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

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 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.

Conclusion: The low oral bioavailability, even after enteric coating, could be attributed to the compound's inherent absorption characteristics and high lipophilicity.

Figure 1

Structure of 1-[(2-chlorophenyl)-diphenylmethyl]-1H-pyrazole (TRAM-34)

Figure 2

Transmission electron microscopy (TEM) of enteric coated TRAM-34 loaded microparticles

Figure 3

Scanning electron micrographs (SEM) of an enteric coated TRAM-34 loaded microparticle

Figure 4

Effect of pH change (pH 1.2 to pH 6.8 after 60 min) on the TRAM-34 release from Eudragit L100 microcapsules. (Mean ± SD, n = 3)

Figure 5

Concentration-time profile of intravenous dosing of TRAM-34 to Rhesus Macaques at single dose of 5 mg/kg.

Figure 6

Concentration-time profile of TRAM-34 powder at 50mg/kg oral dose (♦) and TRAM-34 enteric microparticles at 25 mg/kg oral dose (■) to Rhesus Macaques primates.