Poly(ethylene-alt-propylene)–poly[(N,N-dimethylacrylamide)-grad-(2-methacrylamido glucopyranose)] (PEP–poly(DMA-grad-MAG), or PG) diblock terpolymers were synthesized by combining anionic and reversible addition–fragmentation chain transfer (RAFT) polymerizations. An ω-trithiocarbonate-functionalized PEP homopolymer served as the macromolecular chain transfer agent (macroCTA), and RAFT copolymerizations of DMA and a trimethylsilyl-protected MAG (TMS-MAG) monomer gave a family of PG diblock terpolymers after hydrolysis. The terpolymers had similar degrees of polymerization, and the MAG content ranged from 3.5 to 39 mol % in the hydrophilic block. At 70 °C, the reactivity ratios of DMA (1) and TMS-MAG (2) were determined to be r 1 = 1.86 ± 0.07 and r 2 = 0.16 ± 0.01, and thus the poly(meth)acrylamide blocks in the PG diblock terpolymers were likely to be gradient copolymers. Micellar dispersions from PG diblock polymers in water were examined by cryogenic transmission electron microscopy (cryo-TEM) and dynamic light scattering (DLS). Spherical micelles with core radii of ca. 7 nm and overall hydrodynamic radii of ca. 15 nm were the predominant morphologies observed in all samples prepared by sequential nanoprecipitation and dialysis. The electron-dense MAG moieties greatly increased the native contrast of the micellar coronae, which were clearly viewed as gray halos around the micellar cores in samples with relatively large MAG content. The stability of the glucose-installed micelles was tested in four biologically relevant media, from simple phosphate-buffered saline (PBS) to fetal bovine serum (FBS), using a combination of DLS and cryo-TEM measurements. Micellar dispersions from a PG diblock terpolymer with 16 mol % of MAG of the hydrophilic block were stable in 100% FBS over at least 14 h, suggesting their minimal interactions with serum proteins. Control experiments suggested that micelles composed of PDMA alone in the corona had similar serum stabilities. These sugar-functionalized micelles hold promise as in vivo drug delivery vehicles to possibly prolong circulation time after intravenous administration.

Spray dried dispersions (SDDs), solid dispersions of polymer excipients and active pharmaceuticals, are important to the field of oral drug delivery for improving active stability, bioavailability, and efficacy. Herein, we examine the influence of solution-state polymer assemblies on amorphous spray-dried dispersion (SDD) performance with two BCS II model drugs, phenytoin and probucol. These drugs were spray dried with 4 model polymer excipients consisting of poly(ethylene-alt-propylene) (PEP), N,N,-dimethylacrylamide (DMA), or 2-methacrylamido glucopyranose (MAG): amphiphilic diblock ter- and copolymers, PEP-P(DMA-grad-MAG) and PEP-PDMA, and their respective hydrophilic analogues, P(DMA-grad-MAG) and PDMA. Selective and nonselective solvents for the hydrophilic block of the diblock ter- and copolymers were used to induce or repress solution-state assemblies prior to spray drying. Prespray dried solution-state assemblies of these four polymers were probed with dynamic light scattering (DLS) and showed differences in solution assembly size and structure (free polymer versus aggregates versus micelles). Solid-state structures of spray dried dispersions (SDDs) showed a single glass transition event implying a homogeneous mixture of drug/polymer. Crystallization temperatures and enthalpies indicated that the drugs interact mostly with the DMA-containing portions of the polymers. Scanning electron microscopy was used to determine SDD particle size and morphology for the various polymer-drug pairings. In vitro dissolution tests showed excellent performance for one system, spray-dried PEP-PDMA micelles with probucol. Dissolution structures were investigated through DLS to determine drug-polymer aggregates that lead to enhanced SDD performance. Forced aggregation of the polymer into regular micelle structures was found to be a critical factor to increase the dissolution rate and supersaturation maintenance of SDDs, and may be an attractive platform to exploit in excipient design for oral drug delivery.

Synthetic 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.