Designing synergistic crystallization inhibitors: Bile salt derivatives of cellulose with enhanced hydrophilicity

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 pr...

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Veröffentlicht in:Carbohydrate polymers 2022-09, Vol.292, p.119680-119680, Article 119680
Hauptverfasser: Novo, Diana C., Gao, Chengzhe, Qi, Qingqing, Mosquera-Giraldo, Laura I., Spiering, Glenn A., Moore, Robert B., Taylor, Lynne S., Edgar, Kevin J.
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Sprache:eng
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Zusammenfassung: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. [Display omitted]
ISSN:0144-8617
1879-1344
DOI:10.1016/j.carbpol.2022.119680