Formulation-based approach to support early drug discovery and development efforts: a case study with enteric microencapsulation dosage form development for a triarylmethane derivative TRAM-34; a novel potential immunosuppressant

• Authors: Abeer M. Al-Ghananeem, University of Kentucky; Maggie Abbassi, University of Kentucky; Srishti Shrestha, University of Kentucky; Girija Raman, University of California Davis; Heike Wulff, University of California Davis; Lara Pereira, Emory University; Aftab Ansari, Emory University
• Journal Title: Drug Development and Industrial Pharmacy
• Volume: Volume 36, Number 5
• Publisher: Taylor & Francis: STM, Behavioural Science and Public Health Titles | 2010-05-01, Pages 563-569
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.3109/03639040903329554
• Subjects: Health Sciences, Pharmacology; Health Sciences, Pathology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Chemistry, Medicinal; Pharmacology & Pharmacy; Bioavailability; coacervation; enteric coating; microencapsulation; oral; TRAM-34; K+ CHANNEL; MICROPARTICLES; IKCA1; CELLS

Abstract

Background: Enteric microencapsulation of the potential immunosuppressant TRAM-34 was investigated as a means of enhancing oral drug delivery and minimizing or eliminating hydrolysis of pyrazole-substituted triarylmethane to the respective alcohol. Method: TRAM-34 was successfully enteric microencapsulated by a coacervation method using the pH-sensitive Eudragit L 100 polymer. In this study, we utilized watermiscible organic solvents such as acetone and ethanol, which are considered safe class 3 solvents according to the ICH guideline. We deemed such an approach suitable for safe scale up and for enteric coating application to other compounds of a similar lipophilicity. Results: The resulting microparticles were spherical and uniform with an average particle size of 460 μm at 15 theoretical loading. The encapsulation efficiency was 90 ± 1.9 and the percentage yield was found to be 91.5 ± 0.3. The oral administration in rhesus macaques of TRAM-34-loaded enteric-coated microparticles illustrated six times enhancement in its oral bioavailability. However, the TRAM-34 plasma concentration was less than the therapeutic effective level. Conclusion: The low oral bioavailability, even after enteric coating, could be attributed to the compound's inherent absorption characteristics and high lipophilicity.