Herstellung von Mikropartikeln aus einem abbaubaren Multiblockcopolymer zur Freisetzung von proteinischen Wirkstoffen
Based on the semi-crystalline and biodegradable multiblock-copolymer of poly(p-dioxanon) and poly(?-caprolacton) matrix drug delivery systems (films and particles) are developed for proteins. Protein-loaded microparticles are produced in cylindrical reactors by means of the double emulsification solvent evaporation technique. The loading efficiency of the particles (0,32 - 1,2 wt.-% lysozyme) depends on the experimental parameters (volume of second emulsifier, ethanol as phase mediator in the second emulsifier). Attempts to produce particles by means of the original spray drying method were unsuccesful due to the semi-crystalline property of the polymer. During spraying of the polymer solution, the nozzle is clogged and in the drying chamber, some sticky fibers are formed as well as ruptured spherical particles with a diameter of 10 to 100 µm. SEM shows that a wide size distribution of particles exist. Particles formed by the double emulsification solvent evaporation technique are spherical with a diameter of 0,1 to 2000 µm and a broad size distribution. In most experiments the larger particles (170-1000 µm) represent 80-95% of the total volume. The material properties are examined by analysis of the loaded films. A loading of up to 10 wt.-% protein does not influence the thermal or shape-memory properties of the material. Young's moduli are cut in half (49 MPa) and the buffer or solvent uptake is doubled. There is no difference for the elongation at break for the 5, 10 or 20 wt.-% lysozyme loaded polymer. The strain fixity rate in cyclic thermomechanical tensile tests is in the range of 92% for all polymeric materials, pure or loaded (10 or 20 wt.-% lysozyme). For all samples the strain recovery rate of the first cycle is around 80% and achieves 99% in the following cycles and the transition temperature of the shape memory process is around 31°C. For all samples (0, 5, 10 or 20wt.-% lysozyme) the value of the transition coeffizient ? is (0,26 ( 0,01) 10-1K-1. If the loading is 20 wt.-% lysozyme, the transition is much broader. Hydrolysis of the loaded polymer in hydrochloric acid (pH 1,0), acetate-buffer (pH 4,6) and phosphate-buffer (pH 7,0) proceeds as the hydrolysis of the unloaded polymer with respect to change of chemical composition, thermal properties, mechanical properties and surface topography according to white light interferometry. The hydrolysis of the polymer is enhanced by increased pH value of the solution. Lysozyme released from 10 wt.-% loaded films has a biological activity of 1136 U/mL after 1 d, but the activity is reduced to 9 U/mL after 7 d. Lysozyme released from loaded particles shows an activity of 3 U/mL after 1 d, thus applies to all particles that are produced with different parameter sets. The activity loss of lysozyme is caused by the interactions of the enzyme with methylene chloride under shear stress (homogenizers with 18.000 rpm for 20 s). Investigations show that neither temperature, pressure, or both (to lysozyme powder) nor the vessels, hydrophobic interactions between lysozyme solution and hydrophobic polymer films or shear stress without addition of an organic solvent bate the biological activity of lysozyme.
info:eu-repo/classification/ddc/540, Chemie, Multiblockcopolymer, Shape-Memory, Hydrolyse, Mikropartikel, Sprühtrocknung, W/O/W, Freisetzung, Lysozym
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