(526b) Nanoparticles Comprised of Amorphous Solid Dispersions of Anti-Viral Drugs and Polysaccharides for Oral Drug Delivery: Effect of Polysaccharide Chemistry

For the treatment of many diseases such as 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 tract so that a desirable pharmacokinetic profile may be attained.  Dissolution of drugs is 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 amorphous solid dispersions of anti-viral drugs used to treat HIV and polysaccharides selected for their potential use in oral drug delivery. 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 effect of polysaccharide chemistry on drug loading and release properties was investigated.

Nanoparticles of amorphous dispersions of the antiviral drugs, efavirenz (a reverse transcriptase inhibitor) and ritonavir (a protease inhibitor) with several novel polysaccharides (cellulose esters and a pullulan derivative) were formed by the flash nanoprecipation method under turbulent conditions in a multi-inlet vortex mixer. Particles were purified by dialysis and dried powders were recovered after freeze drying. Particle diameters as measured by dynamic light scattering were in the range 100-200 nm. Nanoparticles of most of the polymers showed significant aggregation after freeze drying but this was reduced by using trehalose as a cryoprotectant. The exception was the polymer carboxymethyl cellulose acetate butyrate which formed nanoparticles that did not require any cryoprotectant for redispersion after freeze drying. In all cases, the target drug loading in the particles was 25 wt % and the drug loading efficiencies for the cellulose ester nanoparticles ranged from 72-96%, while the drug loading efficiency for the pullulan derivative nanoparticles was approximately 62%. 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. All the nanoparticles exhibited increased solution concentration and faster release compared to the pure, as-received drugs that were crystalline.