CN100998870A - Stable polymer micelle medicine carrging system - Google Patents
Stable polymer micelle medicine carrging system Download PDFInfo
- Publication number
- CN100998870A CN100998870A CNA2006101453837A CN200610145383A CN100998870A CN 100998870 A CN100998870 A CN 100998870A CN A2006101453837 A CNA2006101453837 A CN A2006101453837A CN 200610145383 A CN200610145383 A CN 200610145383A CN 100998870 A CN100998870 A CN 100998870A
- Authority
- CN
- China
- Prior art keywords
- pharmaceutical carrier
- amphipathic nature
- lipid
- polymer
- micelle
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Landscapes
- Medicinal Preparation (AREA)
Abstract
A stable polymer micella carrier system for medicines is composed of an amphipathic block copolymer including diblock copolymer and triblock copolymer and a phosphatide chosen from glyceryl phosphatide, sphingomyelin, and their derivatives.
Description
Technical field:
The present invention relates to a kind of stable mixed polymer micelle medicine carrying system and preparation thereof.
Background technology:
Polymer micelle is the drug-loading system at insoluble drug that development in recent years is got up, and has nuclear-shell-like structure, and its center is a hydrophobic parts, and shell is a hydrophilic parts.Polymer micelle can be wrapped in insoluble drug examines the solubilising that partly reaches insoluble drug.Comparing with cosolvent with solubilizing agent commonly used, is material because medicine carrying system of polymer micelle is selected Biodegradable material, and its safety is higher.
It is material that drug-carrying polymer micelle is often selected the biological degradability amphiphilic macromolecule, this class amphipathic nature polyalcohol can be diblock thing A-B type or three block thing A-B-A, the B-A-B type, its structure is seen list of references Torchilin, V.P., Structure and design of polymeric surfactant-based drug deliverysystems.J Control Release, 2001.73 (2-3): p.137-72. to have critical micelle concentration (CMC) lower for block copolymer, the characteristics that drug loading is higher, hydrophilic segment (shell) Polyethylene Glycol often wherein, polyvidone etc., lipophilic portion is polyester often, as oxypropylene, lactic acid, L-lysine, aspartic acid, β-benzoyl-L-aspartate, γ-benzyl-L-glutamate, ketone in oneself, the polymer of spermine.The hydrophilic shell part of polymer micelle can be hidden reticuloendothelial system RES and the huge removing of sneering cell system MPS of monokaryon, give the long cycle performance of polymer micelle, and low particle diameter (being generally less than 100nm) can strengthen the vascular system of blood vessel infiltration supply cancer and cause the easier delay tumor of material, be high-permeability and high anelasticity (the enhanced permeation and retention that Maeda etc. proposes, EPR), give the targeting of polymer micelle to tumor.
Normal direct water dissolution, the dialysis of adopting of straight polymer micelle prepares.This depends primarily on the dissolubility of polymer in water, and the polymer of good water solubility can directly be dissolved in water under room temperature or the high temperature when concentration is higher than CMC, forms the micellar solution of transparent clarification (or slightly light blue opalescence); The polymer of poorly water-soluble then need be dissolved in earlier in the mixed solution that is formed by water and organic solvent, and organic solvent is removed in dialysis again, makes micelle.
In the drug-carrying polymer micelle preparation process, the embedding of medicine is relevant with the character of micelle, medicine.Because hydrophobic interaction is the main drive of medicament solubilization, thereby the micelle hydrophobic chain increases and the enhancing of medicine hydrophobicity all can make micellar drug loading rise; But long hydrophobic chain can make the micelle particle diameter become big, is easily destroyed by reticuloendothelial system, reduces micelle stability.
The preparation method of drug-carrying polymer micelle generally has following several:
1, physically trapping method: this is the most frequently used method, comprises dialysis and oil/water-intra-liquid desiccation method.Preceding method is that medicine and polymer are dissolved in a kind of organic solvent, and the dialysis of reuse water is removed organic solvent fully, and the shortcoming of this method is medicine and the fractional precipitation of micelle meeting generating unit, has influenced medicine amount of wrapping into and medicine carrying efficient.Back method is that the medicine that will be dissolved in organic solvent dropwise adds in the micellar aqueous solution, and organic solvent is removed in volatilization makes medicine enter the micelle kernel.
2, chemical bond method: utilize the hydrophobic chain functional group of drug molecule and polymer that chemical reaction takes place under certain condition, the medicine covalent bonding on polymer, is prepared with direct dissolution method or dialysis then.Utilize the amino of amycin and carboxyl generation condensation reaction under coupling agent 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide (EDC) effect of PEG-aspartate copolymer to make micelle such as [11] such as Yokoyama.
3, electrostatic interaction method: utilize the polymer micelle hydrophobic region of medicine and oppositely charged to combine closely, make micelle by electrostatic force.This method is made simple, and the gained micelle is stable, satisfies but condition is difficult, uses few.
4, gel-redissolution method: this method beginning sees the report of Canadian X.Zhang, and (document Zhang sees reference, X., et al., Anti-tumor efficacy and biodistribution of intravenouspolymeric micellar paclitaxel.Anticancer Drugs, 1997.8 (7): p.696-701.), soon medicine, block copolymer are dissolved in organic solvent, under rotary evaporation, remove organic solvent, can obtain gelling material, add the water redissolution and can directly prepare drug-carrying polymer micelle.
5, emulsifying-solvent evaporated method: soon block copolymer, medicine are dissolved in the polar solvent, and polar solvent comprises acetonitrile, ethanol, dimethyl sulfoxine (DMSO), dimethyl formamide, methanol etc.Under agitation slowly drip water and make into the W/O microemulsion, the phase volume ratio of oil phase and water is usually greater than 50/50 at this moment.Under agitation further splash into the water of capacity, make the variation generation inversion of phases of microemulsion because of phase volume ratio, generate the O/W microemulsion, the phase volume ratio of oil phase and water is usually less than 50/50 at this moment.About 60 ℃, boil off organic solvent under the vacuum condition and get the carrier micelle system.Look stability of drug further filtration sterilization or pressure sterilizing for injection.(mPEG-PDLLA (mPEG-PDLLA) micelle sees reference document Zhang by Canadian X.Zhang report the earliest, X., et al., Anti-tumor efficacy andbiodistribution of intravenous polymeric micellar paclitaxel.AnticancerDrugs, 1997.8 (7): p.696-701.), because its ideal property of solubilizing and EPR behavior have attracted extensive concern, and apply for a patent US5877205 and US5922754.Document Yamamoto sees reference, Y., etal., Long-circulating poly (ethylene glycol)-poly (D, L-lactide) blockcopolymer micelles with modulated surface charge.J Control Release, 2001.77 (1-2): p.27-38.Samyang the Genexol PM of company is to be the paclitaxel polymer of material with mPEG-PDLLA, external better with the intravital biocompatibility of animal, do not see overt toxicity, the experiment that distributes in the paclitaxel isotope body shows, micelle dissociates rapidly after entering in the body, discharges medicine, and polymer can be degraded in 15 hours in vivo.Document Kim sees reference, S.C., et al., In vi vo evaluation ofpolymeric micellar paclitaxel formulation:toxicity and efficacy.JControl Release, 2001.72 (1-3): p.191-202, Genexol PM entered clinical research in 2002 by the FDA approval.
Yet the drug loading and the stability of existing drug-carrying polymer micelle are not high, and general drug loading has only 30%, the polymer micelle less stable after the aqueous dispersion, and medicine is easily revealed, and its physical stability is not high still to influence its further popularization.
With the paclitaxel is that example is when adopting mPEG-PDLLA 55/45 (X/Y, X are the quality of PEG, and Y is the quality of polylactide) preparation paclitaxel polymer micelle, the stability of its aqueous dispersions has only 24 hours, during to 72 hours, surpass 30% medicine leakage, see patent US20030143184.
The method that solves drug-carrying polymer micelle stability at present mainly is to select from polymer.We have applied for a kind of new polymer micelle in Chinese patent CN03105348.3, adopt mPEG, PDLLA mass ratio to prepare polymer micelle less than 50/50 block copolymer, this polymer micelle can improve drug loading and micellar stability owing to increased the lipotropy of nuclear.U.S. Pat 20030143184 adopts the method that the polylactide terminal hydroxyl in the mPEG-PDLLA structure is modified with lipophilic group to improve the lipotropy of nuclear, then improve the stability of paclitaxel polymer micelle, the stability of the aqueous dispersions of this polymer micelle can reach 72 hours.
Although said method can improve the stability of polymer micelle to a certain extent, degree is limited.We are unexpected in test to find that the mixed polymer micelle can improve the physical stability of polymer micelle.This mixed polymer micelle mainly is made up of block polymer, wherein contains lipid components, for example phospholipid, cholesterol, oils and fats etc.
Phospholipid is a kind of liposome component commonly used, has the high characteristics of biocompatibility.Phospholipid can be divided into two big classes: sphingomyelins (sphingomyelins lipid sphyngomyelin) and phosphoglyceride (phosphatide orphosphalipid).Phosphoglyceride is made up of glycerol, fatty acid, phosphoric acid and a part amino alcohol (as choline, ethanolamine, serine or inositol).Sphingomyelins has just replaced glycerol with sphingol.
But (PC) (there are Semen sojae atricolor, brain, seminal fluid, adrenal gland, erythrocyte in the source according to the different phosphoglyceride phosphatidylcholines (lecithin) of amino alcohol, egg yolk, have control liver lipid metabolism, prevent the effect of the formation of fatty liver), PHOSPHATIDYL ETHANOLAMINE (cephalin) (PE) (has the effect that participates in blood clotting), Phosphatidylserine (PS), phosphatidylinositols (PI), phosphatidyl glycerol (PG), diphosphatidylglycerol (cuorin).
In recent years, the PEGization of phospholipid has been prepared medicine carrying phospholipid micelle, yet its drug loading is lower.Block copolymer PEO-PPO-PEO is proved to be the form and the performance that can change the phospholipid bilayer film, see document Torben Ish yand Kell Mortensen, Lamellar-to-Cubic Phase Change in PhospholipidBilayer Systems Incorporated with Block Copolymers:DMPC and PEO-PPO-PEO (P85), Langmuir 2005,21,1766-1775.
So far the micellar report of mixed polymer still.
Summary of the invention:
The object of the present invention is to provide a kind of pharmaceutical carrier, described pharmaceutical carrier is the mixed polymer micelle, promptly is made up of amphipathic nature block polymer and lipid, and this pharmaceutical carrier has the advantages that drug loading is big and stability is high.
Pharmaceutical carrier of the present invention, amphipathic nature block polymer wherein belongs to prior art, can comprise diblock thing and three block things, constitute the amphipathic nature block polymer hydrophilic area and include but not limited to Polyethylene Glycol (PEG), monomethyl Polyethylene Glycol (mPEG), polyvidone, chitosan, polymethylacrylic acid etc. and derivant thereof.Hydrophobic region includes but not limited to polyoxypropylene, polystyrene, polyamino acid (as poly-β-benzoyl-L-aspartic acid, poly-γ-benzyl-L-glutamic acid and poly-aspartate etc.), polyester (polycaprolactone), and available Biodegradable macromolecular material (as polylactic acid, polyglycolic acid and derivant thereof etc.) is as the hydrophobic block of copolymer.Wherein preferred amphipathic nature block polymer is: monomethyl Polyethylene Glycol-b-gathers D, L-lactide copolymer (mPEG-PDLLA).Pharmaceutical carrier of the present invention, the method for amphipathic nature block polymer wherein can adopt aforementioned gel-redissolution method, also can adopt aforesaid emulsifying-solvent evaporated method, wherein preferred gel-redissolution method.
Pharmaceutical carrier of the present invention, lipid wherein comprise phospholipid, cholesterol and other oils and fats material.Phospholipid is selected from phosphoglyceride or sphingomyelins and derivant thereof.The phospholipid that phosphoglyceride is made up of glycerol, fatty acid, phosphoric acid and a part amino alcohol (as choline, ethanolamine, serine or inositol).Sphingomyelins is the phospholipid that has replaced glycerol to obtain with sphingol.According to the different phosphoglycerides of amino alcohol comprise phosphatidylcholine (lecithin) (PC) (there are Semen sojae atricolor, brain, seminal fluid, adrenal gland, erythrocyte in the source, egg yolk), PHOSPHATIDYL ETHANOLAMINE (cephalin) (PE), Phosphatidylserine (PS), phosphatidylinositols (PI), phosphatidyl glycerol (PG), diphosphatidylglycerol (cuorin).The present invention is preferential to be phosphatidylcholine (lecithin).
Pharmaceutical carrier of the present invention, the amphipathic nature block polymer wherein and the proportioning of lipid are 100/0.01-100/99.99, wherein preferred 100/0.5-100/30, most preferably 100/1-100/15.
Pharmaceutical carrier of the present invention can prepare by the following method, and amphipathic nature block polymer and lipid (as phospholipid) are used organic solvent dissolution.Promptly obtain gel mixed polymer micelle pharmaceutical carrier of the present invention after removing organic solvent.Wherein said organic solvent is meant nonaqueous solvent, is selected from but is not limited to: acetonitrile, short chain fatty alcohol, acetone, ether etc.
Pharmaceutical carrier of the present invention also can be in the pharmaceutical compositions process of preparing, as medicine and amphipathic nature block polymer and phospholipid are used organic solvent dissolution jointly.Promptly obtain gel mixed polymer micelle pharmaceutical composition of the present invention after removing organic solvent, the further redissolution of said composition can obtain being lower than the mixed polymer micelle (can reach the state that is lower than 100nm by high speed homogenizationization or the homogenize of high pressure breast if particle diameter is excessive) of 100nm, this polymer micelle can be by certain technology, further be prepared into suitable formulations as lyophilization, spray drying, rotary evaporation, reduction vaporization, thin film evaporation etc., as injection, eye drop, external preparation, oral formulations, aerosol, powder spray etc.
Pharmaceutical carrier of the present invention can one or more medicines of load, comprise various hydrophobic drugs and hydrophilic medicament, hydrophobic drug preferably, and more preferably following medicine:
Antitumor drug: as paclitaxel, 5-fluorouracil, etoposide, melphalan, chlorambucil, hexamethylmelamine, methotrexate, CH3-CCNU, NVB, teniposide, homoharringtonine, hydroxycamptothecin etc.;
Antibiotic medicine: as chloromycetin, erythromycin, erythromycin estolate, erythromycin ethylsuccinate, midecamycin, josamycin, clarithromycin, rokitamycin, sulfadiazine, trimethoprim, nitrofurantoin, sharp secondary flat, rifaximin, Rifandin, dapsone, acedapsone, narrow health azoles etc.;
Cardiovascular drugs: as nifedipine, nicardipine, nitrendipine, nilvadipine, cinnarizine, perhexiline, molsidomine, digitophyllin, digoxin, cedilanid, deacetyllanatoside, Propafenone, amiodarone, nitroglycerin, pentaerithrityl tetranitrate, cyclandelate, tocopheryl nicotinate etc.;
Antidiabetic medicine: as the yellow butyl urea of toluene, glibenclamide, glipizide etc.;
Nonsteroidal anti-inflammatory drug: drain dry spit of fland, Cyproheptadine, pizotifen, ketotifen, Qu Nisi etc. as the chlorine horse.Pharmaceutical carrier of the present invention is when carrying medicament, medicament mixed together, preferable methods is that pharmaceutical carrier of the present invention and medicine are dissolved in the solvent together, preferred organic solvent, again solvent is removed, obtain the mixed gel shape compositions of pharmaceutical carrier of the present invention and medicine, said composition can further be processed into pharmaceutical preparation, and the process of processing pharmaceutical preparation belongs to prior art, as with the injection solution dissolving, make injection.Wherein said organic solvent is meant nonaqueous solvent, be selected from but be not limited to: acetonitrile, short chain fatty alcohol, acetone, pharmaceutical carrier of the present invention such as ether, wherein the derivant of block copolymer hydrophilic area is meant and adopts some organ hydrophilic area is terminal, tissue, cell, organelle, the derivant that molecule has the molecular modification of pathoklisis to obtain comprises protein or polypeptide with tissue or cell-specific, somatomedin, vitamin and analog thereof (as folic acid), polysaccharide, glycopeptide or glycoprotein, steroidal and analog thereof, hormone, cofactor, genetic molecule, the some drugs molecule.As to brain special contain CNSRLHLRC, CENWWGDVC, the segmental polypeptide of WRCVLREGPAGGCAWFNRHRL and CLSSRLDAC, protein; Kidney-specific contained CLPVASC and the segmental polypeptide of CGAREMC, protein; To lung special contain CGFECVRQCPERC, CGFELETC, the segmental polypeptide of CTLRDRNC and CIGEVEVC, protein; To skin special contain the segmental polypeptide of CVALCREACGEGC, protein; To spleen special contain the segmental polypeptide of SWCEPGWCR, protein; To small intestinal special contain the segmental polypeptide of YSGKWGW, protein, to the uterus special contain the segmental polypeptide of GLSGGRS, protein; To the adrenal gland special contain the segmental polypeptide of LMLPRAD, protein; To retinal tissue special contain CRDVVSVIC and the segmental polypeptide of CSCFRDVCC, protein; Have the polypeptide, the protein that suppress integral protein express cell and extracellular matrix protein combination, this proteinoid or polypeptide contain CRGDC, CRGDCL, NGR (AHA), DGR (AHA), CRGDCA, RCDVVV, SLIDIP, TIRSVD, KRGD, RRGP and RGDL fragment; Antibody with tumour-specific; To the solid tumor tunica intima special contain CDCRGDCFC and the segmental polypeptide of CNGRCVSGCAGRC, protein; And other have the molecule of special affinity to tumor cell.
Pharmaceutical carrier of the present invention compared with prior art its advantage is that drug loading is big and stability is high, can obtain proof by the mensuration of micelle particle diameter among the embodiment and the mensuration of medicament contg.The assay method of the micelle particle diameter that relates among the present invention be dynamic light scattering method (dynamic light scattering, DLS).
Description of drawings:
The NMR figure of Fig. 1 mPEG-PDLLA
The changes of contents that room temperature was placed after Fig. 2 etoposide mixed polymer micelle redissolved
The changes of contents that room temperature was placed after Fig. 3 paclitaxel mixed polymer micelle redissolved
The specific embodiment:
Be the embodiment of this patent below, but following embodiment does not limit the interest field of putting this patent.
Take by weighing methyl Polyethylene Glycol 16g and lactide 24g, place airtight reactor, add stannous octoate 50mg toluene solution (2mL), be warming up to 120-140 ℃ and make the solid fusing and remove toluene under stream of nitrogen gas, elevated temperature was to 150-180 ℃ of reaction 6 hours.Cooling gets the white solid crude product.Crude product under agitation adds in the 100ml ether after dissolving with dichloromethane 1ml, filters, and ether washing three times, product vacuum drying 24 hours gets final product.
The quality that the NMR of product (the D-chloroform is a solvent) collection of illustrative plates is confirmed methyl Polyethylene Glycol in the polymer and polylactic acid with 5.2ppm (PLA) and 3.6ppm (PEG) peak area ratio is molecular weight (Fig. 1) when.
Embodiment micellar preparation of 2 etoposide mixed polymers and particle size determination
Take by weighing 1g etoposide, 2g mPEG-PDLLA and lecithin 100mg respectively and place flask, add acetonitrile 200ml, be stirred to dissolving.Slowly boil off acetonitrile (Rotary Evaporators) under 60 ℃, vacuum, after waiting not have obvious acetonitrile and steaming, elevated temperature and vacuum continue to remove acetonitrile and get colourless gelling material.Add 60 ℃ of waters for injection to 150ml, aquation must have light blue opalescent mixed polymer micellar solution.Product promptly gets etoposide mixed polymer micelle (etoposide, mPEG-PDLLA and lecithin, every bottle of 30mg etoposide) with 0.22mm microporous filter membrane Entkeimung postlyophilization.
Take by weighing the 400mg etoposide respectively, 1gmPEG-PDLLA places flask, adds acetonitrile 200ml, is stirred to dissolving.Slowly boil off acetonitrile (Rotary Evaporators) under 60 ℃, vacuum, after waiting not have obvious acetonitrile and steaming, elevated temperature and vacuum continue to remove acetonitrile and get colourless gelling material.Add 60 ℃ of waters for injection to 150ml, aquation must have light blue opalescent polymer micelle solution.Product with 0.22mm microporous filter membrane Entkeimung postlyophilization get final product etoposide polymer micelle (relying on pool and mPEG-PDLLA, every bottle of 30mg etoposide).
Use Ma Erwen particle size determination instrument, adopt the dynamic light scattering law technology, use ZetaSize 3000HS software that the result is handled, record respectively that the micellar micelle particle diameter of etoposide polymer micelle and mixed polymer is respectively 46.30,81.40nm.
The micellar preparation of embodiment 3 paclitaxel mixed polymers
Take by weighing 300mg paclitaxel, 1g mPEG-PDLLA and lecithin 100mg respectively and place flask, add acetonitrile 150ml, be stirred to dissolving.Slowly boil off acetonitrile (Rotary Evaporators) under 60 ℃, vacuum, after waiting not have obvious acetonitrile and steaming, elevated temperature and vacuum continue to remove acetonitrile and get colourless gelling material.Add 60 ℃ of waters for injection to 150ml, aquation must have light blue opalescent mixture, through 12000rpm high speed homogenizer homogenize 30 seconds, obtains mixed polymer micellar solution.Product with 0.22mm microporous filter membrane Entkeimung postlyophilization get final product paclitaxel mixed polymer micelle (paclitaxel, mPEG-PDLLA and lecithin, every bottle of 30mg paclitaxel).
Take by weighing the 300mg paclitaxel respectively, 1gmPEG-PDLLA places flask, adds acetonitrile 150ml, is stirred to dissolving.Slowly boil off acetonitrile (Rotary Evaporators) under 60 ℃, vacuum, after waiting not have obvious acetonitrile and steaming, elevated temperature and vacuum continue to remove acetonitrile and get colourless gelling material.Add 60 ℃ of waters for injection to 150ml, aquation must have light blue opalescent polymer micelle solution.Product with 0.22mm microporous filter membrane Entkeimung postlyophilization get final product paclitaxel polymer micelle (paclitaxel and mPEG-PDLLA, every bottle of 30mg paclitaxel).Use Ma Erwen particle size determination instrument, adopt the dynamic light scattering law technology, use ZetaSize 3000HS software that the result is handled, the particle diameter that records paclitaxel polymer micelle, mixed micelle respectively is 47.35 and 72.10nm.
Getting etoposide polymer micelle, mixed polymer micelle respectively adds 0.9% sodium chloride injection and redissolves and be diluted to etoposide 1mg/mL, mixing.Sample places 25 ℃ of calorstats and cold preservation (4 ℃), and respectively at 24,36,48,60,72,96,120 hours, sampling was filtered, and gets subsequent filtrate, measures etoposide content respectively, the results are shown in Figure 2.As seen, the micellar stability of mixed polymer is significantly improved.
The HPLC method is measured the content of etoposide: chromatographic column is μ Bondpak
TMPhenyl post, mobile phase are acetonitrile-0.02mol.L-1 ammonium dihydrogen phosphate (22: 78), and regulate pH value to 2.5 with phosphoric acid, and flow velocity is 1.0ml/min, and the detection wavelength is 230nm.
Getting paclitaxel polymer micelle, mixed polymer micelle respectively adds 0.9% sodium chloride injection and redissolves and be diluted to paclitaxel 1mg/mL, mixing.Sample places 25 ℃ of calorstats and cold preservation (4 ℃), and respectively at 24,36,48,60,72,96,120 hours, sampling was filtered, and gets subsequent filtrate, measures content of taxol respectively, the results are shown in Figure 3.As seen, the micellar stability of mixed polymer is significantly improved.The HPLC method is measured the content of paclitaxel:
Chromatographic column: ODS (Lichrospher-C18,250 * 4.6mm, 5 μ m)
Mobile phase: methanol-acetonitrile-water (30: 40: 32)
Flow velocity: 1.0ml/min detects wavelength: 226nm
Sensitivity: 1.000AUFS column temperature: 30 ℃.
Claims (10)
1, a kind of pharmaceutical carrier is characterized in that, described pharmaceutical carrier is the mixed polymer micelle, promptly is made up of amphipathic nature block polymer and lipid.
2, the pharmaceutical carrier of claim 1, it is characterized in that, wherein amphipathic nature block polymer comprises diblock thing and three block things, constitutes the amphipathic nature block polymer hydrophilic area and includes but not limited to Polyethylene Glycol, monomethyl Polyethylene Glycol, polyvidone, chitosan, polymethylacrylic acid etc. and derivant thereof; Hydrophobic region then comprises it being polyoxypropylene, polystyrene, polyamino acid, polyester, available Biodegradable macromolecular material.
3, the pharmaceutical carrier of claim 1 is characterized in that, lipid wherein comprises phospholipid, cholesterol and other oils and fats material.Phospholipid is selected from phosphoglyceride or sphingomyelins and derivant thereof.
4, the pharmaceutical carrier of claim 3, it is characterized in that, phosphoglyceride wherein is made up of glycerol, fatty acid, phosphoric acid and a part amino alcohol, and phosphoglyceride is selected from phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, Phosphatidylserine, phosphatidylinositols, phosphatidyl glycerol, diphosphatidylglycerol; Sphingomyelins is the phospholipid that has replaced glycerol to obtain with sphingol.
5, the pharmaceutical carrier of claim 3 is characterized in that, the amphipathic nature block polymer wherein and the proportioning of lipid are 100/0.01-100/99.99.
6, the pharmaceutical carrier of claim 5 is characterized in that, the amphipathic nature block polymer wherein and the proportioning of lipid are 100/0.5-100/30.
7, the pharmaceutical carrier of claim 6 is characterized in that, the amphipathic nature block polymer wherein and the proportioning of lipid are 100/1-100/15.
8, the pharmaceutical carrier of claim 7 is characterized in that, by the poly-D of monomethyl Polyethylene Glycol-b-, L-lactide copolymer and lecithin are formed, and proportioning is 100/1-100/15.
9, the pharmaceutical carrier of claim 3 is characterized in that, can the load hydrophobic drug, comprise antitumor drug, antibiotic medicine, cardiovascular drugs, antidiabetic medicine, nonsteroidal anti-inflammatory drug.
10, the preparation of drug carriers method of claim 1 is characterized in that, process following steps: amphipathic nature block polymer and lipid organic solvent dissolution; Remove organic solvent and obtain spawn, obtain the mixed polymer micelle through redissolution.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200610145383A CN100589843C (en) | 2006-11-27 | 2006-11-27 | Stable polymer micelle medicine carrging system |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200610145383A CN100589843C (en) | 2006-11-27 | 2006-11-27 | Stable polymer micelle medicine carrging system |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN100998870A true CN100998870A (en) | 2007-07-18 |
| CN100589843C CN100589843C (en) | 2010-02-17 |
Family
ID=38257742
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200610145383A Expired - Fee Related CN100589843C (en) | 2006-11-27 | 2006-11-27 | Stable polymer micelle medicine carrging system |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100589843C (en) |
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101829046A (en) * | 2010-05-21 | 2010-09-15 | 中国医学科学院生物医学工程研究所 | Amphipathilic block polymer micelle nano medicament carrying system and preparation method |
| WO2010121455A1 (en) * | 2009-04-21 | 2010-10-28 | 财团法人工业技术研究院 | A drug composition for treating tumor with polymeric micelle encapsulating antineoplastic |
| CN101507706B (en) * | 2009-03-24 | 2011-07-20 | 涂家生 | Biodegradable in-situ solidification sustained-release injector |
| CN102311512A (en) * | 2010-07-09 | 2012-01-11 | 国家纳米科学中心 | Cyclodextrin-aliphatic polyester-phosphatidyl ethanolamine graft polymer and preparation method thereof |
| CN102961322A (en) * | 2012-10-12 | 2013-03-13 | 杭州普施康生物科技有限公司 | Drug-loaded mixed micelle |
| CN103421204A (en) * | 2013-08-20 | 2013-12-04 | 常州大学 | Surface-amphiphilic polyester film and preparation method thereof |
| CN103461359A (en) * | 2013-09-26 | 2013-12-25 | 卞佳林 | Preparation method for spinosad/avilamycin composite polymeric micelle insecticide |
| CN103479573A (en) * | 2013-07-26 | 2014-01-01 | 中国科学院长春应用化学研究所 | Preparation methods for polyethylene glycol monomethyl ether-polyester diblock copolymer micelle and drug-loaded micelle |
| CN103478145A (en) * | 2013-09-26 | 2014-01-01 | 卞佳林 | Spinosyn and avermectin composite polymeric micellar pesticide |
| CN107735170A (en) * | 2015-04-02 | 2018-02-23 | 南洋理工大学 | Tubulose and imitated vesicle structure that polvmeric lipid blend is formed and forming method thereof |
| CN109821024A (en) * | 2019-04-08 | 2019-05-31 | 沈阳药科大学 | ROS producing agent and oxidation response anti-tumor predrug carry micella and its application altogether |
| CN112472686A (en) * | 2020-12-07 | 2021-03-12 | 中国药科大学 | Lipid nanoparticle of PEG-PLA-SN38 linker and preparation method thereof |
| CN116570734A (en) * | 2023-07-13 | 2023-08-11 | 四川大学华西医院 | Core-shell structured drug micelle with targeting function and preparation method thereof |
-
2006
- 2006-11-27 CN CN200610145383A patent/CN100589843C/en not_active Expired - Fee Related
Cited By (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101507706B (en) * | 2009-03-24 | 2011-07-20 | 涂家生 | Biodegradable in-situ solidification sustained-release injector |
| WO2010121455A1 (en) * | 2009-04-21 | 2010-10-28 | 财团法人工业技术研究院 | A drug composition for treating tumor with polymeric micelle encapsulating antineoplastic |
| US8420119B2 (en) | 2009-04-21 | 2013-04-16 | Industrial Technology Research Institute | Drug composition for treating tumor with polymeric micelle encapsulating anti-neoplastic |
| CN101829046A (en) * | 2010-05-21 | 2010-09-15 | 中国医学科学院生物医学工程研究所 | Amphipathilic block polymer micelle nano medicament carrying system and preparation method |
| CN102311512A (en) * | 2010-07-09 | 2012-01-11 | 国家纳米科学中心 | Cyclodextrin-aliphatic polyester-phosphatidyl ethanolamine graft polymer and preparation method thereof |
| CN102311512B (en) * | 2010-07-09 | 2013-04-03 | 国家纳米科学中心 | Cyclodextrin-aliphatic polyester-phosphatidyl ethanolamine graft polymer and preparation method thereof |
| CN102961322A (en) * | 2012-10-12 | 2013-03-13 | 杭州普施康生物科技有限公司 | Drug-loaded mixed micelle |
| CN103479573B (en) * | 2013-07-26 | 2017-04-19 | 中国科学院长春应用化学研究所 | Preparation methods for polyethylene glycol monomethyl ether-polyester diblock copolymer micelle and drug-loaded micelle |
| CN103479573A (en) * | 2013-07-26 | 2014-01-01 | 中国科学院长春应用化学研究所 | Preparation methods for polyethylene glycol monomethyl ether-polyester diblock copolymer micelle and drug-loaded micelle |
| CN103421204A (en) * | 2013-08-20 | 2013-12-04 | 常州大学 | Surface-amphiphilic polyester film and preparation method thereof |
| CN103461359A (en) * | 2013-09-26 | 2013-12-25 | 卞佳林 | Preparation method for spinosad/avilamycin composite polymeric micelle insecticide |
| CN103478145A (en) * | 2013-09-26 | 2014-01-01 | 卞佳林 | Spinosyn and avermectin composite polymeric micellar pesticide |
| CN107735170A (en) * | 2015-04-02 | 2018-02-23 | 南洋理工大学 | Tubulose and imitated vesicle structure that polvmeric lipid blend is formed and forming method thereof |
| CN109821024A (en) * | 2019-04-08 | 2019-05-31 | 沈阳药科大学 | ROS producing agent and oxidation response anti-tumor predrug carry micella and its application altogether |
| CN112472686A (en) * | 2020-12-07 | 2021-03-12 | 中国药科大学 | Lipid nanoparticle of PEG-PLA-SN38 linker and preparation method thereof |
| CN116570734A (en) * | 2023-07-13 | 2023-08-11 | 四川大学华西医院 | Core-shell structured drug micelle with targeting function and preparation method thereof |
| CN116570734B (en) * | 2023-07-13 | 2023-10-13 | 四川大学华西医院 | Core-shell structured drug micelle with targeting function and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN100589843C (en) | 2010-02-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN100589843C (en) | Stable polymer micelle medicine carrging system | |
| Cagel et al. | Polymeric mixed micelles as nanomedicines: Achievements and perspectives | |
| Bose et al. | Nanomicelles: Types, properties and applications in drug delivery | |
| Siew et al. | Enhanced oral absorption of hydrophobic and hydrophilic drugs using quaternary ammonium palmitoyl glycol chitosan nanoparticles | |
| Li et al. | A bio‐inspired rod‐shaped nanoplatform for strongly infecting tumor cells and enhancing the delivery efficiency of anticancer drugs | |
| Bonacucina et al. | Colloidal soft matter as drug delivery system | |
| Ahmed et al. | Shrinkage of a rapidly growing tumor by drug-loaded polymersomes: pH-triggered release through copolymer degradation | |
| CN101972480B (en) | Docetaxel polymeric micelle medicine composition taking amino acid as stabilizing agent | |
| CN101773465B (en) | Polymer micelle medicine carrying system using amino acid as stabilizing agent | |
| Xu et al. | Glutathione-responsive polymeric micelles formed by a biodegradable amphiphilic triblock copolymer for anticancer drug delivery and controlled release | |
| Aliabadi et al. | Micelles of methoxy poly (ethylene oxide)-b-poly (ɛ-caprolactone) as vehicles for the solubilization and controlled delivery of cyclosporine A | |
| Pippa et al. | DPPC: MPOx chimeric advanced Drug Delivery nano Systems (chi-aDDnSs): Physicochemical and structural characterization, stability and drug release studies | |
| US20080181939A1 (en) | Polymersomes and related encapsulating membranes | |
| Kore et al. | Polymeric micelle as multifunctional pharmaceutical carriers | |
| Deshpande et al. | Enhancing cubosome functionality by coating with a single layer of poly-ε-lysine | |
| He et al. | Poly (ethylene glycol)-block-poly (ε-caprolactone)–and phospholipid-based stealth nanoparticles with enhanced therapeutic efficacy on murine breast cancer by improved intracellular drug delivery | |
| Tao et al. | Reduction-responsive gold-nanoparticle-conjugated Pluronic micelles: an effective anti-cancer drug delivery system | |
| CZ20024268A3 (en) | Preparation producing micelles | |
| Li et al. | Preparation and properties of mixed micelles made of Pluronic polymer and PEG-PE | |
| Kapare et al. | Micellar drug delivery system: a review | |
| Pippa et al. | DPPC/poly (2-methyl-2-oxazoline)-grad-poly (2-phenyl-2-oxazoline) chimeric nanostructures as potential drug nanocarriers | |
| Sawant et al. | Polymeric micelles: polyethylene glycol-phosphatidylethanolamine (PEG-PE)-based micelles as an example | |
| Kontogiannopoulos et al. | Advanced drug delivery nanosystems for Shikonin: a calorimetric and electron paramagnetic resonance study | |
| Waglewska et al. | Self-assembled bilosomes with stimuli-responsive properties as bioinspired dual-tunable nanoplatform for pH/temperature-triggered release of hybrid cargo | |
| Lee et al. | Ionically fixed polymeric nanoparticles as a novel drug carrier |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Application publication date: 20070718 Assignee: Sichuan Taiji Pharmaceutical Co., Ltd. of Taiji Group Assignor: Tu Jia|Wu Jianmei Contract record no.: 2014500000056 Denomination of invention: Stable polymer micelle medicine carrging system Granted publication date: 20100217 License type: Common License Record date: 20140804 |
|
| LICC | Enforcement, change and cancellation of record of contracts on the licence for exploitation of a patent or utility model | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20100217 Termination date: 20161127 |