ma-2014-01839s_0002-300x257The use of polymeric matrices (“excipients”) to bind, store, solubilize, transport, and deliver functional small molecules (“actives”) is of widespread importance across an array of industries, and critical pharmaceutical, personal care, agrochemical, and food technology applications. The physical and chemical interactions between excipient and active exert a strong influence over the performance of a given system, dictating such crucial metrics as shelf-life and delivery efficacy (e.g., bioavailability). It is also often the case that these two attributes are in direct competition; strategies that might enhance shelf-life (e.g., large crystallites of active, very high excipient glass transition temperature) can alter the kinetics of dissolution/delivery as well as the active efficacy.

Due to such constraints, and other requirements dictated by a particular technology or application, the delivery of a promising new active often requires corresponding development of a new excipient system, or substantial modification of an existing one, by an approach that is largely Edisonian and time-consuming. Furthermore, as many formulations result in metastable (rather than equilibrium) states, processing history plays a complicated role in performance. It is the overarching goal of this project to understand the way molecular interactions dictate structure in active/excipient combinations, and thereby to enable rational design of efficient, modular and designer storage and delivery systems. Furthermore, by innovative macromolecular design, we aim to produce active/excipient blends in which control over nano- and microstructure can produce equilibrium mixtures, or at least mixtures with sufficiently well defined morphologies, that reliable prediction of performance is possible.

ma-2012-00218n_0009The overarching goal of this project is to develop new polymer-drug conjugates and understand the molecular interactions that dictate macromolecular/supramolecular assembly of these new materials into nano- and micro-architectures. The structure-activity relationships of the polymer-drug systems are being studied in detail in an effort to enable rational design of efficient and modular drug delivery systems to establish pharmaceutical guidelines for oral drug delivery applications.

delivery

Oral Drug Delivery

Swapnil TOC The Reineke Group has been developing tunable synthetic polymers for oral drug delivery (excipient) applications in order to increase the solubility, supersaturation maintenance, and bioavailability of poorly aqueous soluble pharmaceutical candidates. In this study, five well-defined diblock terpolymers were synthesized via reversible addition–fragmentation chain transfer polymerization (RAFT). Drug–polymer spray dried dispersions (SDDs) were prepared with a model drug, probucol, and characterized by differential scanning calorimetry (DSC). These studies revealed that probucol crystallinity decreased with increasing H-bonding sites available in the polymer. The PNIPAm-b-P(DMA-grad-MAT) systems revealed the best performance at pH 6.5, where immediate probucol release and effective maintenance of 100% supersaturation was found, which is important for facilitating drug solubility in more neutral conditions (intestinal environment). This work demonstrates the utility of diblock terpolymers as a potential new excipient platform to optimize design parameters for triggered release and solubilizing hydrophobic drug candidates for oral delivery. Reference: S. Tale, A. Purchel, M. Dalsin, T. M. Reineke "Diblock terpolymers are tunable and pH responsive vehicles to increase hydrophobic drug solubility for oral administration", Mol. Pharmaceutics 2017, 14, 4121–4127.
Open Air TOC In collaboration with the Tirrell and Rowan research groups at The Institute for Molecular Engineering (University of Chicago), we recently investigated the use of in situ enzyme degassing to facilitate the open-to-air reversible addition–fragmentation chain transfer (RAFT) polymerization of hydroxyethyl acrylate (HEA) in a wide range of complex aqueous solvents, including, beer, wine, liquor, and fermentation broth. This enzyme-assisted polymerization procedure is impressively robust, and poly(HEA) was attained with good control over molecular weight and a narrow dispersity in nearly all of the solvents tested. Kinetics experiments on HEA polymerization in whisky and spectroscopic analysis of the purified polymers suggest high end-group fidelity, as does the successful chain extension of a poly(HEA) macro chain transfer agent with narrow dispersity. These results suggest enzyme-assisted RAFT may be a powerful and underutilized tool for high-throughput screening and materials discovery and may simplify the synthesis of well-defined polymers in complex conditions. Reference: D. Schneiderman, J. Ting, A. Purchel, R. Miranda, M. Tirrell, T. M. Reineke, S. Rowan "Open-to-Air RAFT Polymerization in Complex Solvents: From Whisky to Fermentation Broth", ACS Macro Lett. 2018, 7, 406–411.