Amorphous solid dispersions of enzalutamide and novel polysaccharide derivatives: investigation of relationships between polymer structure and performance

Abstract

Amorphous solid dispersion (ASD) is a widely employed formulation technique for drugs with poor aqueous solubility. Polymers are integral components of ASDs, but mechanisms by which polymers lead to the generation and maintenance of supersaturated solutions, which enhance oral absorption in vivo, are poorly understood. Herein, a diverse group of newly synthesized cellulose derivatives was evaluated for their ability to inhibit crystallization of enzalutamide, a poorly soluble compound used to treat prostate cancer. ASDs were prepared from selected polymers, specifically a somewhat hydrophobic polymer that was extremely effective at inhibiting drug crystallization, and a less effective, but more hydrophilic, crystallization inhibitor, that might afford better release. Drug membrane transport rate was evaluated in vitro and compared to in vivo performance, following oral dosing in rats. Good correlation was noted between the in vitro diffusion cell studies and the in vivo data. The ASD formulated with the less effective crystallization inhibitor outperformed the ASD prepared with the highly effective crystallization inhibitor in terms of the amount and rate of drug absorbed in vivo. This study provides valuable insight into key factors impacting oral absorption from enabling ASD formulations, and how best to evaluate such formulations using in vitro approaches.

Combining enabling formulation strategies to generate supersaturated solutions of delamanid: In situ salt formation during amorphous solid dispersion fabrication for more robust release profiles

“…However, size enlargement of DLM-rich droplets occurred in presence of PVPVA, as observed for other systems [37] . Given that drug-rich nanodroplets are thought to be important in improving oral bioavailability for some drugs [53] , [54] , where nanodroplet size may play a role [55] , PVPVA shows disadvantages for ASD formulations relative to HPMCAS and HPMCP. Indeed, the high sensitivity of delamanid to the polymer used to form that ASD is highlighted in Fig.…”

Bottlebrush Polymer Excipients Enhance Drug Solubility: Influence of End-Group Hydrophilicity and Thermoresponsiveness

“…Such APIs are categorized by the Biopharmaceutical Classification System (BCS) as Class II and can be solubilized with polymer excipients using a polymer-amorphous spray-dried dispersion (PASD) in which the amorphous API is suspended in a polymer matrix facilitating rapid dissolution and sustained solubility in aqueous media . Common classes of linear polymers used as excipients are cellulose-based, , polyvinylpyrrolidones, , poly­(ethylene oxide), and poly­(acrylic acid) . Many have been well studied with respect to the micro- and nanoscale interactions with APIs during dissolution. − However, the exploration of these important materials has been limited in the chemical and architectural scope.…”

Boost of solubility and supersaturation of celecoxib via synergistic interactions of methacrylic acid-ethyl acrylate copolymer (1:1) and hydroxypropyl cellulose in ternary amorphous solid dispersions

“…For an optimal performance, the polymer should be able to generate a supersaturated solution rapidly and ideally maintain the state of supersaturation over a long period of time ( Guzmán et al, 2007 ; Sun and Lee, 2013 ). However, generation and maintenance of a supersaturated solution is highly dependent on specific drug-polymer interactions ( Baghel et al, 2018a ; Warren et al, 2010 ; Wilson et al, 2020 ). In this context, the ASD forming polymer is not necessarily the ideal polymer to stabilize supersaturation in aqueous media ( Bachmaier et al, 2021 ; Monschke and Wagner, 2020 ).…”