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

c4py00399c-f2_hi-res-300x226Amphiphilic block copolymers are known to assemble into micelles that are of high interest for actives delivery applications. For example, micellar systems aid in improving aqueous solubility of hydrophobic drugs viaencapsulation within the micelle core. For systemic delivery, the payload must be transported intact to the target site. For tumors, one method is via passive targeting known as the enhanced permeability and retention (EPR) effect. While in circulation, polymer-based micelle carriers encounter numerous biological barriers. Therefore, in vivo delivery systems should possess hydrophilic regions that shield their payload from non-specific interactions with serum proteins, aggregation, and clearance by the reticuloendothelial system (RES) c4py00399c-f4_hi-resto increase circulation lifetime. Polymeric micelles can also lose their payload upon dilution. Biologically, premature release and aggregation can provoke severe side effects, including an acute immunological response, signifying the need to examine the stability and aggregation behavior of micelles in vitro. Herein, we report the synthesis of a trimethylsilyl (TMS)-protected trehalose monomer, 6-deoxy-6-methacrylamido-2,3,4,2′,3′,4′,6′-hepta-O-trimethylsilyl trehalose (TMS-MAT), for creation of amphiphilic block copolymers via RAFT polymerization. A family of polytrehalose (PT)-functionalized diblock terpolymers composed of three different units have been synthesized to create a diblock structure with distinct solubility profiles. An aliphatic hydrocarbon chain, poly(ethylene-alt-propylene) (PEP), has been incorporated as the hydrophobic fragment and a polytrehalose-functionalized gradient block copolymerized with dimethyl acrylamide (DMA) was combined in the hydrophilic unit in the amphiphilic structure. [Read more]
Synthetic and natural polymers hold tremendous potential to improve therapeutic potency, bioavailability, stability, and safety through aiding the solubility of lipophilic drug candidates that may otherwise be clinically inaccessible. For the leading pharmaceutical delivery method (oral administration), one such approach involves maintaining drugs in an amorphous, nonequilibrium state using spray-dried dispersions (SDDs). However, few well-understood vehicles exist, and available formulations employ Edisonian approaches without regard to examining chemical, thermodynamic, and kinetic phenomena. Herein, we present a rational approach to study polymer–drug interactions with a multicomponent polymer platform, inspired by hydroxypropyl methylcellulose acetate succinate (an excipient increasingly utilized as a delivery vehicle). The controlled syntheses of these modular analogs were strategically defined with (i) hydroxypropyl, (ii) methoxy, (iii) acetyl, (iv) succinoyl, and (v) glucose groups to tune the amphiphilicity balance (i–v), ionization near gastrointestinal pH levels (iv), hydrogen bonding (i, iii, iv, v), and glass transition temperature (v). We examined how polymer architecture produces amorphous SDDs with a highly hydrophobic drug model (probucol, log P = 8.9). Dissolution experiments revealed dramatic differences in bioavailability as a function of polymeric chemical specificity. We identify chemically driven interactions as crucial ingredients for facilitating amorphous phase behavior and supersaturation maintenance. [Read more]