CN100457187C - VEGF slowly releasing injection microsphere support and its prepn and use - Google Patents
VEGF slowly releasing injection microsphere support and its prepn and use Download PDFInfo
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- CN100457187C CN100457187C CNB2006101181832A CN200610118183A CN100457187C CN 100457187 C CN100457187 C CN 100457187C CN B2006101181832 A CNB2006101181832 A CN B2006101181832A CN 200610118183 A CN200610118183 A CN 200610118183A CN 100457187 C CN100457187 C CN 100457187C
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Abstract
The VEGF slowly releasing injection microsphere support includes matrix, VEGF, protectant and ammonium bicarbonate. It features the matrix of polylactic acid-hydroxyl acetate copolymer of polylactic acid/hydroxyl acetate ratio 25:75 to 75:25; the protectant comprising zinc carbonate, serum albumin, mycose and mannitol; the weight ratio between VEGF and polylactic acid-hydroxyl acetate copolymer of 1:100000 to 1:10; and the microsphere size of 50-1000 microns. It is prepared through one W/O/W solvent volatilizing process or one fine medicine powder adding W/O/W solvent volatilizing process. The preparation process is simple, easy in operation and high in repeatability. In the microsphere support, protein medicine VEGF may be in vitro released for over 4 weeks in approached zero order kinetic mode. The present invention may be used in the repair and treatment of different kinds of tissue and blood vessel damage.
Description
Technical field
The present invention relates to medical technical field, is a kind of year pharmaceutical grade protein VEGF (vascular endothelial cell growth factor vascular endothelial growth factor, VEGF) slowly releasing injection microsphere support and its production and use.
Background technology
Vascular endothelial cell growth factor (vascular endothelial growth factor, VEGF) be the somatomedin of a kind of specific effect in vascular endothelial cell, can promote the blood vessel that hypertrophy, transfer and the differentiation of blood vessel make new advances, simultaneously because VEGF can strengthen vascular permeability, so be called vascular permeability factor again.From the conditioned medium of Medulla Bovis seu Bubali hypophysis folliculus sternzellen, purified by Ferrara etc. early than 1989.(recombinant human vascular endothelial growth factor, rhVEGF) the treatment ischemic diseases has entered clinical experimental stage and has been expected to become in the near future curative drug from preclinical study widely and has been applied to clinical the recombined human VEGF.(N.Ferrara，K.Alitalo.Clinical?applications?of?angiogenicgrowth?factors?and?their?inhibitors，[J].Nature?Med.1999，5(12)：1359)。Yet, similar to other somatomedin, VEGF causes vivo degradation excessive velocities (Jeffrey L.Cleland Ph.D owing to the half-life is short, Eillen T.Puenas et al.Cuthbertson Development ofpoly-(D, L-Lactide-co-glycolide) microspheres fermulation containing recombinanthuman vascular endothelial growth factor to promote local angiogenesis[J] .controlled Release 2001,72:13), thus limited its clinical practice.
Summary of the invention
The objective of the invention is to overcome the above-mentioned deficiency of prior art, advantage in conjunction with microsphere preparation technology and tissue engineering bracket technology provides slowly releasing injection microsphere support of a kind of VEGF and preparation method thereof, the sustainable release of protein drug VEGF reached for 4 weeks, increase the effect that cell survival rate promotes the formation of its growth increase new vessels thereby reach, be used for the treatment of the ischemic disease.
Biodegradable in recent years macromolecular material is widely used in the preparation and the tissue engineering technique of protein and peptide drugs slow-release microsphere, polylactic acid-glycolic guanidine-acetic acid copolymer [poly (lactide-co-glycolide) wherein, PLGA] because its excellent biological compatibility and biological degradability have been that pharmaceutical polymers uses by drugs approved by FDA.With PLGA as microsphere substrate, the inside and outside degradation experiment proves, in drug release process, whole polymer backbone is the uniformity degraded, decline along with molecular weight, the hydrophilic of framework material strengthens, because the continuous infiltration of moisture makes protein and peptide drugs continue to discharge (Wang YM, Sato H, Horikoshi.In vitro and in vivo evalution of taxol release fromploy (lactic-co-glycotic acid) microspheres containing isopropyl myristate anddegradation of the microspheres.J Control Rel, 1997,49:157).The present invention just is to use PLGA to prepare VEGF sustained-release micro-spheres support as substrate.The present invention is basic basic framework with PLGA, preparation VEGF slowly releasing injection microsphere support, for having cavernous year protein medicine microsphere, hole in the microsphere is planted corresponding cell by cell culture and is navigated to the tissue defect position by injecting pathway on the one hand, and the VEGF in the microsphere can come stimulating cellular growth to be differentiated to form new tissue with constant rate of releasing drug release medicine on the other hand.
VEGF slowly releasing injection microsphere support of the present invention, its composition comprises substrate, VEGF, protective agent and ammonium bicarbonate, it is characterized in that described substrate is polylactic acid: hydroxyacetic acid=25: 75-75: 25 polylactic acid-glycolic guanidine-acetic acid copolymer; Described protective agent comprises zinc carbonate, serum albumin, trehalose and mannitol; The part by weight of VEGF and polylactic acid monohydroxy acetate multipolymer is 1: 100000 to 1: 10, and microspherulite diameter is 50 μ m to 1000 μ m when room temperature.
VEGF slowly releasing injection microsphere support preparation method of the present invention has two kinds:
1.w/o/w solvent evaporation method: adopt w/o/w emulsionization-solvent evaporation method to prepare microsphere
The preparation oil phase
Host material PLGA is dissolved in organic solvent dichloromethane makes oil phase, concentration is 30mg～300mg/ml;
Water in the preparation
Get water in the water-soluble formation of an amount of VEGF and protective agent and ammonium bicarbonate, ammonium bicarbonate concentration is 2%-50%, and VEGF concentration is 1 μ g～1mg/ml, and protective agent is selected from zinc carbonate, serum albumin, trehalose and mannitol etc., and its content is 1～5%;
The preparation microsphere
Interior water is added above-mentioned oil phase homogenizing homogenize (or ultrasonic) form colostrum, colostrum is dripped in 0.01-6% polyvinyl alcohol (PVA) aqueous solution rapidly, (mixing speed is 100～1800rpm) to the abundant homogenize of mechanical agitation, (mixing speed was 100～300rpm) in 4 hours to continue stirring at low speed under the room temperature, washing, collect, lyophilization gets final product.
2. the w/o/w solvent evaporation method that adds with the micropowder form of medicine:
The preparation oil phase
Host material PLGA is dissolved in organic solvent dichloromethane makes oil phase, concentration is 30mg～300mg/ml;
Water in the preparation
Get water in the water-soluble formation of amount of ammonium bicarbonate, ammonium bicarbonate concentration is 2%-50%;
Preparation VEGF micropowder
An amount of Polyethylene Glycol (PEG) and VEGF and protective agent (its ratio is 4: 1: 2) are scattered in the water, after lyophilization,, remove PEG with washed with dichloromethane, centrifugal, obtain the VEGF micropowder, protective agent is selected from zinc carbonate, serum albumin, trehalose and mannitol etc.;
The preparation microsphere
VEGF micropowder and interior water are added oil phase, homogenize dispersion and emulsion mixing forms colostrum, colostrum is dripped in 0.01-6% polyvinyl alcohol (PVA) aqueous solution rapidly, (mixing speed is 100～1800rpm) to the abundant homogenize of mechanical agitation, (mixing speed was 100～300rpm) in 4 hours to continue stirring at low speed under the room temperature, washing is collected, and lyophilization gets final product.
The host material PLGA that the present invention is used, molecular weight are 3000～40000, polylactic acid (PLA): hydroxyacetic acid (PGA) is 25: 75～75: 25, and concentration is 30mg～300mg/ml.Homogenizing homogenize condition is: 2000～10000rpm.
Microsphere support among the present invention has adopted the conventional preparation method of microsphere to combine with the tissue engineering bracket foaming, microsphere support is by vascular endothelial cell growth factor, biodegradable substrate and additive are formed, and are prepared into the VEGF slowly releasing injection microsphere support, see Fig. 1.
VEGF sustained-release micro-spheres of the present invention is through extracorporeal releasing experiment, and slow release reached more than 4 weeks, discharges to meet approximate zero mode, can be used for treating the ischemic treatment of diseases.
Description of drawings
Fig. 1 is the VEGF slowly releasing injection microsphere support,
Fig. 2 is the VEGF release injectable microsphere cumulative in vitro release～time plot of method 1 preparation,
Fig. 3 is the VEGF release injectable microsphere cumulative in vitro release～time plot of method 2 preparations.
The specific embodiment
Embodiment 1:w/o/w solvent evaporation method prepares VEGF sustained-release micro-spheres support
With PLGA (PLA: PGA=75: 25, Mw=10,000) 100mg is dissolved in the 3.2ml dichloromethane and makes oil phase, VEGF3 μ g and ammonium bicarbonate 100mg are dissolved in the double distilled water of 1ml and (include 3% trehalose, 5% mannitol) form interior water, it is added above-mentioned oil phase, the homogenizing homogenize, form the colostrum of w/o, to contain 0.1%PVA solution 120ml and place stirred vessel, with colostrum abundant homogenize of aqueous phase outside stirring (450rpm) quick down adding, after five minutes, rotating speed is adjusted downward to the simultaneously outer water of 200rpm adds the 30ml distilled water, stirred 4 hours microsphere sclerosis back sucking filtration and washing, lyophilization under the room temperature.Irradiation sterilization gets final product after the sealing packing.About particle diameter 500 μ m.
Embodiment 2: medicine prepares VEGF sustained-release micro-spheres support with the w/o/w solvent evaporation method that the micropowder form adds
PEG (PEG6000) 1.2mg and VEGF300 μ g and protective agent (zinc carbonate 600 μ g) are scattered in the 1ml double distilled water, and vortex mixed about 3 minutes, and packing after the lyophilization, with washed with dichloromethane, centrifugal, is removed PEG, obtains the VEGF micropowder.With PLGA (PLA: PGA=75: 25, Mw=10000) 100mg is dissolved in the 3.2ml dichloromethane and makes oil phase, ammonium bicarbonate 100mg is dissolved in the double distilled water of 1ml and (includes 3% trehalose, 5% mannitol) form interior water, it is added above-mentioned oil phase, after the homogenizing homogenize three minutes, add the low speed homogenize one minute again of micronized medicine, form the colostrum of w/o, to contain 0.1%PVA solution 120ml and place stirred vessel, with colostrum abundant homogenize of aqueous phase outside stirring (450rpm) quick down adding, after five minutes, rotating speed is adjusted downward to the simultaneously outer water of 200rpm adds the 30ml distilled water, stirred 4 hours microsphere sclerosis back sucking filtration and washing, lyophilization under the room temperature.Irradiation sterilization gets final product after the sealing packing.About particle diameter 500 μ m.
Embodiment 3:VEGF sustained-release micro-spheres is through extracorporeal releasing experiment
Instrument: 0508-2 type table-type low-speed centrifuge (Shanghai medical apparatus and instruments company limited); XW-80 type vortex mixer (the Shanghai first medical college instrument plant) CARY 100 uv-spectrophotometric instrument (U.S. varian company); CS501 type thermostatic water-circulator bath (PVG Rong Feng scientific instrument company limited), FA1004 type ten thousand/electronic balance (Shanghai balance equipment factory);
Method and operation: precision takes by weighing the pastille microsphere or the about 20mg of blank microsphere places the 7ml centrifuge tube, add 1.5ml 10mM pH 7.2 phosphate buffers and (contain 0.02% Hydrazoic acid,sodium salt as antibacterial, 0.02%F-68 is as wetting agent), place 37 ℃ of water bath with thermostatic control shaking tables, hunting speed 100rpm.Took out centrifuge tube respectively at 1 day, 3 days, place the centrifugal 5min of centrifuge 2000rpm, with the careful sucking-off 2mL of release medium and change the new release medium of equivalent, later on once every method sampling more than 3-4 days, as blank, carry out application of sample with the release supernatant of blank microsphere, record its absorbance in the 562nm place behind the reaction solution by the requirement of BCA test kit, the substitution standard curve calculates and tries to achieve the content that discharges BSA in the liquid.
(1) the VEGF sustained-release micro-spheres support of method 1 preparation
The results are shown in Figure 2.Test shows that pharmaceutical grade protein release in vitro in microsphere support reached more than 4 weeks, and it discharges the approximate zero order kinetics pattern that meets.
(2) the VEGF sustained-release micro-spheres support of method 2 preparations
The results are shown in Figure 3.Test shows that pharmaceutical grade protein release in vitro in microsphere support reached more than 4 weeks, and it discharges the approximate zero order kinetics pattern that meets.
The present invention relates to medical technical field and tissue engineering correlative technology field, is a kind of preparation method of used in tissue engineering micro polymer ball stand and the innovation that the parcel protein drug is used thereof.Novelty of the present invention is, has changed the traditional view that conventional stent need be performed the operation and be implanted, and uses injection type and has reduced the inconvenience that conventional stent need be performed the operation and be implanted, and has increased compliance of patients.The somatomedin proteinoid medicine that in microsphere support, adds promoting growth of cell, make it after injection, slowly to discharge, thereby reach the effect that increases cell survival rate, promotes the cell growth, promote the cell growth and breeding and in vivo the tissue defect position form flesh tissue.The inventive method is easy, easy operating, favorable reproducibility.Pharmaceutical grade protein release in vitro in microsphere support reached more than 4 weeks, and it discharges the approximate zero order kinetics pattern that meets.VEGF slowly releasing injection microsphere support of the present invention can be applicable to damaged reparation of all kinds of tissue blood vessels and treatment.
Claims (4)
1. VEGF slowly releasing injection microsphere support, its composition is substrate, VEGF, protective agent and ammonium bicarbonate, it is characterized in that described substrate is polylactic acid: hydroxyacetic acid=25: 75-75: 25 polylactic acid-glycolic guanidine-acetic acid copolymer; Described protective agent is selected from zinc carbonate, serum albumin, trehalose and mannitol; The part by weight of VEGF and polylactic acid-glycolic guanidine-acetic acid copolymer is 1: 100000 to 1: 10, and microspherulite diameter is 50 μ m to 1000 μ m when room temperature.
2. a kind of VEGF slowly releasing injection microsphere support according to claim 1 is characterized in that its preparation employing w/o/w solvent evaporation method, and concrete steps are as follows:
Substrate is dissolved in organic solvent makes oil phase, concentration is 30mg-300mg/ml; Get water in VEGF, protective agent and the formation soluble in water of foaming agent ammonium bicarbonate, wherein ammonium bicarbonate concentration is 2%-50%, and VEGF concentration is 1 μ g～1mg/ml, and protective agent content is 1～5%; Interior water is added above-mentioned oil phase, emulsifying forms colostrum, colostrum is dripped in the 0.01-6% polyvinyl alcohol water solution rapidly, mixing speed is the abundant homogenize of mechanical agitation under 100～1800rpm, mixing speed is that 100～300rpm stirred 4 hours under the room temperature, washing is collected, and lyophilization promptly gets the VEGF slowly releasing injection microsphere support through the preparation of W/O/W solvent evaporation method.
3. a kind of VEGF slowly releasing injection microsphere support according to claim 1 is characterized in that the w/o/w solvent evaporation method that its preparation adopts medicine to add with the micropowder form, and concrete steps are as follows:
Substrate is dissolved in organic solvent makes oil phase, concentration is 30mg-300mg/ml, gets water in the formation soluble in water of an amount of foaming agent ammonium bicarbonate, and ammonium bicarbonate concentration is 2%-50%; Polyethylene Glycol (PEG), VEGF and protective agent are scattered in the water in 4: 1: 2 ratios, after the lyophilization,, remove PEG, obtain the VEGF micropowder with washed with dichloromethane, centrifugal; Interior water is added oil phase, after water oil phase mixing homogenize a few minutes, add through lyophilization and handle the VEGF micropowder that obtains, homogenize dispersion and emulsion mixing forms colostrum, colostrum is dripped in 0.01-6% polyvinyl alcohol (PVA) aqueous solution rapidly, mixing speed is the abundant homogenize of 100～1800rpm mechanical agitation, mixing speed is that 100～300rpm stirred 4 hours under the room temperature, washing, collect, lyophilization promptly gets the VEGF slowly releasing injection microsphere support of medicine with the w/o/w solvent evaporation method preparation of micropowder form adding.
4. the application of the described a kind of VEGF slowly releasing injection microsphere support of claim 1 in the medicine for preparing damaged reparation of all kinds of tissue blood vessels and treatment.
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| FR2927255B1 (en) * | 2008-02-07 | 2011-08-12 | Keysan Consulting | BIOCOMPATIBLE INJECTABLE PRODUCTS WITH ZINC RELEASE AND / OR ZINC SACCHARIDE SALT AND USES THEREOF. |
| GB0903810D0 (en) * | 2009-03-05 | 2009-04-22 | Regentec Ltd | Delivery system |
| UY33517A (en) * | 2010-07-19 | 2012-02-29 | Astrazeneca Ab | Pharmaceutical depot for 5-fluoro-2 - [[(1S) -1- (5-fluoro-2-pyridyl) ethyl] amino] -6 - [(5-isopropoxy-1H-pyrazol-3-yl) amino] pyridin -3-carbonitrile ?. |
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| CN103550824B (en) * | 2013-11-01 | 2016-03-02 | 南京医科大学附属口腔医院 | A kind of preparation method of support of inducting osseous tissue regeneration |
| CN109420202A (en) * | 2017-08-29 | 2019-03-05 | 李温斌 | Xenogenesis intelligence organizational project sticking patch |
| CN108744035B (en) * | 2018-06-20 | 2021-03-02 | 信阳师范学院 | VEGF (vascular endothelial growth factor) loaded microsphere and method for preparing injectable composite microsphere hydrogel solution by using same |
| CN110179807A (en) * | 2019-05-17 | 2019-08-30 | 温州医科大学附属第二医院、温州医科大学附属育英儿童医院 | Application of the trehalose in the drug that preparation promotes ultra long random flap survival |
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