Drug-Polymer Nanodroplet Formation and Morphology Drive Solubility Enhancement of GDC-0810.

Nanodroplet formation is important to achieve supersaturation of active pharmaceutical ingredients (APIs) in an amorphous solid dispersion. The aim of the current study was to explore how polymer composition, architecture, molar mass, and surfactant concentration affect polymer-drug nanodroplet morphology with the breast cancer API, GDC-0810. The impact of nanodroplet size and morphology on dissolution efficacy and drug loading capacity was explored using polarized light microscopy, dynamic light scattering, and cryogenic transmission electron microscopy. Poly(N-isopropylacrylamide-stat-N,N-dimethylacrylamide) (PND) was synthesized as two linear derivatives and two bottlebrush derivatives with carboxylated or PEGylated end-groups. Hydroxypropyl methylcellulose acetate succinate grade MF (HPMCAS-MF) and poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA) were included as commercial polymer controls. We report the first copolymerization synthesis of a PVPVA bottlebrush copolymer, which was the highest performing excipient in this study, maintaining 688 µg/mL GDC-0810 concentration at 60 wt % drug loading. This is likely due to strong polymer-drug noncovalent interactions and the compaction of GDC-0810 along the PVPVA bottlebrush backbone. Overall, it was observed that the most effective formulations had a hydrodynamic radius less than 25 nm with tightly compacted nanodroplet morphologies.

Protein Stabilization and Delivery: A Case Study of Invasion Plasmid Antigen D Adsorbed on Porous Silica.

Approximately half of all vaccines produced annually are wasted because effectivity is dependent on protein structure and heat exposure disrupts the intermolecular interactions needed to maintain the structure. Thus, most vaccines require a temperature-controlled supply chain to minimize waste. A more sustainable technology was developed via the adsorption of invasion plasmid antigen D (IpaD) onto mesoporous silica, improving the thermal stability of this protein-based therapeutic. Seven silicas were characterized to determine the effects of pore diameter, pore volume, and surface area on protein adsorption. The silica-IpaD complex was then heated above the IpaD denaturing temperature and N,N-dimethyldodecylamine N-oxide was used to remove IpaD from the silica. Circular dichroism confirmed that the adsorbed IpaD after the heat treatment maintained a native secondary structure rich in α-helix content. In contrast, the unprotected IpaD after heat treatment lost its secondary structure. Isotherms using Langmuir, Freundlich, and Temkin models demonstrated that the adsorption of IpaD onto silicas is best fit by the Langmuir model. If pores are less than 15 nm, adsorption is negligible. If the pores are between 15 and 25 nm, then monolayer coverage is achieved and IpaD is protected from thermal denaturing. If pores are larger than 25 nm, the adsorption is a multilayer coverage and it is easier to remove the protein from the silica because of a less-developed hydrogen bond network. This case study provides strong evidence that IpaD is thermally stabilized via adsorption on mesoporous silica with the proper range of pore sizes.