Cellulose-based amorphous solid dispersions enhance rifapentine delivery characteristics in vitro. (15th February 2018)

• Record Type: Journal Article
• Authors: Winslow, Christopher J.; Nichols, Brittany L.B.; Novo, Diana C.; Mosquera-Giraldo, Laura I.; Taylor, Lynne S.; Edgar, Kevin J.; Neilson, Andrew P.
• Is Part Of: Carbohydrate polymers. Volume 182(2018)
• Page Start: 149
• Page End: 158
• Publication Date: 2018-02-15
• Subjects: Rifapentine (PubChem CID: 6323497) -- Rifampicin (PubChem CID: 5458213) -- 3-Formylrifamycin (PubChem CID: 6438444) -- Hydroxypropylmethylcellulose acetate succinate (PubChem CID: 121950); ASD amorphous solid dispersion -- AUC area under the curve -- CASub cellulose acetate suberate -- DSC differential scanning calorimetry -- Tg glass transition temperature -- Tm melting point -- HPMCAS hydroxypropyl methylcellulose acetate succinate -- LLOD lower limit of detection -- LLOQ lower limit of quantification -- Mw molecular weight -- Mn average molecular weight -- Cmax maximum concentration -- PVP polyvinylpyrrolidone -- PXRD X-ray powder diffraction -- RPT rifapentine -- RIF rifampin -- SI supplementary information -- TB tuberculosis -- 3-FR 3-formylrifamycin -- CHC 5-carboxypentyl hydroxypropyl cellulose; Dissolution -- Bioavailability -- Solubility -- Macrolide -- Crystalline; Polysaccharides -- Periodicals; Polysaccharides -- Periodicals; Polysaccharides -- Périodiques; Electronic journals; 547.78
• DOI: 10.1016/j.carbpol.2017.11.024
• Languages: English
• ISSNs: 0144-8617

Abstract

Highlights: Rifapentine, used to treat tuberculosis, has undesirable dissolution properties. Amorphous solid dispersion with cellulose derivatives improved dissolution. Amorphous solid dispersion protected rifapentine from release at gastric pH. Amorphous solid dispersion protected rifapentine from acidic degradation. Amorphous solid dispersion provided rifapentine supersaturation at intestinal pH. Abstract: The efficacy of rifapentine, an oral antibiotic used to treat tuberculosis, may be reduced due to degradation at gastric pH and low solubility at intestinal pH. We hypothesized that delivery properties would be improved in vitro by incorporating rifapentine into pH-responsive amorphous solid dispersions (ASDs) with cellulose derivatives including: hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetate suberate (CASub), and 5-carboxypentyl hydroxypropyl cellulose (CHC). ASDs generally reduced rifapentine release at gastric pH, with CASub affording >31-fold decrease in area under the curve (AUC) compared to rifapentine alone. Critically, reduced gastric dissolution was accompanied by reduced degradation to 3-formylrifamycin. Certain ASDs also enhanced apparent solubility and stabilization of supersaturated solutions at intestinal pH, with HPMCAS providing nearly 4-fold increase in total AUC vs. rifapentine alone. These results suggest that rifapentine delivery via ASD with these cellulosic polymers may improve bioavailability in vivo.