It is estimated that ~60% of anti-cancer small molecules and up to 80% of late-stage investigational compounds are poorly soluble in water, and such compounds are often associated with significant clinical problems, such as inconsistent dosing and variable pharmacokinetics (PK). Dasatinib is an orally bioavailable tyrosine kinase inhibitor (TKI) indicated for the treatment of chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL). Marketed formulations of dasatinib exhibit a number of solubility issues, including pH-dependent solubility, significant drug interactions with antacids, and inter-dose and inter-patient variability. Inconsistent dosing and variable bioavailability can lead to significant therapeutic problems, such as adverse events, poor patient adherence, and decreased clinical efficacy. In this Phase I SBIR project, MAA Laboratories will use their proprietary drug delivery technology (the NanoContTM) to create a stable nanoformulation of dasatinib, which is expected to have improved solubility and oral bioavailability relative to the marketed dasatinib formulation. The NanoContTM drug delivery technology is built on a continuous manufacturing platform and uses a combination of proprietary formulations and process conditions and a patented polymer-coating process to create drug nanoformulations (i.e. composed of pharmaceutical crystals ~100 nm in diameter) with unchanged crystals, long-term product stability (>2 years), and enhanced clinical benefits. The specific objective of this proposal is to advance one of MAA's initial nanoformulated drug products, dasatinib (MAAC-002), through formulation development and preclinical studies, including side-by- side performance comparisons with the currently marketed dasatinib formulation. The central hypothesis of this SBIR Phase I project is that the NanoContTM drug delivery technology can be used to create a stable nanoformulation of dasatinib that exhibits improved oral bioavailability and therapeutic efficiency relative to the currently marketed dasatinib formulation.
In Aim 1, an optimized nanoformulation of MAAC-002 will be generated and aqueous solubility and in vitro dissolution will be measured relative to the marketed formulation of dasatinib.
In Aim 2, the oral bioavailability of MAAC-002 will be investigated relative to the marketed formulation in nude mice.
In Aim 3, we will perform preclinical anti-leukemia therapeutic efficiency studies in mice using multiple ascending doses of MAAC-002 and the dasatinib marketed formulation. The proposed studies will establish proof-of-concept for a novel nanoformulation of dasatinib using direct comparisons to the marketed formulation. A successful result will generate an optimized MAAC-002 product with an improved PK profile, and will prepare this product for IND-enabling safety/toxicology studies and IND submission as part of an SBIR Phase II project.
Many active pharmaceutical ingredients are insoluble in water and are therefore not readily absorbed by the body after oral administration. MAA Laboratories has developed an innovative drug delivery technology that is designed to formulate difficult-to-dissolve drugs into drug products with significantly improved solubility and oral bioavailability. The proposed studies will accelerate MAA's efforts to develop a novel formulation of an anti- leukemia drug product that currently has significant deficiencies related to dosing and bioavailability, which will provide an improved therapeutic option for patients with leukemia.