Designing synergistic crystallization inhibitors: Bile salt derivatives of cellulose with enhanced hydrophilicity. (15th September 2022)

• Record Type: Journal Article
• Authors: Novo, Diana C.; Gao, Chengzhe; Qi, Qingqing; Mosquera-Giraldo, Laura I.; Spiering, Glenn A.; Moore, Robert B.; Taylor, Lynne S.; Edgar, Kevin J.
• Is Part Of: Carbohydrate polymers. Volume 292(2022)
• Publication Date: 2022-09-15
• Subjects: Olefin cross-metathesis -- Bile-salts -- Cellulose -- Amorphous solid dispersion -- Enzalutamide -- Chemoselectivity; Polysaccharides -- Periodicals; Polysaccharides -- Periodicals; Polysaccharides -- Périodiques; Electronic journals; 547.78
• DOI: 10.1016/j.carbpol.2022.119680
• Languages: English
• ISSNs: 0144-8617

Abstract

Abstract: Crystallization inhibitors in amorphous solid dispersions (ASD) enable metastable supersaturated drug solutions that persist for a physiologically relevant time. Olefin cross-metathesis (CM) has successfully provided multifunctional cellulose-based derivatives as candidate ASD matrix polymers. In proof of concept studies, we prepared hydrophobic bile salt/cellulose adducts by CM with naturally occurring bile salts. We hypothesized that increased hydrophilicity would enhance the ability of these conjugates to maximize bioactive supersaturation. Their selective preparation presents a significant synthetic challenge, given polysaccharide reactivity and polysaccharide and bile salt complexity. We prepared such derivatives using a more hydrophilic hydroxypropyl cellulose (HPC) backbone, employing a pent-4-enyl tether (Pen) for appending bile acids. We probed structure-property relationships by varying the nature and degree of substitution of the bile acid substituent (lithocholic or deoxycholic acid). These conjugates are indeed synergistic inhibitors, as demonstrated with the fast-crystallizing prostate cancer drug, enzalutamide. The lithocholic acid methyl ester derivative, AcrMLC-PenHHPCPen (0.64), increased induction time 68 fold vs. drug alone. Graphical abstract: Unlabelled Image