(525a) Invited Speaker: Scalable Manufacturing Methods for Polymeric Nanoparticle Drug Delivery Systems

Although manufacturing technologies for hydrophilic drug carriers, such as solid polymer nanoparticles and liposomes have been well-established, there are fewer approaches for the delivery of hydrophobic drugs. Hydrophobic drug delivery represents a significant bottleneck in therapeutic development, especially for central nervous system therapeutics, which must also cross the blood-brain-barrier (BBB). It is estimated that 98% of small molecule drugs cannot cross BBB, resulting in the failure of 90% of molecules in development by the pharmaceutical industry (1). Thus, additional carriers for hydrophobic drug delivery are critically needed.

Micelle drug delivery carriers offer an attractive option for the solubilization of hydrophobic drugs. However, to be clinically effective manufacturing technologies for micelles should: produce product at high throughput, with high purity and minimal residual solvent, with high encapsulation efficiency, and efficient biodistribution and release at the target site. We are investigating scalable nanomanufacturing approaches for polymeric micelle synthesis, including flash nanoprecipitation (FNP) (2) and electrospray assisted-micelle formation (Aero-IS) (3) that scale-up batch water addition and interfacial instability approaches.

Here, we will discuss nanoparticle carrier design to optimize encapsulation of drugs with differing chemical structure (e.g., dexamethasone steroids, SAHA/vorinostat anti-cancer compounds, and lutein nutraceuticals). Chemical composition strongly influences encapsulation efficiency, but also plays a critical role in the surface properties of the resultant micelle. We will also evaluate competing scalable technologies (i.e., FNP vs. Aero-IS) discussing challenges in solvent removal, drug encapsulation efficiency, and final micelle structure that result from thermodynamic and kinetic limitations of these processes. Finally, we will discuss our efforts to design a drug delivery system for a model therapeutic, SAHA, for the treatment of glioma brain cancers, necessitating delivery across BBB.

References

1. Vlieghe et al., Medicinal Research Reviews, 33(3): 457, 2013.
2. Johnson et al., Physical Review Letters, 91(11): 118302, 2003.
3. Duong et al., Langmuir, 30(14): 3939, 2014.