(692g) Synthesis and Characterization of Drug-Polysaccharide Nanoparticles for Oral Drug Delivery

For the treatment of many diseases such as tuberculosis (TB) and Human Immunodeficiency Virus (HIV), it is important to formulate drugs so that they are released in a controlled and sustained manner.  Polymer-encapsulated drug nanoparticles are particularly interesting due to the enhanced properties that result from interactions between the polymer carrier and the drug and from a reduction in particle dimensions. Oral administration of therapeutic agents represents by far the easiest and most convenient route of drug delivery but it is challenging to design delivery systems optimizing the chemical and morphological stability of a drug in the gastrointestinal (GI) tract so that a desirable pharmacokinetic profile may be attained.  Dissolution of drugs is quite often the rate-limiting step which controls the bioavailability of the drug. Recent work has demonstrated the great potential for using polysaccharides to form complexes with drugs that can result in enhanced oral drug solubility and, thus, enhanced bioavailability due to the disruption of drug crystallinity. This work concerns the synthesis and characterization of nanoparticles comprised of drugs and polysaccharides selected for their potential use in oral drug delivery.

Nanoparticles comprised of drugs encapsulated in carboxymethyl cellulose acetate butyrate (CMCAB) were produced by rapid precipitation and the formulation process and properties of the nanoparticles were investigated. An antibacterial drug – rifampicin used to treat TB - and less soluble anti-viral drugs – ritonavir and efavirenz which are used to treat HIV - were selected as model drugs for this study. The purposes of this research were two-fold. First, the methodology for producing drug-polymer nanoparticles with well-defined particle size distributions was developed. Second, the factors affecting drug loading and release properties were investigated. The nanoparticles were formed under turbulent conditions in a multi-inlet vortex mixer. Particle diameters ranged between 150-400 nm with narrow polydispersity indices as measured by dynamic light scattering. The rifampicin drug loading efficiencies ranged from 14-40% whereas, for the less soluble antiviral drugs, drug loading efficiencies were as high as 85%. X-ray diffraction and differential scanning calorimetry experiments established that the drugs in the drug-polymer nanoparticles were mostly amorphous which is important for increasing the effective solubility and hence bioavailability of the drugs. Dissolution studies in a pH 6.8 buffer at 37^oC were consistent with this, showing an increase in the solubility of the amorphous drug nanoparticles compared to crystalline forms of the drugs.