Y. Zhang, K. Ristroph, J. Feng, S. McManus, R.K. Prud'homme
Keywords: nanoparticle, bioavailability, amorphous drug, malaria, cryptosporidium
Summary:About 40% of drugs with market approval and nearly 90% of molecules in the discovery pipeline are poorly water-soluble, which poses a big challenge in drug discovery and development. Two conventional particle engineering strategies commonly used to improve bioavailability of poorly water-soluble drugs are increasing the specific surface area (e.g., size reduction by mechanical micronization) and producing amorphous form the forms (e.g., holt-melt extrusion). However, for many of class II drugs, those techniques are not adequate to overcome the low bioavailability. Nanocrystals have merged as a new viable tool in this field as it can increase the dissolution rate, apparent solubility, and mucoadhesiveness. At the same time, due to high free surface energy, they are prone to aggregation, resulting in loss of previously increased solubility and increase in physical instability. In our group, we used Flash nanoprecipitation (FNP), a copolymer-directed assembly process, to prepare API (active pharmaceutical ingredient)-loaded nanoparticles with increased specific surface area and reduced drug crystallinity. We specifically focused on drugs fighting global health threat (e.g., cryptosporidium, malaria) and their oral formulation development for pediatric patients. We will show two case studies in the poster. Firstly, we have successfully developed clofazimine nanoparticles with three biocompatible stabilizers, namely, hypromellose acetate succinate (HPMCAS), lecithin, and zein, using FNP technology with high encapsulation efficiency (>93%). Clofazimine is a lipophilic antibiotic and recently was identified as lead hit for Cryptosporidiosis by Caliber Institute for Biomedical Research (CALIBR). To solidify the nanoparticle liquid suspension to redispersible powders for ease of drug administration, storage and transportation, standard lyophilization as well as a more cost-effective alternative approach spray drying were explored. The dissolution kinetics of clofazimine nanoparticles prepared by different surface coatings were studied by a media-swap dissolution test in simulated gastric and intestinal fluid. The crystalline clofazimine powder and its commercial product Lamprene® were also included as comparison. Differential scanning calorimetry and scanning electron microscopy were used to characterize the physical state of the drug in the nanoparticle powders. Additionally, in vivo pharmacokinetics study was carried out in rats to understand the oral bioavailability difference between clofazimine nanoparticles stabilized by distinct stabilizers. Secondly, OZ439 mesylate was a new antimalarial drug developed by Medicines for Malaria Venture (MMV). While it is highly water-soluble, it can quickly recrystallize to an insoluble chloride salt in the stomach, rendering its remarkably compromised oral bioavailability. To make it applicable for our FNP, we applied a strategy named “in situ hydrophobic ion pairing” to prepare a hydrophobic ion complex of OZ439 mesylate with sodium oleate. The nanoparticles formed exhibited satisfactory water redispersibility upon lyophilization and improved dissolution kinetics in water and simulated gastric fluid and intestinal fluids compared to the OZ439 mesylate powder. OZ439 nanoparticles exhibited up to nearly one order magnitude higher supersaturation concentrations compared to free API. Physical characterization of the formulations indicated that encapsulated compound existed in amorphous form, which yielded the supersaturated drug concentrations.