| Inhalable, biodegradable poly(l-lactide) (P(L)LA) microparticles were produced by the method of precipitation with a compressed antisolvent (PCA). This work evaluates the feasibility of using these microparticles for pulmonary drug delivery with specific targeting to alveolar macrophages (AMs) for controlled release treatment of intracellular pathogens such as tuberculosis.; The biocompatibility of biodegradable P(L)LA microparticles was investigated both in vitro and in vivo, by examining the AM cellular response to microparticles of different crystallinity. The in vitro cellular response was characterized by the production of reactive oxygen intermediates produced upon exposure to microparticles. The cellular response elicited by acute exposure to microparticles instilled into guinea pig lungs was also studied.; The clearance rate, retention time and trafficking from the lung of biocompatible, P(L)LA microparticles was determined in mice. Fluorescently labeled P(L)LA microparticles were administered intranasally for introduction into mouse lungs. Microparticle retention and clearance rates were monitored over the course of three weeks. Microparticle translocation to other tissues such as lymph nodes and spleen was also examined.; Hydrophobic ion pairing (HIP) has been utilized to increase the solubility of charged pharmaceutical agents in organic solvents for incorporation into P(L)LA microparticles. Another potential use for HIP is to enhance the transport of pharmaceutical agents through biological barriers. The efficacy of an HIP-tetracycline complex was compared to that of tetracycline HCl by monitoring growth rates of E. coli.; We have developed a model for predicting intracellular drug concentrations over time, following microparticle uptake by AMs. The model uses parameter values based on in vitro data and incorporates the parameters that are important for any controlled release delivery system (e.g. microparticle size, drug loading fraction, rate of drug release from microparticle). The model also takes into account the parameters that would be crucial for an efficacious, intracellular delivery system (i.e. microparticle uptake, drug removal from the cell by efflux, degradation, metabolism, etc). The general model was expanded to describe our specific P(L)LA system that encapsulates ion-paired isoniazid for tuberculosis treatment. |
