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.
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.


METHODS
TRAM-34 was successfully enteric microencapsulated by a coacervation method using the pH-sensitive Eudragit L 100 polymer. In this study, we utilized water-miscible 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 microm 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.


CONCLUSIONS
The low oral bioavailability, even after enteric coating, could be attributed to the compound's inherent absorption characteristics and high lipophilicity.
Al-Ghananeem
Abeer M
AM
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082, USA. amalg0@email.uky.edu
Abbassi
Maggie
M
Shrestha
Srishti
S
Raman
Girija
G
Wulff
Heike
H
Pereira
Lara
L
Ansari
Aftab
A
D000284:Administration, Oral; D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004304:Dosage Forms; D004339:Drug Compounding / Q000379:methods; D055808:Drug Discovery / Q000379:methods*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000737:chemistry*; D008253:Macaca mulatta; D008297:Male; D008697:Methane / Q000008:administration & dosage / Q000031:analogs & derivatives; D011720:Pyrazoles / Q000008:administration & dosage / Q000737:chemistry*; D013608:Tablets, Enteric-Coated
D004304:Dosage Forms; D007166:Immunosuppressive Agents; D011720:Pyrazoles; C411671:TRAM 34; D013608:Tablets, Enteric-Coated; D008697:Methane