Synthesis And Apllication Of P-dioxanone Based Polymer Microparticles In Supercritical Carbon Dioxide

Supercritical carbon dioxide(scCO2) has attracted much attention in recent years as an environmentally friendly medium for materials synthesis and processing, due to its inert, nontoxic, nonflammable nature and natural abundance. scCO2 not only has liquid-like density and dissolving capacity, but also exhibits gas-like diffusivity and viscosity. The synthesis and processing of biodegradable polymers via the medium of scCO2 have advantages to avoid the use of organic solvents and protect the activity of labile ingredients duo to the mild supercritical temperature condition. Therefore, the work based on supercritical techniques with the aim to produce novel biodegradable particles and develop novel drug encapsulation method, is of critical importance in the sense of theoretical value and practical applications.In this thesis, our work focused on the studies of suspension polymerization behavior of p-dioxanone(PDO) and glycolide(GA) monomers in scCO2, whose homopolymers could not be dissolved into traditional organic solvent and have limited biomedical applications due to the inability for solvent processing. There are three issues that we are mainly concerned, including the production of polymeric particles, the control of particle size and morphology, and the realization of particle production at low temperature and in-situ encapsulation of drugs into the particles. The research work is outlined below:(1) Suspension polymerization of p-dioxanone(PDO) or copolymerization of PDO and L-lactide(L-LA) in scCO2 were investigated using poly(ε-caprolactone)-perfluropolyether-poly(ε-caprolactone)(PCL-PFPE-PCL) as stabilizer and stannous octoate as catalyst. The poly(p-dioxanone)(PPDO) particles with the average size of 8 um were successfully obtained in this way. The effects of structure and amount of surfactant and stirring rate on PPDO particles were discussed. The effect of PDO/L-LA feed ratio on the chemical microstructure, morphology and size, as well as crystallization property of P(LLA-co-PDO) products was also investigated. It was found that when the CL/PFPE molar ratio in PCL-PFPE-PCL was 12:1, the PPDO product was collected as fine powder. And the size of the particles was inversely proportional to the content of the stabilizer and the stirring rate. For P(LLA-co-PDO) copolymers, when the PDO monomer in the feedstock was in the range of 5-15 wt%, powderous products were acquired and the size of particles increased gradually with increasing PDO content in the copolymers. The average block length, crystallinity and non-thermal crystallization temperature of L-LA component were also decreased with the increase of PDO content. It turned out that the formation of particles for PPDO and P(LLA-co-PDO) polymers could be ascribed to the chemical microstructure and crystallization property of the polymers.(2) Suspension copolymerization of glycolide(GA) and PDO or polymerization of GA at different temperatures was studied under the above similar synthetic conditions in scCO2. The particles with average size of 20-80 μm were acquired, and by the control of composition and polymerization temperature, regular spherical particles were also achieved. The effects of PDO/GA feed ratio and polymerization temperature on the morphology and size as well as crystallization property of the polymers were investigated. By the comparison of morphology of PLLA and PPDO particles, the factors that affected particle morphology were discussed and the mechanism for the formation of spherical particles was suggested. It was found that when the PDO feed content for P(GA-co-PDO) copolymers was 10 wt%, the product was mainly composed of spherical particles. And with further increasing PDO feed content(20-40 wt%), the percentage of spherical particles in the products decreased, with obvious agglomeration occurred and particle size increased. For PGA products acquired at different temperatures, the low temperature(70-80 oC) samples were irregular particles, while the high temperature(90-100 oC) contained substantial spherical particles. It was indicated that the introduction of PDO units or change of polymerization temperature were effective to control the crystallization behavior of GA segments and avoid the early precipitation of GA crystals in the polymerizing monomer droplets, which were beneficial for the formation of spherical particles.(3) Suspension copolymerization of polyethylene glycol(PEG) and PDO or GA was studied under the above similar synthetic conditions in scCO2. When the molecular weight and feed ratio of PEG were suitable, the particulate products with average size of 10-20 um were acquired. The effects of PEG molecular weight and feed ratio on the size and morphology as well as crystallization behavior of the triblock copolymer products were investigated. It was found that when the molecular weight of PEG was in the range of 2K-6K, and the feed content below 20 wt%, PPDO-PEG-PPDO particles were acquired. And when the feed content of PEG6 K was below 15 wt%, PGA-PEG-PGA particles were also obtained. For the case of PGA-PEG-PGA, if limiting PEG6 K feed content to 10-15 wt%, spherical particles in the products were observed. The particle size and non-isothermal crystallization temperature for both copolymers varied not obviously with the change of PEG content. However, the crystallinity of PGA or PPDO component decreased significantly with increasing PEG content. The introduction of hydrophilic PEG was helpful to enhance the water adsorption ability of the particles. It was indicated that the presence of PEG affected little the crystallizability of the copolymers. But the incompatibility and phase separation between PEG and the crystalline component(PGA or PPDO), the amorphous state of PEG in the particles, and the possible enrichment of PEG phase on the particle surface due to the scCO2 plasticization effect, may play roles together to affect the volume percentage and distribution of crystalline domains within the particles, and thereby their final solidification process.(4) Suspension polymerization of PDO at body temperature(37 oC) in scCO2 was firstly studied in the presence of modified stabilizer and using highly active dibutytin dimethoxide as catalyst, and PPDO particles with average size of 7-50 μm were successfully obtained. The effect of pressure on particle size was investigated and it was found that at 9 MPa, the particles have the smallest size and highest yield. Based on this optimum particle preparation conditions, the in-situ loading of paclitaxel into the particles was realized by pre-mixing the drug with the monomer, and the particulate drug delivery system was thus constructed. It was shown by 1H-NMR and HPLC that the drug loading content(4.25 wt%) and encapsulation efficiency(85.0%) are both high, and the structure and activity of paclitaxel could be preserved well. The initial burst release was not obvious for the formulation and the release was steady and could last more than one month. It was indicated that the developed novel preparation method for particulate drug delivery formulation have the advantages such as mild preparation temperature condition, uniform distribution of drug in the particles and high encapsulation efficiency, and could be applied to a wide range of hydrophobic drugs.In conclusion, in this thesis, a series of biodegradable polyester particles were successfully prepared via suspension polymerization in scCO2, which offers novel usage form and application fields for these materials that could be solvent processed. Particularly, we developed a novel method that combined polymer synthesis, particle preparation and drug loading in a single step, and realized in-situ drug loading during suspension polymerization at low temperature. Thus, the work conducted in this thesis is of critical importance to expand the use of supercritical techniques for the preparation of biodegradable materials and development of novel formulation technique.