Rifampin Stability and Solution Concentration Enhancement Through Amorphous Solid Dispersion in Cellulose ω-Carboxyalkanoate Matrices

• Published in: Journal of pharmaceutical sciences Vol. 107; no. 1; pp. 127 - 138
• Main Authors: Arca, Hale Çiğdem, Mosquera-Giraldo, Laura I., Pereira, Junia M., Sriranganathan, Nammalwar, Taylor, Lynne S., Edgar, Kevin J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2018
• Subjects: amorphous; Biological Availability; biomaterials; Cellulose - analogs & derivatives; Cellulose - chemistry; colonic drug delivery; Drug Carriers - chemistry; drug delivery systems; Drug Delivery Systems - methods; Drug Stability; Hydrogen-Ion Concentration; oral drug delivery; poorly water-soluble drugs; Rifampin - chemistry; solid dispersion; Solubility - drug effects; Solutions - chemistry; poorly water-soluble drugs; drug delivery systems; amorphous; colonic drug delivery; solid dispersion; oral drug delivery; biomaterials
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1016/j.xphs.2017.05.036

Tuberculosis (TB) is a deadly infectious disease; approximately 2 billion people are currently latently infected with the causative agent Mycobacterium tuberculosis. Approximately 8 million new active cases and 2 million deaths due to TB are recorded annually.1 Rifampin (Rif) is a vital first-line TB treatment drug. Its effectiveness is hampered by the high dose required (600 mg 1×/day) and by its moderate, variable bioavailability. These issues can be explained by Rif instability at gastric pH, limited solubility at neutral pH, polymorphism, and stimulation of its own metabolism. To overcome these obstacles, we developed new cellulose-based oral drug delivery systems aiming to increase and make more consistent Rif solubility and bioavailability. Amorphous solid dispersions (ASDs) of Rif with cellulose ω-carboxyalkanoates (cellulose acetate suberate, cellulose acetate propionate adipate, and cellulose acetate butyrate sebacate) were prepared and compared with crystalline Rif (negative) and carboxymethyl cellulose acetate butyrate ASD (positive) controls. Cellulose ω-carboxyalkanoate ASDs prevented acid-catalyzed degradation in conditions mimicking the acidic stomach and provided complete release of intact Rif at intestinal pH. Rif incorporation into ASD in these novel cellulose derivative matrices creates the potential for convenient, robust, consistent, and high Rif oral bioavailability for treatment of TB.