CN103601878B - High-stability polyethylene glycol-polyester polymer and application thereof - Google Patents
High-stability polyethylene glycol-polyester polymer and application thereof Download PDFInfo
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Abstract
The invention belongs to the field of medical technology, relates to a high-stability polyethylene glycol-polyester polymer and an application thereof, and particularly relates to an amphiphilic block copolymer having a hydrophilic block and a hydrophobic block with terminal hydroxyl, wherein the terminal hydroxyl of the hydrophobic block is replaced by a cholic acid group. The hydrophilic A block is any one of ethylene glycol monomethyl ether, polyethylene glycol, polyvinyl alcohol and polyvinylpyrrolidone; the hydrophobic B block is any one of polylactide, polylactide-co-glycolide, polyglycollide, polycaprolactone, polylactide-co-caprolactone, polyglycollide-co-caprolactone and polylactide-co-glycolide-cocaprolactone. The polymer provided by the invention can spontaneously form high-stability micelle in a waterborne medium, and can be used as a carrier of various water-insoluble drugs.
Description
Technical field
The present invention relates to a kind of High-stability polyethylene glycol-polyester polymer and application thereof, be specifically related to amphipathic nature block polymer and the application thereof of the hydrophobic B Hock comprising hydrophilic A Hock and there is terminal hydroxyl.
Background technology
Polymer micelle transports carrier as the effective medicine of one and is subject to extensive concern, and polymer micelle is that it has the typical structure of hydrophobic cores and wetting ability shell by amphipathic macromolecular material spontaneous a kind of self-assembled structures formed in water.Wherein, hydrophobic block forms the hydrophobic cores of bag medicine carrying thing, and hydrophilic block surrounds outer formation wetting ability shell and plays protective effect.Compared with other carrier, block copolymer micelle tool has the following advantages: (1) particle diameter is less, make it not easily to be engulfed by reticuloendothelium RES, thus can circulate in blood for a long time and keep stable, see Weissig V, Whiteman KR, Torchilin VP. Accumulation of protein-loaded long-circulating micelles and liposomes in subcutaneous Lewis lung carcinoma in mice [J]. Pharm Res, 1998,15 (10): 1552-1556.; (2) nano level particle diameter makes carrier micelle show better cell-penetrating ability at target position, with reference to Maeda H, Wu J, Sawa T,
et al. Tumor vascular permeability and the EPR effect in macromolecular therapeutics:a review [J]. J Control Release, 2000,65 (1-2): 271-284.; (3) there is lower micelle-forming concentration (CMC) value, with reference to Lavasanifar A, Samuel J, Kwon GS. Poly (ethylene oxide)-block-poly (L-amino acid) micelles for drug delivery [J]. Adv Drug Deliv Rev, 2002,54 (2): 169-190, in blood circulation, not easily destroyed micellar structure by hemodilution, more stable; (4) solubilising insoluble drug; insoluble drug is wrapped in the kernel of polymer micelle; improve bioavailability; because there is the protection of hydrophilic segment macromole micella outside; make it not easily adsorb with protein and phagocytic cell and identify; the not easily inactivation because of enzyme liberating, thus ensure, in blood plasma and the residence time in tissue, to reach the effect of passive target by increasing infiltration and retention effect.
Have in the pharmaceutical carrier of the nanosized of water-wetted surface at these, polymer micelle generally includes a hundreds of segmented copolymer, and diameter is approximately 20nm to 100nm.Polymer micelle have two spherical common-central zone, be responsible for load dewatering medicament dense arrangement hydrophobic substance core and the shell be made up of hydrophilic substance hiding health RES can be cycled to used in blood for a long time.Although they have, unique advantage such as size is little, solubleness is high, sterilizing is simple and Drug controlled release, and owing to may occur that the medicine combined is quickly released in vivo, therefore the physical stability of these carriers is key issues.
If the concentration of multipolymer is on micelle-forming concentration (CMC), so micella is exactly thermodynamically stable.Like this, the copolymer systems with low CMC value is used just may to improve the body internal stability of micella.Kinetic stability refers to the rate of decomposition of micella.Rate of decomposition depends on the physical condition of micelle cores.The micella than those with low glass state invert point dissociates slowly by the micella formed by the multipolymer comprising the hydrophobic block with high glass transition temperature.They also may be subject to many impacts that can affect the same factor of single aggressiveness rate of exchange between micella.Have been found that the rate of exchange of single aggressiveness depends on the hydrophobic content of solvent in many factors such as core, multipolymer and length that is hydrophilic and hydrophobic block.
Existing poly glycol monomethyl ether-polylactide (mPEG-PDLLA) polymer micelle enters clinical investigation phase because it has good biocompatibility.In clinical precursor, research shows that the mPEG-PDLLA polymer micelle carrying taxol is compared to free paclitaxel, and its maximum tolerated dose (MTD) improves 3 times.In the tissue comprising liver,spleen,kidney taxol drug concentration be the 2-3 of free paclitaxel doubly.But its physical stability is poor, namely carrier micelle starts to occur obvious drug leakage at room temperature 24 hours, and drug loading significantly reduces.Due to the existence of this shortcoming, this drug delivery system is all limited by very large in preparation, preservation and clinical application.Such as in preparation process, the temperature of aquation needs to control, below 35 degrees Celsius, can not contact high temperature in sterilization process.In preservation, carrier micelle can only keep stable within 24 hours, therefore can not transport as a solution, preserved.In clinical application, because this polymer micelle mainly relies on passive target to target organ distribution, this process need for some time completes, if the less stable of micella, drug leakage will occur before arrival target organ, curative effect is reduced, toxicity increases.Therefore, the stability how improving this polymer micelle is a very important problem.
The method improving polymer latex beam stability improves the hydrophobicity of polymkeric substance.In order to do like this, just should the molecular weight of telomerized polymer or concentration, but along with the increase of molecular weight, its biodegradability is also in reduction, and therefore, polymkeric substance is just insufficient from the excretion of health, and they are gathered in organ and cause toxic action at that.In addition, in US Patent No. 6458373 B1, drugs of low aqueous solubility is dissolved in the emulsion form with alpha-tocopherol.According to this patent, in order to stable emulsion, employ the PEGization vitamin-E as surfactant.PEGization vitamin-E has the structure similar to amphiphilic block copolymer, and wherein segmented copolymer comprises hydrophilic block and hydrophobic block, and the tocopherol of high hydrophobicity improves the avidity of multipolymer and drugs of low aqueous solubility, so just can dissolve drugs of low aqueous solubility.
Summary of the invention
The object of the present invention is to provide a kind of pharmaceutical carrier, this pharmaceutical carrier has the advantages that drug loading is large and stability is high.
The present invention is achieved through the following technical solutions:
Pharmaceutical carrier of the present invention contains hydrophilic A Hock and hydrophobic B Hock, and its structure is A-B type Synthetic rubber, isoprene-styrene, hydrogenated, block, diblock or B-A-B type triblock copolymer.Wherein said hydrophobic B Hock terminal hydroxyl is replaced by cholic acid (cholic acid, CA).Wherein hydrophilic A Hock be selected from poly glycol monomethyl ether, polyoxyethylene glycol, polyvinyl alcohol and polyvinylpyrrolidone wherein any one; Wherein hydrophobic B Hock be selected from the caproic acid lactone of polylactide, polylactide-co-glycolide, PGA, polycaprolactone, polylactide-altogether-caproic acid lactone, PGA-altogether-caproic acid lactone and polylactide-co-glycolide-altogether wherein any one.
The weight ratio of hydrophilic A Hock and hydrophobic B Hock is at 10:90 ~ 90:10, preferred: 40:60 ~ 60:40.
Wherein the number-average molecular weight of hydrophilic A Hock is 396 to 49984 dalton, preferably: 1496 ~ 5984 dalton.
Wherein the number-average molecular weight of hydrophobic B Hock is 360 to 49968 dalton, preferably: 1800 ~ 3960 dalton.
Wherein the cholic acid group Replacement rate of the terminal hydroxyl of hydrophobic B Hock is between 5%-100%, preferably: 30-75%.
Segmented copolymer of the present invention may be used for preparing polypeptide drug-loaded micelle solution, and described preparation method is film dispersion method, solvent evaporated method, lyophilization and dialysis method etc.Film dispersion method is dissolved in a kind of organic solvent by polymkeric substance and medicine, ultrasonicly make after it fully dissolves, under reduced pressure, rotary evaporation removing organic solvent obtains the film containing medicine, add suitable aqueous vehicles hydrated films again, obtain clarifying the polypeptide drug-loaded micelle solution with opalescence, centrifugal, filtering with microporous membrane, obtains micellar solution.
Solvent evaporated method is dissolved in polarity or non-polar solvent by segmented copolymer, medicine, under agitation drips water gradually or mixes with aqueous phase, then boiling off organic solvent down at a certain temperature, obtain micellar solution.
After lyophilization means the organic solvent (ethanol, the trimethyl carbinol etc.) medicine and polymkeric substance being dissolved in and can be used for freeze-drying, then mix with water, namely obtain carrier micelle through freeze-drying except after desolventizing, after aquation, form micellar solution.
Described block copolymer micelle may be used for bag and carries various hydrophobic drug, comprise antitumor drug (as taxol, 5 FU 5 fluorouracil, Etoposide, melphalan, Chlorambucil, hexamethylmelamine, Rheumatrex, Semustine, NVB, teniposide, cephalotaxus alkaloids, hydroxycamptothecine etc.), microbiotic is (as paraxin, erythromycin, erythromycin estolate, erythromycin ethylsuccinate, mydecamycin, josamycin, clarithromycin, rokitamycin, Sulphadiazine Sodium, Trimethyl phosphate, furadantin, Rifampin, rifaximin, Rifandin, dapsone, acedapsone, miconazole etc.), cardiovascular agent is (as nifedipine, nicardipine, nitrendipine, nilvadipine, CN, perhexiline, molsidomine, Myodigin, digoxin), NSAID (non-steroidal anti-inflammatory drug) is (as Cyproheptadine, Somigran, ketotifen etc.).The medicine carrying ratio of hydrophobic drug in block copolymer micelle, between 1% ~ 50%, is preferably between 5% ~ 30%.The particle diameter of carrier micelle, between 15nm ~ 500nm, is preferably between 20nm ~ 200nm.
The mensuration of segmented copolymer micelle-forming concentration (CMC): the CMC value in the present invention adopts accurate, reliable fluorescent spectrometry to record.Fluorescent spectrometry needs to use a kind of fluorescent probe material, and conventional is pyrene.Pyrene is a kind of hydrophobic aromatic compound, to environment polar sensitive.When the concentration of amphipathic molecule is lower than CMC, can not form micella in solution, pyrene is dissolved in the water of polarity; Along with the concentration of amphipathic molecule is higher than CMC, micelle formation, pyrene distributes to the hydrophobic part of micelle inner core, thus enter nonpolar environment, then can observe a series of change in its fluorescence spectrum, as fluorescence intensity will increase, vibrate fine structure in emmission spectrum and change.Therefore, by with I in the emmission spectrum of pyrene
1/ I
3than (scanning under fixing excitation wavelength, I
1, I
3to represent in emmission spectrum the fluorescence intensity ratio at first and three strongest ones peak respectively) or excitation spectrum in I
338/ I
333the apparent CMC of amphiphile, amphiphilic molecule can be obtained than (excitation spectrum medium wavelength is respectively the fluorescence intensity ratio of 338nm and 333nm) concentration mapping to amphiphile, amphiphilic molecule.Namely the point that in figure, slope changes is the stagnation point forming micella, and namely the concentration of corresponding amphiphile, amphiphilic molecule be CMC.
The amphipathic nature block polymer that cholic acid provided by the invention is modified has following advantage relative to former multipolymer: 1. the hydrophobicity that improve multipolymer hydrophobic block, does not obviously change molecular weight and the biodegradability of former multipolymer; 2. the modification of multipolymer hydrophobic block end cholic acid group significantly improves the avidity of hydrophobic block and poorly water soluble drugs, and therefore, the drug loading of multipolymer is higher, and the stability of carrier micelle is better.3. the hydrophobic forces of cholic acid group contributes to improving the stability of carrier micelle in preparation and put procedure, is conducive to simplifying commercial process; 4. the hydrophobic forces of cholic acid group contributes to reducing the leakage of medicine in blood circulation, is conducive to the targeting improving carrier micelle, thus obtains better result for the treatment of.
Accompanying drawing explanation
Fig. 1 is the chemical structural formula of mPEG-PDLLA-CA.
Fig. 2 is the NMR collection of illustrative plates of PEG-PDLLA-cholic acid (substitution value 30%).
Fig. 3 is the NMR collection of illustrative plates of PEG-PDLLA-cholic acid (substitution value 60%).
Fig. 4 is the NMR collection of illustrative plates of PEG-PDLLA-cholic acid (substitution value 75%).
Fig. 5 is the NMR collection of illustrative plates of PEG-PDLLA-cholic acid (substitution value 90%).
Fig. 6 is the NMR collection of illustrative plates of polylactide-co-glycolide-PEG-PDLLA-altogether-glycollide.
Fig. 7 is the NMR collection of illustrative plates of poly glycol monomethyl ether-polylactide-co-glycolide.
Fig. 8 is made collection of illustrative plates by measuring CMC value.
Fig. 9 is the particle diameter carrying taxol polymer micelle.
Figure 10 is the particle diameter carrying amphotericin B polymer micelle.
Figure 11 is the particle diameter carrying Zorubicin polymer micelle.
Figure 12 is the particle diameter carrying itraconazole polymer micelle.
Figure 13 is the physical stability experiment of carrying taxol polymer micelle.
Figure 14 is the release profiles carrying taxol polymer micelle.
Embodiment
Be embodiments of the invention below, but following embodiment does not limit the interest field of this patent.
the synthesis of embodiment 1 amphipathic nature block polymer mPEG-PDLLA-CA
Adopt ring-opening polymerization method synthesis mPEG-PDLLA di-block copolymer.Polymerizing pipe is after chromic acid lotion soaks, and distilled water wash, drying is rear for subsequent use.Take a certain proportion of poly glycol monomethyl ether (mPEG2000) to load in dry polymerizing pipe with lactide monomer, then add catalyzer stannous iso caprylate Sn (Oct)
2(consumption is 1 ‰ of reactant weight), after high pure nitrogen deoxygenation, tube sealing under vacuum, reacts 6h at 140 DEG C, baking oven, obtains the semi-solid product of pale yellow transparent.Gained crude product cools, and transfers in small beaker, precipitate, suction filtration crystallisate in cold-trap with a large amount of ether with a small amount of methylene dichloride after dissolving, two sections of polymkeric substance that this operation repetition twice must be purer.Put into vacuum drier more afterwards, dry 3 days, productive rate was more than 80%.By regulating the ratio of poly glycol monomethyl ether and the rac-Lactide dropped into, obtain the segmented copolymer that mPEG:PDLLA mass ratio is 4:6,5:5 and 6:4 respectively.
Take a certain amount of mPEG-PDLLA synthesized respectively, carbonyl dimidazoles and cholic acid are in beaker, it is made to dissolve completely with appropriate DMF, cholic acid/DMF solution and carbonyl dimidazoles/DMF solution are transferred in round-bottomed flask, activate in stirring at room temperature 30 points, then add wherein by mPEG-PDLLA/DMF solution, 60 degrees Celsius are reacted 48 hours.After stopped reaction, product is transferred in dialysis, dialyses and remove unreacted small-molecule substance in three days.Then lyophilize obtains product.The structural formula of product is shown in Fig. 1, and wherein x is the polymkeric substance of hydrophilic block, and between 9 ~ 1136, preferably 34 ~ 136, y is the polymkeric substance of hydrophobic block, between 5 ~ 694, and preferably 25 ~ 55.
Peak area relative method is adopted to measure the substitution value of cholic acid.The hydrogen atom chemical shift that cholic acid 18 carbon atoms are ined succession is 0.72, the hydrogen atom chemical shift that end group methoxyl group in mPEG-PDLLA is ined succession is 3.4, less owing to disturbing near these two chemical shifts, and do not repeat in respective molecule, select these two peaks to carry out area, calculate substitution value (D%=A
0.72/ A
3.4).When the ratio of cholic acid and polymkeric substance input amount is respectively mol ratio 1:3,3:4,1:1 and 2:1, synthesizes cholic acid substitution value and be respectively 30%, the mPEG-PDLLA-CA of 60%, 75% and 90%.
The different cholic acid substitution value of mPEG-PDLLA-CA() NMR collection of illustrative plates (deuterochloroform is solvent) see Fig. 2-5.Polylactide-co-glycolide-PEG-PDLLA-glycollide altogether, the NMR collection of illustrative plates of poly glycol monomethyl ether-polylactide-co-glycolide is respectively Fig. 6, Fig. 7.
the mensuration of embodiment 2 block copolymer C MC
(1) preparation of storing solution
The preparation of pyrene storing solution: take 6mg pyrene and be placed in the brown volumetric flask of 50mL, adds acetone solution and is diluted to scale and be made into 6 × 10
-4molL
-1pyrene solution.Precision measures in 1.0mL to 25mL volumetric flask, adds acetone constant volume, and obtaining concentration is 2.4 × 10
-5molL
-1pyrene solution, accurate draw in the brown volumetric flask of 10mL to 100mL, it is 2.4 × 10 that acetone is settled to final concentration
-6molL
-1, obtain the storing solution of pyrene.
The preparation of polymkeric substance storing solution: take 20mg mPEG-PDLLA-CA segmented copolymer and be placed in 20mL volumetric flask, distilled water dissolves and is diluted to scale, obtaining concentration is 1 mgmL
-1polymkeric substance storing solution.
(2) mensuration of CMC
The preparation of sample: add 500uL pyrene storing solution respectively in 10 mL volumetric flasks, fling to acetone 60 DEG C of water-baths, then add the polymers soln of different concns, constant volume, make the concentration range 10 of polymkeric substance
-4-10
-1gL
-1, pyrene concentration is 1.2 × 10
-7molL
-1.Ultrasonic 30min, concussion for several times makes dissolution homogeneity, should first ultrasonic 30min after sample makes, and lucifuge dark place is placed to spend the night and made fully to balance between pyrene and micella.
(3) fluorescence condition is determined
According to excitation wavelength determination maximum emission wavelength, measure the principle of maximum excitation wavelength with emission wavelength, determine that the emission wavelength of pyrene probe is 390 nm.The excitation spectrum of scanning samples, measures the fluorescence intensity I of sample at 338 nm, 333 nm places of a series of different concns
338and I
333, with copolymer concentration (gL
-1) logarithmic value be X-axis, I
338/ I
333for Y-axis mapping, by the CMC value of the catastrophe point determination polymkeric substance of curve.
Fluorescence condition: emission wavelength 390nm
Excitation wavelength range 305 ~ 350nm
Excite and launch slit width and be 5nm.
Quartz sample pool 1 cm × 1 cm
Result shows, under pH7.4,37 DEG C of conditions, to record mPEG-PDLLA-CA(substitution value 75% by making curve near tangent (see figure 8)) micelle-forming concentration of copolymer micelle is 3.24 × 10
-3g/L, CMC(6.26 × 10 of the polymkeric substance mPEG-PDLLA before replacing with cholic acid
-3g/L) compare, CMC is lower, illustrates that segmented copolymer has lower micelle-forming concentration, existence that can be more stable.
the preparation of embodiment 3 years taxol polymer micelles and particle size determination
Lyophilization: first take 7mg taxol and be dissolved in the trimethyl carbinol, then with the aqueous solution containing mPEG-PDLLA-CA segmented copolymer 20mg, make water/trimethyl carbinol volume ratio be 70:30.Mixing solutions is degerming with the filtering with microporous membrane of 0.22um after stirring 3h at 4 DEG C, and lyophilize, must carry taxol polymer micelle freeze-drying micella, water for injection or other solvent dilute before use.
Dialysis method: weighing m PEG-PDLLA-CA segmented copolymer 20mg and taxol 7mg is dissolved in 10mlL DMSO respectively, ultrasonic 10min, stirring spends the night makes its segment fully stretch, instill the distilled water of 20% in advance, stir 2h, use distill water dialysis 24h, change dialysis medium at set intervals.The centrifugal 10min of last 10000 rpm/min, remove free PTX and polymkeric substance, product, with 0.22um millipore filtration Entkeimung, obtains transparent micellar solution.
Film dispersion method: weighing m PEG-PDLLA-CA segmented copolymer 20mg and taxol 7mg is in eggplant-shape bottle respectively, measure 10mL acetonitrile, the ultrasonic polymkeric substance that makes fully dissolves, 60 DEG C of Water Under baths, rotary evaporation 30 minutes removing organic solvents, then 10mL physiological saline is added, 30 DEG C of Water Underizations 15 minutes.After aquation terminates, 12000r/min centrifugal ten minutes, gets supernatant, and product, with 0.22 μm of millipore filtration Entkeimung, namely obtains carrying taxol polymer micelle solution.
Use Malvern particle size determination instrument, adopt dynamic light scattering law technology, record lyophilization respectively, the particle diameter of taxol polymer micelle prepared by dialysis method and film dispersion method is 89.47nm, 44.72nm and 54.35nm.The carrier micelle particle diameter that wherein film dispersion method is obtained is shown in Fig. 9.
the preparation of embodiment 4 years amphotericin B polymer micelles and particle size determination
Weighing m PEG-PDLLA-CA segmented copolymer, and the amphotericin B storing solution measuring 5mL is in eggplant-shape bottle, measure 10mL acetonitrile, the ultrasonic polymkeric substance that makes fully dissolves, 60 DEG C of Water Under baths, rotary evaporation 30 minutes removing organic solvent, then adds 10mL physiological saline, 30 DEG C of Water Underizations 15 minutes.After aquation terminates, 12000r/min centrifugal ten minutes, gets supernatant, and product, with 0.22 μm of millipore filtration Entkeimung, namely obtains carrying amphotericin B polymer micelle solution.
Use Malvern particle size determination instrument, adopt dynamic light scattering law technology, the particle diameter recording amphotericin B polymer micelle is 47.51nm.See Figure 10.
the preparation of embodiment 5 years Zorubicin polymer micelles and particle size determination
Weighing m PEG-PDLLA-CA segmented copolymer, and measure 5mL Zorubicin storing solution in eggplant-shape bottle, the ultrasonic polymkeric substance that makes fully dissolves, 60 DEG C of Water Under baths, rotary evaporation 30 minutes removing organic solvent, then adds 10mL physiological saline, 30 DEG C of Water Underizations 15 minutes.After aquation terminates, 12000r/min centrifugal ten minutes, gets supernatant, and product, with 0.22 μm of millipore filtration Entkeimung, namely obtains carrying Zorubicin polymer micelle solution.
Use Malvern particle size determination instrument, adopt dynamic light scattering law technology, the particle diameter recording Zorubicin polymer micelle is 16.95nm.See Figure 11.
the preparation of embodiment 6 years itraconazole polymer micelles and particle size determination
Weighing m PEG-PDLLA-CA segmented copolymer 20mg and itraconazole 8mg is in eggplant-shape bottle respectively, and measure 10mL acetonitrile, the ultrasonic polymkeric substance that makes fully dissolves, 60 DEG C of Water Under baths, rotary evaporation 30 minutes removing organic solvent, then adds 10mL physiological saline, 30 DEG C of Water Underizations 15 minutes.After aquation terminates, 12000r/min centrifugal ten minutes, gets supernatant, and product, with 0.22 μm of millipore filtration Entkeimung, namely obtains carrying itraconazole polymer micelle solution.
Use Malvern particle size determination instrument, adopt dynamic light scattering law technology, the particle diameter recording itraconazole polymer micelle is 84.18nm.See Figure 12.
embodiment 7 different carriers material carries the comparison of taxol micella physical stability
(mPEG and PDLLA block mass ratio is respectively the mPEG-PDLLA of 4:6,5:5 and 6:4 and cholic acid substitution value is respectively 30% to get different carriers material respectively, 60%, the mPEG-PDLLA-CA of 75%) prepare carry taxol micella 20ml, be placed in 25 DEG C of thermostat containers, respectively at 2,4,6,9,21,24,30,48 hours, sampling, filter, get subsequent filtrate, measure content of taxol respectively, the results are shown in Figure 13.The stability that visible mPEG-PDLLA-CA carries taxol micella is much higher than mPEG-PDLLA, and along with the increase of cholic acid substitution value, stability strengthens.
HPLC method measures the content of taxol:
Chromatographic column: Hypersil ODS C
18post (4.6 × 150 mm, 5 um, enlightening horse)
Moving phase: acetonitrile-water (60:40, v/v)
Flow velocity: 1.0 mLmin
-1
Column temperature: 25 DEG C
Determined wavelength: 230 nm
Sample size: 20 uL.
the comparison of embodiment 8 years taxol mPEG-PDLLA-CA polymer micelles and mPEG-PDLLA micella release
MPEG-PDLLA(4:6 by preparing) carry taxol micella and mPEG-PDLLA-CA(substitution value 75%) carry taxol micella respectively with normal saline dilution to 0.25 mg/mL, precision pipettes in 0.5 mL to MWCO3500 dialysis tubing, using pH 7.4 phosphate buffered saline buffer 50 mL of 0.5% Tween 80 as release medium, load in 100 mL tool plug Erlenmeyer flasks, be placed in 37 DEG C of shaking tables, rotating speed 100 rpm, respectively at 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48h gets 1 mL and supplements 1 mL blank medium simultaneously, after dilution subsequent filtrate, feed liquor measures content mutually, and draw cumulative release curve.Adopt the drug level in high effective liquid chromatography for measuring release medium, calculate cumulative release amount and draw cumulative release curve, seeing Figure 14.The drug release behavior of the drug-carrying polymer micelle before and after cholic acid is modified is more slow compared with before modification.Accumulation dissolution calculation formula is as follows:
In formula:
the cumulative release amount of-PTX, %;
the displaced volume of-PBS;
the drug level discharged during-the i-th displacement sampling, μ g/mL;
the volume of-release medium;
the content of DTX in-carrier micelle, mg.
Compared with the polyethylene glycol-ester copolymer of unmodified, the drug loading of polyethylene glycol-ester copolymer micella that cholic acid is modified significantly improve with physical stability to significantly improving, still can place in room temperature when drug loading is up to 20-30% and remain stable in 48 hours, this superiority improves polyethylene glycol-ester copolymer and is producing and the shortcoming of clinical application.The increase of drug loading contributes to the dosage reducing solid support material, and this is improving the security of medication, reduces and produces unnecessary toxic side effect aspect have tremendous improvement owing to taking in too much auxiliary material.In addition, the release in vitro of carrier micelle is starkly lower than the multipolymer of unmodified, and slowly-releasing feature is obvious, and the targeting that it is expected in its body is better.
Claims (14)
1. a high stability polymkeric substance, containing hydrophilic A Hock and hydrophobic B Hock, is characterized in that, the terminal hydroxyl of hydrophobic B Hock is replaced by cholic acid group; Wherein hydrophilic A Hock is selected from poly glycol monomethyl ether, polyoxyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone or polyacrylamide; Wherein hydrophobic B Hock is selected from polylactide, polylactide-co-glycolide, polycaprolactone, polylactide-altogether-caproic acid lactone, PGA-altogether-caproic acid lactone or polylactide-co-glycolide-caproic acid lactone altogether.
2. polymkeric substance according to claim 1, is characterized in that, the molecular structure of polymkeric substance is A-B type Synthetic rubber, isoprene-styrene, hydrogenated, block, diblock or B-A-B type triblock copolymer.
3. polymkeric substance according to claim 1, is characterized in that, the weight ratio of hydrophilic A Hock and hydrophobic B Hock is 10:90 ~ 90:10.
4. polymkeric substance according to claim 1, is characterized in that, the weight ratio of hydrophilic A Hock and hydrophobic B Hock is 40:60 ~ 60:40.
5. according to the polymkeric substance described in claim 1, it is characterized in that, wherein the number-average molecular weight of hydrophilic block is 396 to 49984 dalton.
6. polymkeric substance according to claim 1, is characterized in that, the number-average molecular weight of hydrophilic block is 1496 ~ 5984 dalton.
7. according to the polymkeric substance described in claim 1, it is characterized in that, wherein the number-average molecular weight of hydrophobic block is 360 to 49968 dalton.
8. polymkeric substance according to claim 1, is characterized in that, the number-average molecular weight of hydrophobic block is 1800 ~ 3960 dalton.
9. polymkeric substance according to claim 1, is characterized in that, wherein the cholic acid group Replacement rate of the terminal hydroxyl of hydrophobic block is between 5%-100%.
10. polymkeric substance according to claim 1, is characterized in that, the cholic acid group Replacement rate of the terminal hydroxyl of hydrophobic block is 30 ~ 75%.
11. polymkeric substance according to claim 1, is characterized in that, hydrophilic A Hock is polyoxyethylene glycol, and hydrophobic B Hock is polylactide-cholic acid.
The polymkeric substance of 12. claim 1-11 described in any one is preparing the application in drug-carrying polymer micelle.
13. application according to claim 12, is characterized in that, described medicine is selected from antitumor drug, antibiotic medicine, cardiovascular agent, antidiabetic medicine or nonsteroidal anti-inflammatory drug.
14. application according to claim 13, it is characterized in that, described medicine is taxol, 5 FU 5 fluorouracil, Etoposide, melphalan, Chlorambucil, hexamethylmelamine, Rheumatrex, Semustine, NVB, teniposide, cephalotaxus alkaloids, hydroxycamptothecine, paraxin, erythromycin, erythromycin estolate, erythromycin ethylsuccinate, mydecamycin, josamycin, clarithromycin, rokitamycin, Sulphadiazine Sodium, Trimethyl phosphate, furadantin, Rifampin, rifaximin, Rifandin, dapsone, acedapsone, miconazole, nifedipine, nicardipine, nitrendipine, nilvadipine, CN, perhexiline, molsidomine, Myodigin, digoxin, Cyproheptadine, Somigran, ketotifen.
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