Development of a self-emulsifying formulation that reduces the food effect for torcetrapib

Area of Science:

• Pharmacology
• Drug Delivery Systems
• Atherosclerosis Research

Background:

• Torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, is a lipophilic drug for atherosclerosis.
• Early clinical trials showed a significant food effect with torcetrapib softgels.
• Need for improved drug delivery to enhance absorption and reduce variability.

Purpose of the Study:

• To develop self-emulsifying drug delivery systems (SEDDS) for torcetrapib.
• To reduce the food effect and increase the dose per capsule.
• To investigate the impact of formulation components on torcetrapib absorption.

Main Methods:

• Formulation of SEDDS with varying components like medium chain triglyceride (MCT), triacetin, Polysorbate 80, Capmul MCM, and Cremophor RH40.
• Pharmacokinetic studies in dogs to evaluate absorption, food effect, and dose proportionality.
• Analysis of emulsion droplet size and in vitro lipolysis.

Main Results:

• A specific MCT/Triacetin/Polysorbate 80/Capmul MCM (MTPC) formulation reduced the food effect from 5- to 3-fold in dogs.
• SEDDS formulations accelerated absorption and decreased variability.
• Increased Cremophor RH40 content reduced food effect, with no effect at 50% concentration. MTPC showed good dose proportionality.

Conclusions:

• SEDDS formulations offer a promising approach to improve torcetrapib oral bioavailability.
• Formulation optimization can mitigate the food effect and enhance drug absorption for atherosclerosis treatment.
• Further in vitro lipolysis studies will elucidate in vitro-in vivo correlations for torcetrapib SEDDS.