarbonyl (Fmoc) group, because in Fmoc group, the delocalization scope of electron cloud is very large, therefore, it is possible to and containing phenyl ring, very strong conjugation is formed between the medicine of the groups such as double bond, and paclitaxel is also rich in the medicine of phenyl ring exactly, therefore prepare high molecular polymer with this and can have very strong interaction with paclitaxel, and drug molecule is limited to firmly " in core " not easily stripping of micelle, obtained a kind of inside and outside has the micelle medicine carrying system of high stability, the targeting of the tumor tissues of medicine can be improved.
Summary of the invention
According to description technical background content, technical problem solved by the invention is, improves the active force between polymer micelle and paclitaxel, thus makes it, in drug effect process, can high stabilityly to exist, and improves the targeting of paclitaxel for tumor tissues.
Based on above-mentioned purpose, the invention provides a kind of paclitaxel micelle medicine carrying system, described drug-loading system is made up of the paclitaxel of mass fraction to be the amphipathic nature block polymer of 80%-99.9% and mass fraction be 0.1-20%, described amphipathic nature block polymer comprises hydrophilic segment and hydrophobic chain segment, hydrophilic segment is the Polyethylene Glycol of molecular weight 100-6000 or the methoxy poly (ethylene glycol) of molecular weight 300-6000, hydrophobic chain is the polylactide of molecular weight 200-6000, hydrophobic chain carries out end-blocking with the group containing fluorenes methoxy carboxyl and/or the aminoacid containing benzene ring structure, the part by weight of Polyethylene Glycol or methoxy poly (ethylene glycol) and polylactide is 0.1-30: 1.
In amphipathic chimeric micelle medicine carrying system, hydrophobic chain also can carry out end-blocking with other aminoacid; Further preferably, hydrophobic chain can carry out end-blocking by phenylalanine.
Above-mentioned drug-loading system, wherein, the part by weight of Polyethylene Glycol or methoxy poly (ethylene glycol) and polylactide is 0.5-10: 1.
Because methoxy poly (ethylene glycol) is different with the molecular weight of polylactide, cause their composition drug-loading system stability variant.So, above-mentioned drug-loading system, preferably, hydrophilic chain is the methoxy poly (ethylene glycol) of molecular weight 300-4000, and hydrophobic chain is the polylactide of molecular weight 300-5000; More preferably, hydrophilic chain is the methoxy poly (ethylene glycol) of molecular weight 600-3000, and hydrophobic chain is the polylactide of molecular weight 400-4000; Wherein, the part by weight of Polyethylene Glycol or methoxy poly (ethylene glycol) and polylactide is 0.5-10: 1.
In a preferred embodiment of the invention, above-mentioned drug-loading system is made up of the paclitaxel of mass fraction to be the amphipathic nature block polymer of 90%-97% and mass fraction be 3-10%; The methoxy poly (ethylene glycol) of described hydrophilic segment to be molecular weight be 1500-3000, hydrophobic chain is the polylactide of molecular weight 1000-2000, this hydrophobic chain carries out end-blocking with the group containing fluorenes methoxy carboxyl and/or the aminoacid containing benzene ring structure, and the part by weight of methoxy poly (ethylene glycol) and polylactide is 0.5-10: 1.
Above-mentioned drug-loading system, wherein hydrophobic chain carries out end-blocking with the group containing fluorenes methoxy carboxyl and/or the aminoacid containing benzene ring structure, and the group of described fluorenes methoxy carboxyl can be the arbitrary or combination of 6-fluorenylmethyloxycarbonyl amino or 6-fluorenylmethyloxycarbonyl amino oxygen carbonylamino caproic acid.Further preferably, hydrophobic chain carries out end-blocking with the arbitrary or combination of 6-fluorenylmethyloxycarbonyl amino-2-t-butoxycarbonyl amino caproic acid, 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid, 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino phenylalanine, 6-fluorenylmethyloxycarbonyl amino-2-t-butoxycarbonyl amino phenylalanine.
Group containing fluorenes methoxy carboxyl of the present invention is more preferably arbitrary or its combination in 6-fluorenylmethyloxycarbonyl amino, 6-fluorenylmethyloxycarbonyl amino-2-t-butoxycarbonyl amino caproic acid, 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid.
In a preferred embodiment of the invention, above-mentioned drug-loading system is made up of the paclitaxel of mass fraction to be the amphipathic nature block polymer of 80%-99.9% and mass fraction be 0.1-20%, preferably, above-mentioned drug-loading system is made up of the paclitaxel of mass fraction to be the amphipathic nature block polymer of 85%-98% and mass fraction be 2-15%, namely, the drug loading 2%-15% of copolymer, more preferably, be made up of the paclitaxel of mass fraction to be the amphipathic nature block polymer of 90%-97% and mass fraction be 3-10%; The methoxy poly (ethylene glycol) of described hydrophilic segment to be molecular weight be 1500-3000, hydrophobic chain is the polylactide of molecular weight 1000-2000, and this hydrophobic chain carries out end-blocking with the group containing fluorenes methoxy carboxyl and/or the aminoacid containing benzene ring structure.
Preferably, the described group containing fluorenes methoxy carboxyl is 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid and/or 6-fluorenylmethyloxycarbonyl amino-2-t-butoxycarbonyl amino caproic acid.
In general micelle medicine carrying system, the drug loading of copolymer is no more than 5%, drug loading higher than 5% in the field of business comparison is difficult to accomplish, in drug-loading system of the present invention, the drug loading of copolymer can meet or exceed 5%, the highest more than 15%, improve the active force between polymer micelle and paclitaxel, thus make it can high stabilityly to exist in drug effect process, improve the targeting of paclitaxel for tumor tissues.This is obvious beneficial effect of the present invention, is also one of innovative point of the present invention.
Above-mentioned drug-loading system can effectively solve micellar hydrophobic chain and drug interaction power is weak, the technical barrier of drug-loading system poor stability, and this is the beneficial effect of another aspect of the present invention.
In addition, now for clinical formulation for paclitaxel, using Cremophor EL and ethanol as cosolvent, make thick injection concentrated solution, production technology is for adopting Cremophor EL and dissolve with ethanol, then lyophilizing removing ethanol, and process dangerous is large, need before lyophilizing to ensure sterile working, not only complex operation and cost is huge.In addition, research in recent years also finds, Cremophor EL easily causes anaphylaxis in vivo, and can cause the side effect such as hematotoxicity and fluid retention, and therefore before Clinical practice, patient need carry out desensitization process and close observation infusion process.
Therefore lyophilized formulations administration can be adopted by required drug-loading system just to seem particularly important.
Paclitaxel micelle medicine carrying system provided by the invention, except the paclitaxel containing effective dose, further comprises a kind of novel amphipathic sex-mosaicism copolymer, this copolymer is made up of jointly hydrophilic section and hydrophobic section, hydrophilic section has selected Polyethylene Glycol (PEG) or methoxy poly (ethylene glycol) (mPEG), these two kinds have polymer and have good biocompatibility and biodegradability, hydrophobic section then needs with polylactide, thus construct PEG-PLA or mPEG-PLA polymer, and on the terminal hydroxyl of PEG-PLA or mPEG-PLA, introduce fluorenylmethyloxycarbonyl (Fmoc) group, because in Fmoc group, the delocalization scope of electron cloud is very large, therefore, it is possible to and containing phenyl ring, very strong conjugation is formed between the medicine of the groups such as double bond, and paclitaxel is also rich in the medicine of phenyl ring exactly, therefore prepare high molecular polymer with this and can have very strong interaction with paclitaxel, and drug molecule is limited to firmly " in core " not easily stripping of micelle, obtained a kind of inside and outside has the micelle medicine carrying system of high stability, the targeting of the tumor tissues of medicine can be improved.
In an embodiment of the present invention, provide a kind of preparation method of drug-loading system, comprise
(1) Polyethylene Glycol or methoxy poly (ethylene glycol) are joined in polymerization bottle, heat up and stir and evacuation, lactide is added after cooling, stannous octoate, reactant high temperature polymerization afterproduct dichloromethane dissolves, and filters to obtain solid polyethylene glycol or methoxy poly (ethylene glycol) block polymer after precipitation;
(2) triethylamine is added after being dissolved by fluorenylmethyloxycarbonyl amino anhydrous tetrahydro furan, add pivalyl chloride after cooling, have precipitation to generate, reactant continues reaction after heating up, cross evaporating solvent after filtering impurity and, to dry, obtain new penta acid anhydride that thick liquid is fluorenylmethyloxycarbonyl amino;
(3) Polyethylene Glycol or methoxy poly (ethylene glycol) block polymer are dissolved in dichloromethane, add triethylamine, 4-pyrollidinopyridine, after this solution is cooled, new penta acid anhydride of the fluorenylmethyloxycarbonyl amino of above-mentioned reaction gained is dissolved in dichloromethane, after join in the dichloromethane solution of Polyethylene Glycol or methoxy poly (ethylene glycol) block polymer, stir after heat up, continue stirring reaction.Filter solid is the amino-terminated Polyethylene Glycol of fluorenylmethyloxycarbonyl or methoxy poly (ethylene glycol)-polylactide block polymer after reactant precipitation;
(4) polymer and paclitaxel are made micellar solution.
In a preferred embodiment of the invention, additionally provide a kind of preparation method of drug-loading system, comprising:
(1) synthesis of mPEG-PLA
Polyethylene Glycol or methoxy poly (ethylene glycol) are joined in polymerization bottle, heat up and stir and evacuation, add lactide after cooling, stannous octoate, reactant dissolves through high temperature polymerization afterproduct dichloromethane, filters to obtain solid polyethylene glycol or methoxy poly (ethylene glycol) block polymer after precipitation;
(2) anhydride preparation
Triethylamine is added after being dissolved by 6-fluorenylmethyloxycarbonyl amino-2-t-butoxycarbonyl amino caproic acid anhydrous tetrahydro furan, pivalyl chloride is added after cooling, precipitation is had to generate, reactant continues reaction after heating up, cross evaporating solvent after filtering impurity extremely dry, obtaining thick liquid is new penta acid anhydride of 6-fluorenylmethyloxycarbonyl amino-2-t-butoxycarbonyl amino caproic acid;
(3) end capping reaction
Polyethylene Glycol or methoxy poly (ethylene glycol) block polymer are dissolved in dichloromethane, add triethylamine, 4-pyrollidinopyridine, after this solution is cooled, new penta acid anhydride of 6-fluorenylmethyloxycarbonyl amino-2-t-butoxycarbonyl amino caproic acid of above-mentioned reaction gained is dissolved in dichloromethane, after join in the dichloromethane solution of Polyethylene Glycol or methoxy poly (ethylene glycol) block polymer, stir after heat up, continue stirring reaction.Filter solid is Polyethylene Glycol or the methoxy poly (ethylene glycol)-polylactide block polymer of 6-fluorenylmethyloxycarbonyl amino-2-t-butoxycarbonyl amino caproic acid end-blocking after reactant precipitation;
(4) micelle freeze-drying synthesis
By polymer, paclitaxel and and suitable excipient substance make micellar solution after carry out lyophilizing.
According to above-mentioned preparation method, present invention also offers a kind of preferred method, comprise the following steps:
(1) 10g methoxy poly (ethylene glycol) 2000 joins in polymerization bottle, heat up and stir and evacuation, add lactide 11g after cooling, stannous octoate 5.5mg, reactant high temperature polymerization afterproduct dichloromethane dissolves, and filters white solid had both been mPEG-PLA block polymer after precipitation;
(2) 11.7g6-fluorenylmethyloxycarbonyl amino-2-t-butoxycarbonyl amino caproic acid anhydrous tetrahydro furan adds 3-10mL triethylamine after dissolving, and adds pivalyl chloride 2-5mL after cooling, has precipitation to generate.Continue reaction 1h after reactant intensification, cross evaporating solvent after filtering impurity extremely dry, obtaining thick liquid is new penta acid anhydride of 6-fluorenylmethyloxycarbonyl amino-2-t-butoxycarbonyl amino caproic acid;
(3) 20gmPEG-PLA is dissolved in dichloromethane, add triethylamine 5mL, 4-pyrollidinopyridine 1.0g, after this solution is cooled, new penta acid anhydride of 6-fluorenylmethyloxycarbonyl amino-2-t-butoxycarbonyl amino caproic acid of above-mentioned reaction gained is dissolved in dichloromethane, after join in the dichloromethane solution of mPEG-PLA, heat up after stirring reaction 1h, continue stirring reaction.Filter solid had both been the methoxy poly (ethylene glycol)-polylactide block polymer (mPEG-PLA-Lys (Fmoc)) of 6-fluorenylmethyloxycarbonyl amino-2-t-butoxycarbonyl amino caproic acid end-blocking after reactant precipitation.
Present invention also offers the preparation method that described drug-loading system is prepared into lyophilized formulations, comprising: by freeze-dried mixed with lyophilizing adjuvant for obtained for above-mentioned steps (4) micellar solution, namely obtain lyophilized formulations.
The step of aseptic process is also had before preferred described step of freeze drying.
Above-mentioned synthesis route is as follows:
(4) by polymer, paclitaxel and and suitable excipient substance make micellar solution after carry out lyophilizing.
According to method described above, wherein excipient substance is freeze-dried excipient, preferably before step of freeze drying, has aseptic process step.Described freeze-dried excipient can be one or more combinations of lactose, mannitol, sorbitol, xylitol, sucrose, trehalose, fructose, glucose, sodium alginate or gelatin, preferred lactose or mannitol.
According to above-mentioned preparation method, preferred 100mg paclitaxel and 1900mgmPEG-PLA-Lys (Fmoc) are dissolved in 20mL ethanol at 45 DEG C, rotary evaporation adds 20mL ultra-pure water and dissolves medicine film after removing ethanol, after gained solution adds 500mg mannitol after 0.22um membrane filtration, lyophilizing obtains paclitaxel micelle freeze-drying powder.
A kind of lyophilized formulations of paclitaxel micelle medicine carrying system can have been prepared by said method.
Present invention also offers the lyophilized formulations containing above-mentioned drug-loading system, described lyophilized formulations is made up of drug-loading system and lyophilizing adjuvant, paclitaxel and lyophilizing adjuvant weight ratio be 1: 0.1-50, preferably, the weight ratio of paclitaxel and lyophilizing adjuvant is 1: 0.5-30, more preferably, the weight ratio of paclitaxel and lyophilizing adjuvant is 1: 1-10.Described lyophilizing adjuvant is one or more combinations of lactose, mannitol, xylitol, sorbitol, sucrose, trehalose, fructose, glucose, sodium alginate or gelatin.
In a preferred embodiment of the invention, in amphipathic nature block polymer described in above-mentioned drug-loading system, the weight ratio of paclitaxel and pharmaceutical excipients is 1: 0.5-30, described copolymer drug loading is 2-15%, the methoxy poly (ethylene glycol) of described hydrophilic segment to be molecular weight be 1500-3000, hydrophobic chain is the polylactide of molecular weight 1000-2000, and this hydrophobic chain carries out end-blocking with the group containing fluorenes methoxy carboxyl; Described excipient substance is lactose or mannitol.
The present invention is loaded with the polymer micelle lyophilized formulations of paclitaxel, substantially increase the dissolubility of paclitaxel, and the micelle particle diameter of preparation is little, envelop rate is high, good stability, has the feature such as passive target and long circulating, wherein mPEG-PLA-Lys (Fmoc) block polymer has the effect overcoming multidrug resistance, the micelle energy significantly increasing medicament be prepared into, in intracellular accumulation, can be applicable to reversing tumor many drug resistances field, has good application prospect.
Present invention also offers the application of drug-loading system in the medicine of preparation treatment tumor containing paclitaxel.
Accompanying drawing explanation
Fig. 1 is synthesis mPEG
2000-PLA
1300the molecular weight and molecualr weight distribution system of polymer.
Fig. 2 is methoxy poly (ethylene glycol)-polylactide block copolymer (mPEG
2000-PLA
1300-Lys (Fmoc)) nucleus magnetic hydrogen spectrum.
Detailed description of the invention
Inventor verifies practicality and the beneficial effect of the compounds of this invention by following experiment.
Reiterate: following experiment is the exemplary experiment in R&D process of the present invention in numerous experiment, do not contained with limit all experiments that invention people does for the present invention, object is only that setting forth the present invention by those data is provided with features and application.
Embodiment 1
The preparation of methoxy poly (ethylene glycol)-polylactide block copolymer
1) mPEG
2000-PLA
1300synthesis
10g methoxy poly (ethylene glycol) 2000 joins in polymerization bottle, be warming up to 130 DEG C to stir and evacuation 1h, D is added after being cooled to room temperature, L-lactide 11g, stannous octoate 5.5mg, vacuum tightness polymerization bottle, reactant dissolves at 130 DEG C of polymerization 15h afterproduct dichloromethane, filters white solid had both been mPEG after ice ether sedimentation
2000-PLA
1300block copolymer, it is 3300 that nuclear-magnetism calculates polymer molecular weight, and gel permeation chromatography (GelPermeationChromatography, GPC) measures high molecular molecular weight and molecular weight distribution index is respectively 4596,1.06.(as Fig. 1 and Fig. 1 data table related 1).
Table 1 Generalized Relative peak value
2) end capping reaction
11.7g6-fluorenylmethyloxycarbonyl amino-2-t-butoxycarbonyl amino caproic acid 50mL anhydrous tetrahydro furan adds 3.5mL triethylamine after dissolving, and adds pivalyl chloride 3.05mL after being cooled to-10 DEG C, and adularescent precipitation generates at once.Reactant is warming up to and 0 DEG C of reaction 2h follow-up continuing is warming up to 25 DEG C of reaction 1h, crosses evaporating solvent after filtering insoluble matter extremely dry that colourless viscous liquid is new penta acid anhydride of 6-fluorenylmethyloxycarbonyl amino-2-t-butoxycarbonyl amino caproic acid.
20gmPEG
2000-PLA
1300be dissolved in 100mL dichloromethane, add triethylamine 3.5mL, 4-pyrollidinopyridine 0.37g, after this solution is cooled to 0 DEG C, join in the dichloromethane solution of mPEG-PLA after new penta acid anhydride of 6-fluorenylmethyloxycarbonyl amino-2-t-butoxycarbonyl amino caproic acid of above-mentioned reaction gained is dissolved in 50mL dichloromethane, be warming up to 25 DEG C after stirring reaction 1h and continue stirring reaction 24h.Filter white solid had both been the methoxy poly (ethylene glycol)-polylactide block copolymer (mPEG of 6-fluorenylmethyloxycarbonyl amino-2-t-butoxycarbonyl amino caproic acid end-blocking after reactant ice ether sedimentation
2000-PLA
1300-Lys (Fmoc)) nucleus magnetic hydrogen spectrum is shown in Fig. 2.
Embodiment 2
1) mPEG
2000-PLA
1000synthesis
10g methoxy poly (ethylene glycol) 2000 joins in polymerization bottle, be warming up to 130 DEG C to stir and evacuation 1h, D is added after being cooled to room temperature, L-lactide 7g, stannous octoate 3mg, vacuum tightness polymerization bottle, reactant dissolves at 130 DEG C of polymerization 15h afterproduct dichloromethane, filters white solid had both been mPEG after ice ether sedimentation
2000-PLA
1000block copolymer, it is that 3000, GPC measures high molecular molecular weight and molecular weight distribution index is respectively 3943 that nuclear-magnetism calculates polymer molecular weight, 1.05.
2) end capping reaction
11.7g6-fluorenylmethyloxycarbonyl amino-2-t-butoxycarbonyl amino caproic acid 50mL anhydrous tetrahydro furan adds 3-10mL triethylamine after dissolving, and adds pivalyl chloride 2-5mL after being cooled to-10 DEG C, and adularescent precipitation generates at once.Reactant is warming up to and 0 DEG C of reaction 2h follow-up continuing is warming up to 25 DEG C of reaction 1h, crosses evaporating solvent after filtering insoluble matter extremely dry that colourless viscous liquid is new penta acid anhydride of 6-fluorenylmethyloxycarbonyl amino-2-t-butoxycarbonyl amino caproic acid.
20gmPEG
2000-PLA
1000be dissolved in 100mL dichloromethane, add triethylamine 3.5mL, 4-pyrollidinopyridine 0.37g, after this solution is cooled to 0 DEG C, join in the dichloromethane solution of mPEG-PLA after new penta acid anhydride of 6-fluorenylmethyloxycarbonyl amino-2-t-butoxycarbonyl amino caproic acid of above-mentioned reaction gained is dissolved in 50mL dichloromethane, be warming up to 25 DEG C after stirring reaction 1h and continue stirring reaction 24h.Filter white solid had both been the methoxy poly (ethylene glycol)-polylactide block copolymer (mPEG of 6-fluorenylmethyloxycarbonyl amino-2-t-butoxycarbonyl amino caproic acid end-blocking after reactant ice ether sedimentation
2000-PLA
1000-Lys (Fmoc))
Embodiment 3
1) mPEG
2000-PLA
1500synthesis
10g methoxy poly (ethylene glycol) 2000 joins in polymerization bottle, be warming up to 130 DEG C to stir and evacuation 1h, D is added after being cooled to room temperature, L-lactide 13g, stannous octoate 6mg, vacuum tightness polymerization bottle, reactant dissolves at 130 DEG C of polymerization 15h afterproduct dichloromethane, filters white solid had both been mPEG after ice ether sedimentation
2000-PLA
1300block copolymer, it is that 3500, GPC measures high molecular molecular weight and molecular weight distribution index is respectively 4746 that nuclear-magnetism calculates polymer molecular weight, 1.06.
2) end capping reaction
11.7g6-fluorenylmethyloxycarbonyl amino-2-t-butoxycarbonyl amino caproic acid 50mL anhydrous tetrahydro furan adds 3.5mL triethylamine after dissolving, and adds pivalyl chloride 3.05mL after being cooled to-10 DEG C), adularescent precipitation generates at once.Reactant is warming up to and 0 DEG C of reaction 2h follow-up continuing is warming up to 25 DEG C of reaction 1h, crosses evaporating solvent after filtering insoluble matter extremely dry that colourless viscous liquid is new penta acid anhydride of 6-fluorenylmethyloxycarbonyl amino-2-t-butoxycarbonyl amino caproic acid.
20gmPEG
2000-PLA
1500be dissolved in 100mL dichloromethane, add triethylamine 3.5mL, 4-pyrollidinopyridine 0.37g, after this solution is cooled to 0 DEG C, join in the dichloromethane solution of mPEG-PLA after new penta acid anhydride of 6-fluorenylmethyloxycarbonyl amino-2-t-butoxycarbonyl amino caproic acid of above-mentioned reaction gained is dissolved in 50mL dichloromethane, be warming up to 25 DEG C after stirring reaction 1h and continue stirring reaction 24h.Filter white solid had both been the methoxy poly (ethylene glycol)-polylactide block copolymer (mPEG of 6-fluorenylmethyloxycarbonyl amino-2-t-butoxycarbonyl amino caproic acid end-blocking after reactant ice ether sedimentation
2000-PLA
1500-Lys (Fmoc))
Embodiment 4
1) mPEG
2000-PLA
1800synthesis
10g methoxy poly (ethylene glycol) 2000 joins in polymerization bottle, be warming up to 130 DEG C to stir and evacuation 1h, D is added, L-lactide 15g, stannous octoate 8mg after being cooled to room temperature, vacuum tightness polymerization bottle, reactant dissolves at 130 DEG C of polymerization 15h afterproduct dichloromethane, and filter white solid had been both mPEG2000-PLA1800 block copolymer after ice ether sedimentation, it is 3800 that nuclear-magnetism calculates polymer molecular weight, GPC measures high molecular molecular weight and molecular weight distribution index is respectively 4938, and 1.06.
2) end capping reaction
11.7g6-fluorenylmethyloxycarbonyl amino-2-t-butoxycarbonyl amino caproic acid 50mL anhydrous tetrahydro furan adds 3.5mL triethylamine after dissolving, and adds pivalyl chloride 3.05mL after being cooled to-10 DEG C, and adularescent precipitation generates at once.Reactant is warming up to and 0 DEG C of reaction 2h follow-up continuing is warming up to 25 DEG C of reaction 1h, crosses evaporating solvent after filtering insoluble matter extremely dry that colourless viscous liquid is new penta acid anhydride of 6-fluorenylmethyloxycarbonyl amino-2-t-butoxycarbonyl amino caproic acid.
20gmPEG
2000-PLA
1800be dissolved in 100mL dichloromethane, add triethylamine 3.5mL, 4-pyrollidinopyridine 0.37g, after this solution is cooled to 0 DEG C, join in the dichloromethane solution of mPEG-PLA after new penta acid anhydride of 6-fluorenylmethyloxycarbonyl amino-2-t-butoxycarbonyl amino caproic acid of above-mentioned reaction gained is dissolved in 50mL dichloromethane, be warming up to 25 DEG C after stirring reaction 1h and continue stirring reaction 24h.Filter white solid had both been the methoxy poly (ethylene glycol)-polylactide block copolymer (mPEG of 6-fluorenylmethyloxycarbonyl amino-2-t-butoxycarbonyl amino caproic acid end-blocking after reactant ice ether sedimentation
2000-PLA
1800-Lys (Fmoc)).
Embodiment 5
30mg paclitaxel and the mPEG obtained by embodiment 1
2000-PLA
1300-Lys (Fmoc) 1470mg is dissolved in 20mL ethanol at 45 DEG C, rotary evaporation adds 2mL ultra-pure water and dissolves medicine film after removing ethanol, after gained solution adds 750mg mannitol after 0.22um membrane filtration, lyophilizing obtains paclitaxel micelle freeze-drying powder, drug loading 2%.
Embodiment 6
The mPEG that 100mg paclitaxel and embodiment 1 obtain
2000-PLA
1300-Lys (Fmoc) 1900mg is dissolved in 20mL ethanol in 45 DEG C, rotary evaporation dissolves medicine film except adding 20mL ultra-pure water after ethanol, after gained solution adds 500mg mannitol after 0.22um membrane filtration, lyophilizing obtains paclitaxel micelle freeze-drying powder, drug loading 5%.
Embodiment 7
150mg paclitaxel and the mPEG obtained by embodiment 2
2000-PLA
1000-Lys (Fmoc) 14.85g is dissolved in 50mL ethanol at 45 DEG C, rotary evaporation adds 50mL ultra-pure water and dissolves medicine film after removing ethanol, after adding 150mg mannitol, the lyophilizing after 0.22um membrane filtration of gained solution obtains paclitaxel micelle freeze-drying powder, drug loading 1%.
Embodiment 8
75mg paclitaxel and the mPEG obtained by embodiment 3
2000-PLA
1500-Lys (Fmoc) 675mg is dissolved in 10mL ethanol at 45 DEG C, rotary evaporation adds 10mL ultra-pure water and dissolves medicine film after removing ethanol, after gained solution adds 750mg sucrose after 0.22um membrane filtration, lyophilizing obtains paclitaxel micelle freeze-drying powder, drug loading 10%.
Embodiment 9
10mg paclitaxel and the mPEG obtained by embodiment 4
2000-PLA
1800-Lys (Fmoc) 45mg is dissolved in 5mL ethanol at 45 DEG C, rotary evaporation adds 5mL ultra-pure water and dissolves medicine film after removing ethanol, after gained solution adds 250mg glucose after 0.22um membrane filtration, lyophilizing obtains paclitaxel micelle freeze-drying powder, drug loading 18.2%.
Embodiment 10
Prepare mPEG respectively
2000-PLA
1300/ paclitaxel micellar solution and mPEG
2000-PLA
1300-Lys (Fmoc)/paclitaxel micellar solution (drug level is 2mg/mL), in two kinds of micellar solution, add hyclone (FBS) respectively and regulate serum-concentration to 50%, adopt the change of size of Dynamic Light Scattering Determination different time micelle, the initial particle of two kinds of paclitaxel micelles all at about 20nm, then mPEG
2000-PLA
1300-Lys (Fmoc)/paclitaxel micelle in the blood solution of 50% after 12h particle diameter still there is no significant change; But mPEG
2000-PLA
1300the micelle particle size distribution that/paclitaxel micelle records in the serum solution of 50% obviously broadens, and illustrates that micelle there occurs gathering.As can be seen here, mPEG
2000-PLA
1300-Lys (Fmoc)/paclitaxel micelle has very high stability.
Ultra-pure water of the present invention is water for injection, is known to the skilled person.
The present invention is not limited to above-mentioned embodiment, anyone other any or akin products identical with the present invention drawn under enlightenment of the present invention, is all not precluded within outside protection scope of the present invention.
Claims (14)
1. a paclitaxel micelle medicine carrying system, it is characterized in that, described drug-loading system is made up of the paclitaxel of mass fraction to be the amphipathic nature block polymer of 80%-99.9% and mass fraction be 0.1-20%, described amphipathic nature block polymer comprises hydrophilic segment and hydrophobic chain segment, hydrophilic segment is the Polyethylene Glycol of molecular weight 100-6000 or the methoxy poly (ethylene glycol) of molecular weight 300-6000, hydrophobic chain segment is the polylactide of molecular weight 200-6000, hydrophobic chain segment carries out end-blocking with the group containing fluorenes methoxy carboxyl and/or the aminoacid containing benzene ring structure, the part by weight of Polyethylene Glycol or methoxy poly (ethylene glycol) and polylactide is 0.1-30: 1.
2. drug-loading system according to claim 1, it is characterized in that, hydrophilic chain is the methoxy poly (ethylene glycol) of molecular weight 300-4000, and hydrophobic chain is the polylactide of molecular weight 300-5000; The part by weight of Polyethylene Glycol or methoxy poly (ethylene glycol) and polylactide is 0.5-10: 1.
3. drug-loading system according to claim 1, it is characterized in that, hydrophilic chain is the methoxy poly (ethylene glycol) of molecular weight 600-3000, and hydrophobic chain is the polylactide of molecular weight 400-4000; The part by weight of Polyethylene Glycol or methoxy poly (ethylene glycol) and polylactide is 0.5-10: 1.
4. drug-loading system according to any one of claim 1-3, is characterized in that, described drug-loading system is made up of the paclitaxel of mass fraction to be the amphipathic nature block polymer of 90%-97% and mass fraction be 3-10%; The methoxy poly (ethylene glycol) of described hydrophilic segment to be molecular weight be 1500-3000, hydrophobic chain segment is the polylactide of molecular weight 1000-2000, this hydrophobic chain segment carries out end-blocking with the group containing fluorenes methoxy carboxyl and/or the aminoacid containing benzene ring structure, and the part by weight of methoxy poly (ethylene glycol) and polylactide is 0.5-10: 1.
5. drug-loading system according to claim 1, it is characterized in that, the described group containing fluorenes methoxy carboxyl is arbitrary or its combination in 6-fluorenylmethyloxycarbonyl amino, 6-fluorenylmethyloxycarbonyl amino-2-t-butoxycarbonyl amino caproic acid, 6-fluorenylmethyloxycarbonyl amino-2-benzyloxycarbonyl amino caproic acid.
6. the lyophilized formulations containing drug-loading system described in claim 1, it is characterized in that, described lyophilized formulations is made up of drug-loading system and lyophilizing adjuvant, paclitaxel and lyophilizing adjuvant weight ratio be 1: 0.1-50.
7. lyophilized formulations according to claim 6, is characterized in that, the weight ratio of described paclitaxel and lyophilizing adjuvant is 1: 0.5-30.
8. lyophilized formulations according to claim 6, is characterized in that, the weight ratio of described paclitaxel and lyophilizing adjuvant is 1: 1-10.
9. lyophilized formulations according to claim 1, is characterized in that, described lyophilizing adjuvant is one or more combinations of lactose, mannitol, xylitol, sorbitol, sucrose, trehalose, fructose, glucose, sodium alginate or gelatin.
10. a preparation method for drug-loading system described in claim 1, is characterized in that, comprises the following steps:
(1) Polyethylene Glycol or methoxy poly (ethylene glycol) are joined in polymerization bottle, heat up and stir and evacuation, lactide is added after cooling, stannous octoate, reactant high temperature polymerization afterproduct dichloromethane dissolves, and filters to obtain solid polyethylene glycol or methoxy poly (ethylene glycol) block polymer after precipitation;
(2) triethylamine is added after being dissolved by fluorenylmethyloxycarbonyl amino anhydrous tetrahydro furan, add pivalyl chloride after cooling, have precipitation to generate, reactant continues reaction after heating up, cross evaporating solvent after filtering impurity and, to dry, obtain new penta acid anhydride that thick liquid is fluorenylmethyloxycarbonyl amino;
(3) Polyethylene Glycol or methoxy poly (ethylene glycol) block polymer are dissolved in dichloromethane, add triethylamine, 4-pyrollidinopyridine, after this solution is cooled, new penta acid anhydride of the fluorenylmethyloxycarbonyl amino of above-mentioned reaction gained is dissolved in dichloromethane, after join in the dichloromethane solution of Polyethylene Glycol or methoxy poly (ethylene glycol) block polymer, stir after heat up, continue stirring reaction.Filter solid is the amino-terminated Polyethylene Glycol of fluorenylmethyloxycarbonyl or methoxy poly (ethylene glycol)-polylactide block polymer after reactant precipitation;
(4) polymer and paclitaxel are made micellar solution.
11. preparation methoies as claimed in claim 10, is characterized in that, comprise the following steps:
(1) 10g methoxy poly (ethylene glycol) 2000 joins in polymerization bottle, heat up and stir and evacuation, add lactide 11g after cooling, stannous octoate 5.5mg, reactant high temperature polymerization afterproduct dichloromethane dissolves, and filters white solid had both been mPEG-PLA block polymer after ether sedimentation;
(2) 11.7g6-fluorenylmethyloxycarbonyl amino-2-t-butoxycarbonyl amino caproic acid anhydrous tetrahydro furan adds 3-10mL triethylamine after dissolving, and adds pivalyl chloride 2-5mL after cooling, has precipitation to generate.Continue reaction 1h after reactant intensification, cross evaporating solvent after filtering impurity extremely dry, obtaining thick liquid is new penta acid anhydride of 6-fluorenylmethyloxycarbonyl amino-2-t-butoxycarbonyl amino caproic acid;
(3) 20gmPEG-PLA is dissolved in dichloromethane, add triethylamine 5mL, 4-pyrollidinopyridine 1.0g, after this solution is cooled, new penta acid anhydride of 6-fluorenylmethyloxycarbonyl amino-2-t-butoxycarbonyl amino caproic acid of above-mentioned reaction gained is dissolved in dichloromethane, after join in the dichloromethane solution of mPEG-PLA, heat up after stirring reaction 1h, continue stirring reaction.Filter solid had both been the methoxy poly (ethylene glycol)-polylactide block polymer (mPEG-PLA-Lys (Fmoc)) of 6-fluorenylmethyloxycarbonyl amino-2-t-butoxycarbonyl amino caproic acid end-blocking after reactant precipitation;
(4) polymer and paclitaxel are made micellar solution.
12. preparation methoies as claimed in claim 11, it is characterized in that, described drug-loading system is prepared into lyophilized formulations, comprises the following steps:
By step (4) gained micellar solution and lyophilizing adjuvant freeze-dried mixed, obtained lyophilized formulations.
13. preparation methoies according to claim 10, is characterized in that there is the step of aseptic process before described step of freeze drying.
Drug-loading system described in 14. 1 kinds of claim 1 is in the application of the medicine of preparation treatment tumor disease.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105732965A (en) * | 2016-02-23 | 2016-07-06 | 山东华铂凯盛生物科技有限公司 | Preparing method and application of segmented copolymer based on nonlinearity |
| CN109206598A (en) * | 2018-09-10 | 2019-01-15 | 武汉轻工大学 | The preparation method and pharmaceutical carrier of polyethylene glycol-polylactide block copolymer |
| WO2019158037A1 (en) | 2018-02-13 | 2019-08-22 | 上海时莱生物技术有限公司 | Amphiphilic block copolymer, preparation method thereof and nanomicelle drug-loading system |
| CN110585131A (en) * | 2019-09-20 | 2019-12-20 | 宁夏医科大学 | Chemotherapy drug co-loaded 1-methyltryptophan immune prodrug micelle, preparation method and application thereof |
| CN112110834A (en) * | 2019-06-19 | 2020-12-22 | 浙江智达药业有限公司 | Modified hydrophobic auxiliary material and preparation method and application thereof |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102423301A (en) * | 2011-11-18 | 2012-04-25 | 上海微丸医药开发有限公司 | Preparation method of paclitaxel nano micelle |
| CN103172819A (en) * | 2013-03-01 | 2013-06-26 | 中国科学院长春应用化学研究所 | Biodegradable polyurethane with amino on side chain and preparation method and application thereof |
| CN103497306A (en) * | 2013-10-12 | 2014-01-08 | 中国科学院长春应用化学研究所 | ABA type triblock biodegradable polyurethane with amino side chains and preparation method and uses thereof |
| CN103768013A (en) * | 2014-01-17 | 2014-05-07 | 丽珠医药集团股份有限公司 | Paclitaxel polymer micelle by using refined amphiphilic block copolymer as carrier |
| CN104510705A (en) * | 2014-05-10 | 2015-04-15 | 上海珀理玫化学科技有限公司 | Paclitaxel micelle preparation |
| CN104510703A (en) * | 2014-05-10 | 2015-04-15 | 上海珀理玫化学科技有限公司 | Paclitaxel micelle preparation |
| CN104511020A (en) * | 2014-05-10 | 2015-04-15 | 上海珀理玫化学科技有限公司 | Medicinal composition of paclitaxel |
| CN104856950A (en) * | 2014-02-25 | 2015-08-26 | 苏州雷纳药物研发有限公司 | Paclitaxel micelle drug load system and preparation method thereof |
-
2015
- 2015-10-16 CN CN201510690018.3A patent/CN105287377A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102423301A (en) * | 2011-11-18 | 2012-04-25 | 上海微丸医药开发有限公司 | Preparation method of paclitaxel nano micelle |
| CN103172819A (en) * | 2013-03-01 | 2013-06-26 | 中国科学院长春应用化学研究所 | Biodegradable polyurethane with amino on side chain and preparation method and application thereof |
| CN103497306A (en) * | 2013-10-12 | 2014-01-08 | 中国科学院长春应用化学研究所 | ABA type triblock biodegradable polyurethane with amino side chains and preparation method and uses thereof |
| CN103768013A (en) * | 2014-01-17 | 2014-05-07 | 丽珠医药集团股份有限公司 | Paclitaxel polymer micelle by using refined amphiphilic block copolymer as carrier |
| CN104856950A (en) * | 2014-02-25 | 2015-08-26 | 苏州雷纳药物研发有限公司 | Paclitaxel micelle drug load system and preparation method thereof |
| CN104510705A (en) * | 2014-05-10 | 2015-04-15 | 上海珀理玫化学科技有限公司 | Paclitaxel micelle preparation |
| CN104510703A (en) * | 2014-05-10 | 2015-04-15 | 上海珀理玫化学科技有限公司 | Paclitaxel micelle preparation |
| CN104511020A (en) * | 2014-05-10 | 2015-04-15 | 上海珀理玫化学科技有限公司 | Medicinal composition of paclitaxel |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105732965A (en) * | 2016-02-23 | 2016-07-06 | 山东华铂凯盛生物科技有限公司 | Preparing method and application of segmented copolymer based on nonlinearity |
| WO2019158037A1 (en) | 2018-02-13 | 2019-08-22 | 上海时莱生物技术有限公司 | Amphiphilic block copolymer, preparation method thereof and nanomicelle drug-loading system |
| US11225551B2 (en) | 2018-02-13 | 2022-01-18 | Selection Bioscience Llc | Amphiphilic block copolymer, preparation method thereof and nanomicelle drug-loading system |
| CN109206598A (en) * | 2018-09-10 | 2019-01-15 | 武汉轻工大学 | The preparation method and pharmaceutical carrier of polyethylene glycol-polylactide block copolymer |
| CN112110834A (en) * | 2019-06-19 | 2020-12-22 | 浙江智达药业有限公司 | Modified hydrophobic auxiliary material and preparation method and application thereof |
| CN112110834B (en) * | 2019-06-19 | 2022-10-21 | 浙江智达药业有限公司 | Modified hydrophobic auxiliary material and preparation method and application thereof |
| CN110585131A (en) * | 2019-09-20 | 2019-12-20 | 宁夏医科大学 | Chemotherapy drug co-loaded 1-methyltryptophan immune prodrug micelle, preparation method and application thereof |
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