CN1206002C - Combined polymer-medicine micelle and its prepn process - Google Patents
Combined polymer-medicine micelle and its prepn process Download PDFInfo
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention mainly provides a combined polymer medicine micelle for controlling the release of hydrophobic medicine, which contains two or more kinds of amphiphilic block copolymers and one or more kinds of hydrophobic medicine, wherein the hydrophilic segments of the amphiphilic block copolymers are copolymers of polyethyleneglycol or epoxy ethane and propylene oxide, and the hydrophobic segments of the amphiphilic block copolymers are selected from biodegradable poly-D, L-lactic acid (PDLLA), poly-L-lactic acid(PDLA), polylactide-glycolide (PLGA) and polycaprolactone (PCL) or a mixture of the ingredients. The micelle can be a water dispersion solution or freeze-drying powder, and the combined polymer medicine micelle can be prepared by means of a solid-phase melting dispersion method and a solvent evaporation method or a dialysis method. The present invention has the advantages that the medicine release performance of the micelle can be effectively controlled by regulating the proportions of different kinds of the amphiphilic block copolymers which form the micelle, and medicine micelles needed by different medicine or different application occasions can be obtained conveniently.
Description
Technical field
The present invention relates to micellar drug delivery system of a kind of combination copolymer and preparation method thereof, the micelle volume of forming by at least two kinds of amphipathic nature block polymers and at least a medicine, its lyophilized powder is easy to redispersion in water, form the medicine micellar dispersion, by the adjusting of copolymer ratio, the drug release that can be effectively controlled, have more the controlled drug delivery system of therapeutic effect.
Background technology
The biodegradable polymers nanoparticle can be realized the targeting of medicine and controlled, improves the medicine particularly bioavailability, the effect that heightens the effect of a treatment of hydrophobic drug thereby play.But easily by protein adsorption and reticuloendothelial cell identification and seizure, circulation time in vivo is short for the polymer nanoparticle of surface hydrophobicity.Therefore, it is very necessary hydrophilic modification to be carried out on its surface.By block or grafted method, make hydrophilic polyglycol chain cover the surface of hydrophobic polymer nanoparticle, can improve the hydrophilic of biodegradable polymers nanoparticle effectively, prolong nanoparticle circulation time in vivo.
Biodegradable amphipathic nature block polymer has and the similar character of micromolecule surfactant, but its critical micelle concentration is far smaller than micromolecular critical micelle concentration, and nontoxic.Amphipathic nature block polymer forms the micelle of nucleocapsid structure in water, hydrophobic drug is physically worked in coordination with and entered micellar kernel.European patent 0397307A2 adopts the method for chemical bonding hydrophobic drug to be connected to the hydrophobic section of polyoxyethylene-polyamino acid.Although this copolymer can form polymer micelle in water, but must in copolymer, introduce the bonding position.European patent 0583955A2 adopts the Amphiphilic Block Copolymer Micelles physics parcel hydrophobic drug among the European patent 0397307A2.But because polyamino acid may cause immunoreation, and the polypeptide key easily decomposes by the body endoenzyme, and the release of the medicine that is wrapped is wayward.
European patent 0552802A2 has disclosed a kind of polyoxyethylene-polylactic-acid block copolymer micelle of chemical crosslinking, but this chemical crosslinking must be used cross-linking agent or adopt ultraviolet or the mode of heating, and the biocompatibility of cross-linked copolymer nanoparticle or safety also need be verified.
United States Patent (USP) 4745160 has been reported a kind of polyoxyethylene-poly-(D, L-lactic acid) amphipathic copolymer, and this copolymer can be used as the dispersant or the suspending agent of hydrophobic drug.Use and solvent close ester that dissolve each other in the preparation process with water.The mixture of polymer, medicine and organic solvent is added in the entry, and the hydrophobic section precipitating comes out to form nanoparticle.
The relative molecular mass of United States Patent (USP) 5543158 described poly-alkyl diol-polylactic acid amphiphilic copolymers is excessive, and is insoluble in water.Ultrasonic or stir under, the organic solution of polymer and medicine added forms drug-carrying nanometer particle in the entry, but this nanoparticle is insoluble in water.
European patent 0520888A1 has disclosed a kind of polylactic acid-polyoxyethylene block copolymer, and polylactic acid section relative molecular mass is higher, must form the soliquid of nanoparticle under the condition of emulsifying agent.
United States Patent (USP) 6322805B1 has disclosed a kind of relative molecular mass at 1430-6000, the block copolymer that wherein contains hydrophilic section Polyethylene Glycol 50%-70% (mass percent), this polymer wraps up hydrophobic drug effectively, formed nano-micelle is solvable in water, make hydrophobic drug solubilising in water, and make medicine continue to discharge.But this patent is described to be the aqueous solution of this carrier micelle, is unsuitable for to store and transportation.
On the document to adopting control that biodegradable amphipathic nature block polymer such as polylactic acid-polyoxyethylene block copolymer, polycaprolactone-polyethyleneglycol block copolymer prepare the micellar pharmacokinetics of medicine, release mechanism, release etc. to carry out more research.But up to the present, patent and pertinent literature all adopt single amphipathic nature block polymer or itself and polylactic acid, polyethylene glycol blending comes carrying medicament, the control of drug loading amount and emission levels is the molecular weight by controlling polymers mainly, hydrophobic and length and ratio the hydrophilic block realize, make that the adjusting of drug release rate is difficult, for satisfying the requirement of different pharmaceutical to load capacity and rate of release, need the preparation different molecular weight, different dredging/the hydrophilic block ratio of polymer, this not only defines the range of application of the block polymer of a kind of molecular weight and structure, also makes the exploitation of different pharmaceutical controlled release preparation be subjected to very big restriction.
Summary of the invention
The object of the present invention is to provide the micellar preparation method of medicine of a kind of combination copolymer medicine micelle and conveniently adjusted micelle medicine carrying amount and release performance.
The present invention mainly provides a kind of can control the combination copolymer medicine micelle that hydrophobic drug discharges, wherein contain two or more block copolymer of amphipathic two or many blocks and one or more hydrophobic drug, its Chinese medicine accounts for the 0.001%-40% of medicine and total polymer, amphipathic nature block polymer accounts for the 60%-99.999% of medicine and total polymer weight, the hydrophilic section of described amphipathic nature block polymer is the copolymer of Polyethylene Glycol or oxirane and expoxy propane, hydrophobic section is selected from biodegradable poly-(D, L-lactic acid) (PDLLA), gather (L-lactic acid) (PDLA), gather (lactide-Acetic acid, hydroxy-, bimol. cyclic ester) (PLGA), polycaprolactone (PCL) or their mixture; Wherein hydrophilic section accounts for the 40%-70% of total polymer weight, and the content of preferred hydrophilic section accounts for the 50-60% of polymer total amount.The micellar advantage of this combination copolymer medicine is by regulating the ratio of the micellar different types of amphipathic nature block polymer of composition, can control drug loading and micellar medicine-releasing performance effectively, obtain to satisfy the needed medicine micelle in different pharmaceutical or application scenario more conveniently.
The present invention provides especially and has been selected from: anticarcinogen, anti-inflammation analgesic; Immunosuppressant; Remed for hepatopathy; Hormonal composition; Chemotherapeutic; Metabolic drug; The digestive tract disease curative; The treatment of respiratory diseases medicine; Antiallergic agent; The central nervous system disease curative; The peripheral nerve disease curative; And the medicine micelle composition of blood circulation diseases curative, preferably certainly: paclitaxel, Docetaxel, amycin, teniposide, etoposide, daunorubicin, methotrexate, ametycin, indomethacin, ibuprofen, ring spore bacterium and diphenyl dimethyl carboxylate, preferred especially paclitaxel and Docetaxel.
Amphipathic nature block polymer in the pharmaceutical composition of the present invention is selected from biodegradable poly-(D especially, L-lactic acid)-polyethyleneglycol block copolymer (PDLLA-PEG), poly-(L-lactic acid)-polyethyleneglycol block copolymer (PLLA-PEG), poly-(lactide-Acetic acid, hydroxy-, bimol. cyclic ester)-polyethyleneglycol block copolymer (PLGA-PEG) and polycaprolactone-polyethyleneglycol block copolymer (PCL-PEG), in these amphipathic nature block polymers, with the poly glycol monomethyl ether is hydrophilic section, with poly-(D, L-lactic acid), poly-(L-lactic acid), poly-(lactide-Acetic acid, hydroxy-, bimol. cyclic ester), polycaprolactone is the micelle that the diblock copolymer of hydrophobic section is more suitable for being used for preparing hydrophobic drug, wherein preferably poly-(D, L-lactic acid)-poly glycol monomethyl ether diblock copolymer and poly-(L-lactic acid)-poly glycol monomethyl ether diblock copolymer.
Because the degradation rate of poly-(DL-lactic acid), poly-(L-lactic acid), poly-(lactide-Acetic acid, hydroxy-, bimol. cyclic ester), polycaprolactone is different with accumulation shape, they show different medicine carrying abilities and control drug release character with the block copolymer of Polyethylene Glycol, PDLLA-PEG and PLGA-PEG have degradation rate and drug release rate faster, are applicable to the short-term drug release; PLLA-PEG has slower degradation rate and drug release rate, and the degradation rate of PCL-PEG and drug release rate are slower, are applicable to long lasting drug delivery system.Therefore, the applied in any combination by above-mentioned different block copolymers prepares medicine micelle volume, can more easily satisfy the requirement of different pharmaceutical and preparation, avoids being subjected to the synthetic restriction of polymer.Preferably include PDLLA-PEG in the combination copolymer, component can be selected from one or more in PLA-PEG, PLGA-PEG, the PCL-PEG amphipathic nature block polymer as required in addition.Wish rapid delivery of pharmaceuticals, can select PDLLA-PEG and PLGA-PEG combination; Moderate PDLLA-PEG and the PLLA-PEG of selecting of rate of releasing drug makes up; Wish that long-acting release can consider PDLLA-PEG and PCL-PEG combination, or PDLLA-PEG, PLLA-PEG make up with PCL-PEG.The ratio of different block copolymers can be selected as required in the combination copolymer medicine micelle, and wherein the ratio that accounts for of PDLLA-PEG is big more, and rate of release is big more, lasting drug release time is short more, and the ratio that PCL-PEG accounts for is big more, and rate of release is more little, and lasting drug release time is long more.
For guaranteeing that the medicine micelle has the redispersibility of good drug loading, sustained release, stability, lyophilized powder and the timely degradation property of polymer, the molecular weight of selected amphipathic nature block polymer should be in the 500-100000 scope, and preferable range is 2000-20000; The molecular weight of used Polyethylene Glycol is 200-30000, preferred 1000-5000, preferred especially 2000 technical scheme.
The present invention provides a kind of medicine micelle that contains paclitaxel or Docetaxel especially, medicine accounts for the 1%-30% of micelle component, amphipathic nature block polymer is poly-(D, L-lactic acid)-Polyethylene Glycol diblock copolymer and poly-(L-lactic acid)-Polyethylene Glycol diblock copolymer, wherein poly-(D, L-lactic acid)-Polyethylene Glycol diblock copolymer accounts for more than 50% of polymer total amount.
The present invention simultaneously also provides a kind of medicine micelle that contains ibuprofen especially, ibuprofen accounts for the 1%-40% of micelle component, amphipathic nature block polymer is poly-(D, L-lactic acid)-Polyethylene Glycol diblock copolymer and poly-(L-lactic acid)-Polyethylene Glycol diblock copolymer, wherein poly-(D, L-lactic acid)-Polyethylene Glycol diblock copolymer accounts for the polymer total amount and is preferably more than 50%.
Preferably a kind of lyophilized powder of the existence form of medicine micelle composition provided by the invention, this lyophilized powder can be scattered in the water certainly, forms the micellar aqueous dispersions of combination copolymer medicine, and the micelle size is in the 10-500 nanometer range.And the combination copolymer micelle also can exist and use with other pharmaceutically acceptable carrier is common, prepares pharmaceutical preparation oral or injection.
The micellar preparation method of combination copolymer medicine involved in the present invention is by medicine and polymer mixed solution are disperseed in water, remove organic solvent after, form the micellar aqueous dispersions of combination copolymer medicine, lyophilizing, its lyophilized powder; Can be undertaken by following two kinds of methods: first method is first with selected different types of polymer premixing, and then preparation medicine micelle, all contains mixture of polymers in each medicine micelle; Second method is to adopt single polymer to prepare the medicine micelle respectively, and then mixes formation combination copolymer medicine micelle volume.Concrete steps are as follows:
(1) hydrophobic drug and amphipathic nature block polymer are dissolved in the organic solvent, or the solution of the organic solvent of hydrophobic drug is joined in the aqueous dispersions of amphipathic nature block polymer, form the solution of its mixture, the ratio of organic solvent and water is 1/1-1/100, and organic solvent is selected from volatile solvent: dichloromethane, oxolane, acetonitrile, acetone, chloroform and mixed solvent thereof;
(2) medicine of above-mentioned preparation and the solution of mixture of polymers are removed organic solvent by the solid phase fusion dispersion method, the solution that is about to medicine and mixture of polymers heats under polymer melting temperature, evaporate solvent, form the solid blend thing of polymer and medicine, add the hot water that is equivalent to polymer melting temperature then, promptly form the combination copolymer micelle aqueous dispersions of medicine under stirring or the ultrasound wave; Or remove organic solvent by solvent evaporated method, the mixed solution that is about to hydrophobic drug and amphipathic nature block polymer evaporates solvent under stirring or ultrasound wave, obtain combination copolymer medicine micelle aqueous dispersions; Or remove organic solvent by dialysis, and promptly adopt dialyser, the solution of medicine and mixture of polymers carried out dialysis with respect to water, obtain combination copolymer medicine micelle aqueous dispersions;
(3) the combination copolymer medicine micelle aqueous dispersions that adopts membrane filter that (2) are prepared filters, and obtains clarifying combination copolymer medicine micelle aqueous dispersions.
(4) the polymeric medicine micelle aqueous dispersions with (3) preparation carries out lyophilization, obtains polymeric medicine micelle freeze-drying powder, and this lyophilized powder can be scattered in the aqueous systems with the medicine micelle form again certainly, forms combination copolymer medicine micelle aqueous dispersions; This step can be according to the needs of the product that will produce, optional whether enforcement.
That the drug-carrying polymer micelle lyophilized powder of above-mentioned preparation is applicable to is oral, injection, and through mucous membrane or percutaneous drug delivery, and has and be easy to store, transport, use advantage easily, can be according to patient's needs, and the water that employing contains heterogeneity disperses.
The micellar particle diameter of combination copolymer medicine among the present invention is in the 10-500nm scope.
The invention provides a kind of polymer drug-carried micelle volume that is easy to regulate drug release rate, be to use by the physical combination of two kinds of amphipathic nature block polymers of different nature, the medicine micelle that preparation has suitable drug loading and sustained release character, made things convenient for the preparation of the medicine micellar preparation of different pharmaceutical, different release requests, avoided polymer molecular weight and block than the limitation of regulating.The micellar lyophilized powder of this combination copolymer medicine, also be easy to form the micellar aqueous dispersions of medicine from being dispersed in the aqueous systems under not adding condition of stirring, it is convenient to be easy to store, to transport and to use, can adopt the water that contains heterogeneity to disperse according to patient's needs.
Description of drawings
Fig. 1 is the micellar particle size distribution figure of polymer paclitaxel of embodiment 2 preparations of light scattering method measuring, Fig. 2 is the micellar transmission electron microscope photo of polymer paclitaxel of embodiment 2 preparations, Fig. 3 is the micellar particle size distribution figure of polymer paclitaxel of embodiment 5 preparations of light scattering method measuring, and Fig. 4 is the micellar vitro drug release curve of polymeric medicine of different embodiment preparations; Micelle comes from a: embodiment 1; B: embodiment 2; C: embodiment 10; D: embodiment 9; E: embodiment 6; F: embodiment 8; G: embodiment 7.
The specific embodiment
With embodiment the present invention further is illustrated again below.
Preparation example 1:
The L-lactic acid 17g of adding 88% in a round-bottomed flask, molecular weight is 2000 poly glycol monomethyl ether (MePEG) 15g, after the sealing, under nitrogen protection, 140 ℃ of decompressions dewatered 2 hours.Add the inferior stannum 0.06g of octoate catalyst then under the normal pressure, 200 ℃, be lower than under the condition of 20mmHg pressure, logical nitrogen and carried out melt polycondensation reaction 8 hours.Reaction is dissolved in chloroform to product after finishing, and carries out precipitating at the mixed solution that adds 4～10 parts 1: 4 acetone of volume ratio below 10 ℃ then, centrifugalize, and 30 ℃～50 ℃ vacuum dryings get product P LLA-MePEG diblock copolymer.
Preparation example 2:
Repeat the step of preparation example 1, different is to replace poly glycol monomethyl ether with Polyethylene Glycol (PEG), makes PLLA-PEG-PLLA.
Preparation example 3:
Repeat the step of preparation example 1, the D with 85%, L-lactic acid replaces L-lactic acid, gets the PDLLA-MePEG diblock copolymer.
Preparation example 4:
Repeat preparation example 2 steps, the D with 85%, L-lactic acid replaces L-lactic acid, gets three sections copolymers of PDLLA-PEG-PDLLA.
Preparation example 5
Device and operation replace L-lactic acid with embodiment 1 with caprolactone, get the PCL-MePEG diblock copolymer.
Preparation example 6
Device and operation replace L-lactic acid with embodiment 2 with caprolactone, get the PCL-PEG-PCL triblock copolymer.
Preparation example 7
Install and operate, replace L-lactic acid, get the PLGA-MePEG diblock copolymer with lactide and Acetic acid, hydroxy-, bimol. cyclic ester with embodiment 1.
Embodiment 1
95mg PDLLA-MePEG (preparation example 3) is dissolved in 2mL acetone with the 5mg paclitaxel; under nitrogen protection; be heated to 60 ℃ of evaporations 2 hours; obtain the solid mixt of medicine and copolymer; behind the room temperature vacuum drying; the solid mixt of medicine and copolymer is preheated to transparent glue at 60 ℃; stir distilled water (or the phosphate buffer (PBS that adds 60 ℃ down; pH7.6)) 10mL; form medicine micellar solution; centrifugal or isolated by filtration, clear liquid is the micellar aqueous dispersions of combination copolymer paclitaxel, and the micellar aqueous dispersions lyophilization of paclitaxel is got combination copolymer paclitaxel micelle freeze-drying powder.With the micellar particle diameter of dynamic light scattering determination, the micellar character of medicine sees Table 1 and Fig. 4.
Embodiment 2
1mg PLLA-MePEG (preparation example 1) and 94mg PDLLA-MePEG (preparation example 3) are dissolved in 2mL acetone with the 5mg paclitaxel; under nitrogen protection; be heated to 60 ℃ of evaporations 2 hours; obtain the solid mixt of medicine and copolymer; behind the room temperature vacuum drying; the solid mixt of medicine and copolymer is preheated to transparent glue at 60 ℃; stir distilled water (or the phosphate buffer (PBS that adds 60 ℃ down; pH7.6)) 10mL; form medicine micellar solution; centrifugal or isolated by filtration, clear liquid is the micellar aqueous dispersions of combination copolymer paclitaxel, and the micellar aqueous dispersions lyophilization of paclitaxel is got combination copolymer paclitaxel micelle freeze-drying powder.The micellar character of the medicine of gained sees Table 1 and Fig. 1,2,4.
Embodiment 3:
The employing ibuprofen is a hydrophobic drug, prepares the micellar aqueous dispersions of combination copolymer ibuprofen by embodiment 2 steps, and lyophilization gets combination copolymer ibuprofen micelle freeze-drying powder, and the ibuprofen micelle character of gained sees Table 1.
Embodiment 4:
According to embodiment 2 steps, adopt 1mgPLLA-MePEG and 69mg PLGA-MePEG and 30mg ibuprofen, the micellar aqueous dispersions of preparation combination copolymer ibuprofen, lyophilization gets combination copolymer ibuprofen micelle freeze-drying powder, and the ibuprofen micelle character of gained sees Table 1.
Embodiment 5:
Step according to embodiment 2, adopt 1mgPLLA-MePEG and 69mg PDLLA-MePEG and 30mg paclitaxel, the micellar aqueous dispersions of preparation combination copolymer paclitaxel gets combination copolymer paclitaxel micelle freeze-drying powder with the micellar aqueous dispersions lyophilization of paclitaxel.The micellar character of medicine sees Table 1 and Fig. 3.
Embodiment 6:
Step according to embodiment 1, adopt 45mgPLLA-MePEG and 50mg PDLLA-MePEG and 5mg paclitaxel, the micellar aqueous dispersions of preparation combination copolymer paclitaxel gets combination copolymer paclitaxel micelle freeze-drying powder with the micellar aqueous dispersions lyophilization of paclitaxel.The micellar character of the medicine of gained sees Table 1 and Fig. 4.
Embodiment 7:
Step according to embodiment 2, adopt 30mgPLLA-MePEG, 30mg PCL-MePEG and 35mgPDLLA-MePEG and 5mg paclitaxel, the micellar aqueous dispersions of preparation combination copolymer paclitaxel gets combination copolymer paclitaxel micelle freeze-drying powder with the micellar aqueous dispersions lyophilization of paclitaxel.The micellar character of the medicine of gained sees Table 1 and Fig. 4.
Embodiment 8:
90mgPLLA-MePEG and 5mg PDLLA-MePEG and 5mg paclitaxel, be dissolved in 10mL acetone together, under magnetic agitation, slowly be added drop-wise in the 10mL distilled water, the PEG segment migrates to water in drop, form the solubilising micelle of parcel paclitaxel, and is intact up to solvent evaporates, the micelle kernel solidifies balling-up, centrifugalize or filtration, clear liquid are the micellar aqueous dispersions of combination copolymer paclitaxel, and the micellar aqueous dispersions lyophilization of paclitaxel is got combination copolymer paclitaxel micelle freeze-drying powder.The micellar character of the medicine of gained sees Table 1 and Fig. 4.
Embodiment 9:
10mgPLLA-MePEG and 85mg PDLLA-MePEG are dissolved in the 10mL acetone with the 5mg Docetaxel, place in the bag filter, with 3L distilled water dialysis 5-24 hour, centrifugalize or filtration, clear liquid then is the micellar aqueous dispersions of combination copolymer paclitaxel, and the micellar aqueous dispersions lyophilization of Docetaxel is got combination copolymer Docetaxel micelle freeze-drying powder.The micellar character of the medicine of gained sees Table 1.
Embodiment 10
5mgPLLA-MePEG and 90mg PDLLA-MePEG are dissolved in the 10mL water, acetone (10mL) solution that adds the 5mg Docetaxel then, under magnetic agitation, placed 24 hours, medicine infiltrates in the polymer micelle, form the solubilising micelle of parcel Docetaxel, intact up to solvent evaporates, the micelle kernel solidifies balling-up, centrifugalize or filtration, clear liquid is the micellar aqueous dispersions of combination copolymer Docetaxel, and the micellar aqueous dispersions lyophilization of Docetaxel is got combination copolymer paclitaxel micelle freeze-drying powder.The micellar character of the medicine of gained sees Table 1 and Fig. 4.
Embodiment 11
Press the method for embodiment 1, the combination micelle for preparing (1) 2.5mg paclitaxel and 45mg PLLA-MePEG respectively, (2) the combination micelle of 2.5mg paclitaxel and 50mg PDLLA-MePEG, micelle aqueous dispersions with (1) and (2) mixes then, form combination copolymer medicine micelle aqueous dispersions, lyophilizing makes lyophilized powder.The micellar character of the medicine of gained sees Table 1
Embodiment 12
Take by weighing the combination copolymer medicine micelle freeze-drying powder 100mg of embodiment 2 preparations, add 10mL distilled water and phosphate buffer, the jog number minute can all dissolve, find after tested, the form of drug-carrying polymer nanoparticle, particle diameter and particle size distribution do not change, and illustrate that lyophilization can keep the character of nanoparticle constant.
Embodiment 13
Take by weighing the combination copolymer medicine micelle freeze-drying powder of the foregoing description preparation, adopt high performance liquid chromatography, acetonitrile is a mobile phase, measures the drug loading of lyophilized powder, the results are shown in the table 1.
Embodiment 14
Take by weighing the combination copolymer medicine micelle freeze-drying powder 5mg of the foregoing description preparation, in bag filter,, place the 95mL phosphate buffer to carry out extracorporeal releasing experiment then, stir with the dissolving of 10mL phosphate buffer.Phosphate buffer 1 0mL outside certain hour is got bag filter analyzes medicament contg with HPLC, replenishes the fresh phosphoric salt buffer of equivalent simultaneously, and the result as shown in Figure 1.As seen do not dash forward in dispose procedure and release the phenomenon generation, whole dispose procedure is the feature that continues release.
The character of table 1 drug-carrying polymer nano freeze-dried powder
Implementing polymeric medicine drug loading envelop rate mean diameter 48h accumulation releases
Example (mass ratio) is (%) (nm) high-volume (%) (%)
1 PDLLA-MePEG paclitaxel 4.89 97.8 47 85.6
2 PLLA-MePEG/PDLLA-MePEG paclitaxels 4.81 96.2 48 77.2
(1/94)
3 PLLA-MePEG/PDLLA-MePEG ibuprofen 4.79 95.8 39 76.7
(1/94)
4 PLLA-MePEG/PDLLA-MePEG ibuprofen 26.1 87.0 105 38.1
(1/69)
5 PLGA-MePEG/PDLLA-MePEG paclitaxels 25.4 84.7 113 39.7
(1/69)
6 PLLA-MePEG/PDLLA-MePEG paclitaxels 4.84 96.8 42 42.6
(45/50)
7 PLLA-MePEG/PDLLA-MePEG paclitaxels 4.56 91.2 40 32.1
/PCL-MePEG(30/30/35)
8 PLLA-MePEG/PDLLA-MePEG paclitaxels 4.68 93.6 56 34.6
(90/5)
9 PLLA-MePEG/PDLLA-MePEG polyenoid purple 4.87 97.4 62 57.3
(10/85) China fir alcohol
10 PLLA-MePEG/PDLLA-MePEG polyenoid purple 4.61 92.2 45 75.3
(5/90) China fir alcohol
11 PLLA-MePEG/PDLLA-MePEG paclitaxels 4.85 97.0 43 40.3
(45/50)
Claims (8)
1. combination copolymer medicine micelle, wherein contain at least two kinds of amphipathic nature block polymers and one or more hydrophobic drug, its Chinese medicine accounts for the 0.001%-40% of medicine and copolymer gross weight, and amphipathic nature block polymer accounts for the 60%-99.999% of medicine and total polymer weight; The hydrophilic section of described amphipathic nature block polymer is the copolymer of Polyethylene Glycol or oxirane and expoxy propane, hydrophobic section is selected from biodegradable poly-(D, L-lactic acid), poly-(L-lactic acid), poly-(lactide-Acetic acid, hydroxy-, bimol. cyclic ester), polycaprolactone or their mixture; Wherein the molecular weight of amphipathic nature block polymer is 500-100000; Wherein the hydrophilic section total amount of copolymer accounts for the 30%-70% of copolymer gross weight; Described combination copolymer medicine micelle is present in micelle content in the micelle aqueous dispersions below 50%, particle diameter is in the 10-500nm scope, or a kind of lyophilized powder of micelle aqueous dispersions, this lyophilized powder can be scattered in the water certainly, forms the combination copolymer medicine micellar aqueous dispersions of micelle size in the 10-500 nanometer range.
2. combination copolymer medicine micelle according to claim 1, wherein the hydrophilic section total amount of copolymer accounts for the 45-60% of total polymer weight.
3. combination copolymer medicine micelle according to claim 1, wherein said hydrophobic drug is selected from paclitaxel, Docetaxel, ibuprofen.
4. according to a combination copolymer medicine micelle of claim 1, wherein the molecular weight of amphipathic nature block polymer is 2000-20000.
5. according to the combination copolymer medicine micelle of claim 1, wherein amphipathic nature block polymer is selected from biodegradable poly-(D, L-lactic acid)-polyethyleneglycol block copolymer, poly-(L-lactic acid)-poly-7 glycol block copolymers, poly-(lactide-Acetic acid, hydroxy-, bimol. cyclic ester)-polyethyleneglycol block copolymer and polycaprolactone-polyethylene glycol block copolymer.
6. combination copolymer medicine micelle according to claim 5, amphipathic nature block polymer is to be hydrophilic section with poly-7 glycol monomethyl ethers, with poly-(D, L-lactic acid), poly-(L-lactic acid), poly-(lactide-Acetic acid, hydroxy-, bimol. cyclic ester), polycaprolactone are the diblock copolymer of hydrophobic section, wherein preferably poly-(D, L-lactic acid)-poly glycol monomethyl ether diblock copolymer and poly-(L-lactic acid)-poly glycol monomethyl ether diblock copolymer.
7. according to claim 3 or 6 described combination copolymer medicine micelles, wherein, hydrophobic drug is paclitaxel or Docetaxel, accounts for the 1%-30% of micelle component; Amphipathic nature block polymer is poly-(D, L-lactic acid)-poly glycol monomethyl ether diblock copolymer and poly-(L-lactic acid)-poly glycol monomethyl ether diblock copolymer, wherein poly-(D, L-lactic acid)-poly glycol monomethyl ether diblock copolymer accounts for more than 50% of copolymer total amount.
8. the micellar preparation method of the described combination copolymer medicine of claim 1 is by medicine and polymer mixed solution are disperseed in water, remove organic solvent after, form the micellar aqueous dispersions of combination copolymer medicine, lyophilizing, its lyophilized powder; In the preparation process, medicine can be simultaneously prepares the micelle aqueous dispersions with the polymeric blends of selected two or more; Also can with medicine respectively with single polymer manufacture micelle aqueous dispersions after, will mix by the micelle aqueous dispersions of list-polymer manufacture again, obtain combination copolymer medicine micelle aqueous dispersions; Concrete steps are as follows:
(1) hydrophobic drug and amphipathic nature block polymer are dissolved in the organic solvent, or the solution of the organic solvent of hydrophobic drug is joined in the aqueous dispersions of amphipathic nature block polymer, form the solution of its mixture, the ratio of organic solvent and water is 1/1-1/100, and organic solvent is selected from volatile solvent: dichloromethane, oxolane, acetonitrile, acetone, chloroform and mixed solvent thereof;
(2) medicine of above-mentioned preparation and the solution of mixture of polymers are removed organic solvent by the solid phase fusion dispersion method, the solution that is about to medicine and mixture of polymers heats under polymer melting temperature, evaporate solvent, form the solid blend thing of polymer and medicine, add the hot water that is equivalent to polymer melting temperature then, promptly form the combination copolymer micelle aqueous dispersions of medicine under stirring or the ultrasound wave; Or remove organic solvent by solvent evaporated method, the mixed solution that is about to hydrophobic drug and amphipathic nature block polymer evaporates solvent under stirring or ultrasound wave, obtain combination copolymer medicine micelle aqueous dispersions; Or remove organic solvent by dialysis, and promptly adopt dialyser, the solution of medicine and mixture of polymers carried out dialysis with respect to water, obtain combination copolymer medicine micelle aqueous dispersions;
(3) the combination copolymer medicine micelle aqueous dispersions that adopts membrane filter that (2) are prepared filters, and obtains clarifying combination copolymer medicine micelle aqueous dispersions.
(4) the polymeric medicine micelle aqueous dispersions with (3) preparation carries out lyophilization, obtains polymeric medicine micelle freeze-drying powder, and this lyophilized powder can be scattered in the aqueous systems with the medicine micelle form again certainly, forms combination copolymer medicine micelle aqueous dispersions; This step can be according to the needs of the product that will produce, optional whether enforcement.
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| CN100539988C (en) * | 2003-06-27 | 2009-09-16 | 株式会社太平洋 | Self-aggregating polymer nanoparticles containing physiologically active ingredients and external liniment containing the same |
| US20060198891A1 (en) | 2004-11-29 | 2006-09-07 | Francois Ravenelle | Solid formulations of liquid biologically active agents |
| CN1320927C (en) * | 2005-01-27 | 2007-06-13 | 浙江大学 | Drug-loading system of polymer micelles imitating cell membrane |
| CN1961962B (en) * | 2006-11-30 | 2010-05-12 | 中国科学院长春应用化学研究所 | Amphiphilic triblock copolymer-paclitaxel bonded drug and its synthesis method |
| CN101200532B (en) * | 2006-12-12 | 2011-04-27 | 上海杰事杰新材料股份有限公司 | Method for preparing high molecular weight polycaprolactone biodegradable material hollow spheres |
| CN101880265A (en) * | 2010-06-09 | 2010-11-10 | 江南大学 | Acid-sensitive polymer micelle pharmaceutical composition and preparation method |
| CN103301072B (en) * | 2013-06-04 | 2015-07-01 | 上海中医药大学附属普陀医院 | Preparation method of sorafenib nanoparticles |
| CN103690512B (en) * | 2013-12-24 | 2016-03-09 | 浙江尖峰药业有限公司 | A kind of deoxypodophyllotoxin polymer micelle lyophilized formulations |
| CN104761710B (en) * | 2014-02-14 | 2016-06-29 | 苏州海特比奥生物技术有限公司 | A kind of mPEG-PDLLA and preparation method thereof |
| CN105982868B (en) * | 2015-12-23 | 2018-07-03 | 山东华铂凯盛生物科技有限公司 | A kind of La Luotasai water soluble powders injection and its application |
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| WO2021137610A1 (en) * | 2019-12-31 | 2021-07-08 | 주식회사 삼양홀딩스 | Method for producing nanoparticles comprising low-molecular-weight amphiphilic block copolymer |
| KR102688394B1 (en) * | 2020-12-10 | 2024-07-25 | 주식회사 삼양홀딩스 | Method for preparing polymeric micelle nanoparticle capable of reducing reconstitution time |
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