mp7b00458_si_001.pdf (2.62 MB)
Diblock Terpolymers Are Tunable and pH Responsive Vehicles To Increase Hydrophobic Drug Solubility for Oral Administration
journal contribution
posted on 2017-09-22, 00:00 authored by Swapnil Tale, Anatolii A. Purchel, Molly C. Dalsin, Theresa M. ReinekeSynthetic polymers
offer tunable platforms to create new oral drug
delivery vehicles (excipients) to increase solubility, supersaturation
maintenance, and bioavailability of poorly aqueous soluble pharmaceutical
candidates. Five well-defined diblock terpolymers were synthesized
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 copolymer of N,N-dimethylacrylamide
(DMA) and 2-methacrylamidotrehalose (MAT). This family of diblock
terpolymers offers hydrophobic, hydrophilic, or H-bonding functionalities
to serve as noncovalent 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
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).
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 and effective 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 of diblock terpolymers as a potential new excipient platform
to optimize design parameters for triggered release and solubilizing
hydrophobic drug candidates for oral delivery.