Abstract
Poor drug solubility and consequently poor bioavailability are major impediments to new drug innovation, and they limit the performance of many existing drugs. In recent years amorphous solid dispersion (ASD) has emerged as one of the most effective approaches for enhancing drug solution concentration, and thereby bioavailability, including in many marketed drug formulations. Recently efforts have been under way in several laboratories to design new ASD polymers, rather than relying on polymers that are already in FDA-approved formulations, but were not designed as ASD polymers. We describe here the design and synthesis of a new class of polymers, alkyl cellulose ω-carboxyesters, for ASD formulation. We synthesize these polymers by reaction of cellulose alkyl ethers with monoprotected (benzyl ester), monofunctional long chain acid chlorides, followed by protecting group removal using mild hydrogenolysis to form the target alkyl cellulose ω-carboxyalkanoate. These new amphiphilic polymers have high glass transition temperatures (Tg), tunable carboxyl content for controlling release pH and drug-polymer interactions, and certain members of this new group of amphiphilic cellulose ether esters are shown to be successful at forming ASDs with the important model drug ritonavir. These ASDs efficiently release ritonavir at small intestine pH, creating the maximum attainable amorphous solubility (20 μg/mL), and maintaining it for a time period substantially greater than the normal residence time in the absorptive region of the stomach and small intestine. Members of this new class of alkyl cellulose ω-carboxyester amphiphiles show significant potential as ASD polymers for enhancing oral bioavailability of otherwise poorly soluble drugs.
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Acknowledgements
We thank Ashland Inc. for their kind donation of EC used in this work. We thank the NSF for funding this work through award 1312157-IIP. We are grateful to the Macromolecules and Interfaces Institute (MII), and the Institute for Critical Technologies and Applied Science (ICTAS) at Virginia Tech for their financial, facility, and educational support. We thank Dr. Ann Norris for assistance with XRD experiments, and Mr. Scott Radzinski and Mr. Kevin Drummey for assistance with SEC experiments.
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Arca, H.C., Mosquera-Giraldo, L.I., Taylor, L.S. et al. Synthesis and characterization of alkyl cellulose ω-carboxyesters for amorphous solid dispersion. Cellulose 24, 609–625 (2017). https://doi.org/10.1007/s10570-016-1156-y
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DOI: https://doi.org/10.1007/s10570-016-1156-y