Designing synergistic crystallization inhibitors: Bile salt derivatives of cellulose with enhanced hydrophilicity.
Carbohydr Polym
; 292: 119680, 2022 Sep 15.
Article
em En
| MEDLINE
| ID: mdl-35725174
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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Ácidos e Sais Biliares
/
Celulose
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article