Diblock Terpolymers Are Tunable and pH Responsive Vehicles To Increase Hydrophobic Drug Solubility for Oral Administration
28. September 2017
Synthetic polymers offer tunable platforms to create new oral drugdelivery vehicles (excipients) to increase solubility, supersaturation maintenance, and bioavailability of poorly aqueous soluble pharmaceutical candidates. Five well-defined diblock terpolymers weresynthesized via reversible addition–fragmentation chain transfer polymerization (RAFT) and consist of a first block of either poly(ethylene-alt-propylene) (PEP),poly(N-isopropylacrylamide) (PNIPAm), or poly(N,N-diethylaminoethyl methacrylate) (PDEAEMA) and a second hydrophilic block consisting of a gradient copolymerof N,N-dimethylacrylamide (DMA) and 2-methacrylamidotrehalose (MAT). This family of diblock terpolymers offers hydrophobic, hydrophilic, or H-bonding functionalities to serve asnoncovalent sites of drug binding. Drug–polymer spray dried dispersions (SDDs) were created with a model drug, probucol, and characterized by differential scanning calorimetry (DSC). These studiesrevealed 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).However, the PDEAEMA-b-P(DMA-grad-MAT) system revealed poor probucol dissolution at pH 6.5 and 5.1. Alternatively, at an acidic pH of 3.1, a rapid and high dissolution profile andeffective supersaturation maintenance of up to 90% of the drug was found, which could be useful for triggering drug release in acidic environments (stomach). The PEP-b-P(DMA-grad-MAT)system showed poor performance (only ∼20% of drug solubility at pH 6.5), which was attributed to the low solubility of the polymers in the dissolution media. This work demonstrates the utility ofdiblock terpolymers as a potential new excipient platform to optimize design parameters for triggered release and solubilizing hydrophobic drug candidates for oral delivery.