Enhanced Performance of Blended Polymer Excipients in Delivering a Hydrophobic Drug through the Synergistic Action of Micelles and HPMCAS

Abstract

Blends of hydroxypropyl methylcellulose acetate succinate (HPMCAS) and dodecyl (C)-tailed poly(N-isopropylacrylamide) (PNIPAm) were systematically explored as a model system to dispense the active ingredient phenytoin by rapid dissolution, followed by the suppression of drug crystallization for an extended period. Dynamic and static light scattering revealed that C-PNIPAm polymers, synthesized by reversible addition-fragmentation chain-transfer polymerization, self-assembled into micelles with dodecyl cores in phosphate-buffered saline (PBS, pH 6.5). A synergistic effect on drug supersaturation was documented during in vitro dissolution tests by varying the blending ratio, with HPMACS primarily aiding in rapid dissolution and PNIPAm maintaining supersaturation. Polarized light and cryogenic transmission electron microscopy experiments revealed that C-PNIPAm micelles maintain drug supersaturation by inhibiting both crystal nucleation and growth. Cross-peaks between the phenyl group of phenytoin and the isopropyl group of C-PNIPAm in 2D H nuclear Overhauser effect (NOESY) spectra confirmed the existence of drug-polymer intermolecular interactions in solution. Phenytoin and polymer diffusion coefficients, measured by diffusion-ordered NMR spectroscopy (DOSY), demonstrated that the drug-polymer association constant increased with increasing local density of the corona chains, coincident with a reduction in C-PNIPAm molecular weight. These findings demonstrate a new strategy for exploiting the versatility of polymer blends through the use of self-assembled micelles in the design of advanced excipients.

Approaches to increase mechanistic understanding and aid in the selection of precipitation inhibitors for supersaturating formulations – a PEARRL review

“…Conversely, the diffusion coefficient decreased dramatically in the presence of C 12 ‐PNIPAm, in a concentration‐dependent manner. This provided the researchers with strong evidence that the C 12 ‐PNIPAm was responsible for the remarkable sustained supersaturation that was observed upon dissolution of this novel SDD, as well as the mechanism taking place within the corona of the micelles, which was not present in the C 2 variant …”

“…Furthermore, it was observed that the C 12 ‐PNIPAm inhibited precipitation of the supersaturated phenytoin by inclusion of the drug within the corona of the micelles, rather than the core. It was also concluded that the HPMCAS in the formulation had little effect on sustaining the supersaturation compared to C 12 ‐PNIPAm, which instead, was responsible for the enhanced dissolution of the drug from the SDD . These conclusions were reached using both NOESY and DOSY data.…”

“…Diffusion‐ordered spectroscopy was an essential part of a study assessing the suitability of a novel spray‐dried dispersion matrix, HPMCAS and dodecyl (C 12 ) poly(N‐isopropylacrylamide) (PNIPAm), for the system's suitability to enhance the delivery of a poorly soluble drug, phenytoin . After dissolution of the solid dispersion, the C 12 ‐PNIPAm polymers formed micelles with the dodecyl groups, which successfully sustained the supersaturated state of phenytoin generated by the spray‐dried dispersion (SDD).…”

Miktoarm Star Polymers with Environment‐Selective ROS/GSH Responsive Locations: From Modular Synthesis to Tuned Drug Release through Micellar Partial Corona Shedding and/or Core Disassembly

“…In drug loaded micelles, as recent studies have demonstrated, a proportion of the drug molecules is also associated with PEG coronae. [ 82–84 ] Thus, “partial corona shedding” would affect drug release both indirectly by aiding in core‐to‐environment diffusion and directly by freeing drug‐associated PEG chains. An interesting distinction can be made between the drug release profiles for miktoarm star polymer‐based and the diblock copolymer micelles.…”

Critical Excipient Properties for the Dissolution Enhancement of Phenytoin

“…15−19 Specifically, low-molar-mass, micelle-forming poly( N -isopropylacrylamide) (PNiPAm) homopolymer has performed well, both on its own 18 and when blended with hydroxypropyl methylcellulose acetate succinate (HPMCAS). 17 Poly( N , N -dimethylacrylamide- co - N -isopropylacrylamide) (PDMAm- co -PNiPAm) containing ∼70 mol % N -isopropylacrylamide has also performed well, both as free chains and as in the corona of self-assembled micelles. 16,19…”