The Research On The Preparation Of Biodegradable Phosphazene/Polyester Drug-Loaded Microparticles By Electrohydrodynamic Atomization And The Formation Mechanism Of Different Microparticles Morphologies

The Research on the Preparation of Biodegradable Phosphazene/Polyester Drug-Loaded Microparticles by Electrohydrodynamic Atomization and the Formation Mechanism of Different Microparticles MorphologiesPolymeric microspheres are regarded as a promising controlled drug release delivery system with a good number of advantages such as fine controlled sphere size, controlled release rate, prolonged function time, reduced adverse biological reaction and relatively low dose, and can be applied in target drug delivery of tissues and organs. The common processing methods of microspheres incorporate emulsion, phase separation, spray drying, electrospraying and so on. Previous studies showed electrospraying, as a microsphere processing technique which can achieve controllable sphere diameter (from tens of nanometers to a few micrometers) and controllable morphologies (smooth or porous), is the only method capable of obtaining highly monodispersed particles. Besides, electrospray outweighs other preparing methods in that it can exercise a good control of particle diameters, which is of vital importance because of two reasons. On the one hand, the particle's mobility and aggregation in specific area are closely dependent on its size; on the other hand, monodispersed particles' release behavior is in a uniform rate, and can be better controlled.In the light of the merits of electrospraying in terms of controlling microsphere size as well as other advantages, and the special properties of polyphosphazene, the application of this technique to preparing polyphosphazene drug delivery microspheres can yield better performed polymer drug-control microspheres. Prior researches on electrospraying mostly focused on the control of size and size distribution of microspheres. In the present study, two types of amino acid ester substituted polyphosphazene were synthesized, and the solvent's influence law on their electrosprayed morphologies was presented. Efforts were made to achieve morphology control of eletrosprayed amino acid ester substituted polyphosphazene microsphere, and to achieve size control by controlling various processing parameters. Furthermore, two biodegradable polyesters PLGA and PCL were synthesized and studied to verify and extend the law which was derived from the electrospraying of polyphosphazene microsphere. It is found that the solvent's influences on morphology of polyester polymers and on that of polyphosphazene are different while the influence of processing parameter on the size of both types of polymers is identical.1. Due to the special structure and properties of polymer, the products of glycin/phenylalanine ethyl ester substituted PGPP by electrospraying in tetrahydrofuran solvent were plate shaped microparticles. With different solvent, we can obtain particles with different morphologies, such as bowl-shaped and wrinkled sphere, which were close to spherical spheres. Besides, the decreasing of molecular weight can further produced microspheres much closer to spherical ones. After analyzing the morphologies of particles in relation to solvents, we get that it is the different properties of solvents that lead to different morphologies of microparticles. By comparing the upper limit condensation of polymer in different solvents and the ultimate morphologies of microparticles, it is discovered that among all the properties of the solvent the key parameters determining the shape of microparticles are the volatilization rate of solvent and the solubility of polymer. With the similar volatilization rate, the solvent which has poor dissolving capability will raise the upper limit concentration of polymer in electrospraying, and hence will increase the solid content and make the microparticles closer to spheres. Additionally, the solution of the polymer with smaller macromolecular weight has a higher concentration for electrospray owing to the higher entanglement concentration, and spherical microspheres tend to be obtained out of these polymers due to the motion ability of macromolecules. Thus, the solvent and the macromolecular weight are key factors in determining the morphologies of electrosprayed PGPP microparticles.The diameter of particles can be controlled by such processing parameters as liquid flow rate, applied voltage and nozzle-plate distance, among which liquid flow is the key factor influencing the diameter. The size of particles ranges from 2.2μm to 3.2μm as the flow rate increasing. Furthermore, the electrical conductivity and surface tension of solution also play roles in the formation of particles. Higher electrical conductivity and lower surface tension of solution will produce an increasing number of small microparticles, with the average diameter decreasing to 1.5μm.2. The glycin/phenylalanine ethyl ester mixed substituted polyphosphazene (PAGP) has different properties from PGPP, since PAGP has smaller steric hindrance with lactamine ethyl ester in comparison with phenylalanine ethyl ester in PGPP. PAGP has higher diffusion capability in the solution, so it can produce spherical microparticles by electrospray in various solvents. However, there are significant differences in terms of upper limit concentration in different solvents. In good solvent the upper limit concentration is lower. The size can be adjusted by changing liquid flow rate, voltage, and nozzle-plate distance, and the particle diameter can be controlled in a size range between 2μm and 3μm.3. Amino acid ester substituted polyphosphazene microspheres carrying protein particles were prepared by means of electrospray technique. In the preparation process, it was found that the protein particles within the microspheres did not exert influence on microsphere morphology. Besides, the drug release behavior of protein particles within two different types of amino acid ester substituted polyphosphazenes were also probed into, and the finding was that different structures and properties of polymers have greatly influenced the final drug release behavior of microspheres.4. The influence of the solvent and molecular weight on the electrospray process of PLGA was examined. The adoption of different solvent led to different morphologies of microspheres varying from spherical ones to collapsed ones. The corresponding relation between the morphology of microspheres and the solubility of the solvent was observed, and it is found that as the intrinsic viscosity of polymers decreased, i.e. the decreasing of the solubility of the polymer in the solvent, the collapsed microspheres occurred. On the basis of the comparison among different solvents, it is obtained that in the electrospray of PLGA, the interaction between the polymer and the solvent influenced the volatilization, which led to differences in microsphere morphologies. Since the interaction between the good solvent and the polymer is strong, the solvent is kept from removing from the solution. On the contrary, because the interaction between the solvent and polymer is weak, the removal of polymer solvent has been less affected. Therefore, the polymer molecules in good solvent have more time to diffuse toward the core, and in the process of falling down, continuous splitting is achieved due to the less increase of the droplet concentration caused by slow volatilization. However, in the poor solvent, the swift removal of solvent makes the solution concentration of the exterior jet increase to the entanglement concentration to yield fibers. Therefore, in the PLGA electrospray process, good solvent can be adopted when producing the spherical microspheres, and the poor solvent can be utilized to obtain the collapsed microspheres. As for the size control, the average diameter of particles can be controlled by means of adjusting parameters such as the flow rate, voltage, and nozzle-plate distance. By controlling these parameters, the microspheres with the controllable average diameter ranging from 5μm to 8μm can be obtained. 5. The preparation of PCL by electrospray. Different morphologies of microspheres can be prepared by changing the solvent. Previous literature has reported on the spherical PCL microspheres, while in the present study, the bowl shaped PCL microspheres were yielded by utilizing a different solvent. The factor influencing the morphologies of microspheres lies also in the interaction between the polymer and the solvent. By adjusting the flow rate, voltage, and nozzle-plate distance, the diameters of microspheres, were within the controllable spectrum between 9μm and 14μm.6. Based on the results of the experiments on electrospray of amino acid ester substituted polyphosphazene and biodegradable aliphatic polyester and the rules of morphology and diameter control derived from the results, this paper analyzed the mechanism of electrospray of polymer solution from the perspective of interactions among macromolecules in polymer solution and different solubility of polymers in different solvents, and finally established an explanatory model of electrospray of polymer solution.