title: Modulating Drug Release and Enhancing the Oral Bioavailability of Torcetrapib with Solid Lipid Dispersion Formulations.
abstract: The development of drug dispersions using solid lipids is a novel formulation strategy that can help address the challenges of poor drug solubility and systemic exposure after oral administration. The highly lipophilic and poorly water-soluble drug torcetrapib could be effectively formulated into solid lipid microparticles (SLMs) using an anti-solvent precipitation strategy. Acoustic milling was subsequently used to obtain solid lipid nanoparticles (SLNs). Torcetrapib was successfully incorporated into the lipid matrix in an amorphous state. Spherical SLMs with mean particle size of approximately 15-18 μm were produced with high drug encapsulation efficiency (>96%) while SLNs were produced with a mean particle size of 155 nm and excellent colloidal stability. The in vitro drug release and the in vivo absorption of the solid lipid micro- and nanoparticles after oral dosing in rats were evaluated against conventional crystalline drug powders as well as a spray dried amorphous polymer dispersion formulation. Interestingly, the in vitro drug release rate from the lipid particles could be tuned for immediate or extended release by controlling either the particle size or the precipitation temperature used when forming the drug-lipid particles. This change in the rate of drug release was manifested in vivo with changes in Tmax as well. In addition, in vivo pharmacokinetic studies revealed a significant increase (∼6 to 11-fold) in oral bioavailability in rats dosed with the SLMs and SLNs compared to conventional drug powders. Importantly, this formulation approach can be performed rapidly on a small scale, making it ideal as a formulation technology for use early in the drug discovery timeframe.
authors.affiliation: Discovery Pharmaceutical Sciences, Merck & Co., Inc., 126 E. Lincoln Ave., Rahway, NJ, 07065, USA.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., 126 E. Lincoln Ave., Rahway, NJ, 07065, USA.
authors.forename: Gino M
authors.initials: GM
authors.lastname: Salituro
authors.affiliation: Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., 126 E. Lincoln Ave., Rahway, NJ, 07065, USA.
authors.forename: Keun-Joong
authors.initials: KJ
authors.lastname: Lee
authors.affiliation: Discovery Pharmaceutical Sciences, Merck & Co., Inc., 126 E. Lincoln Ave., Rahway, NJ, 07065, USA.
authors.forename: Annette
authors.initials: A
authors.lastname: Bak
authors.affiliation: Discovery Pharmaceutical Sciences, Merck & Co., Inc., 126 E. Lincoln Ave., Rahway, NJ, 07065, USA. dennis_leung@merck.com.
authors.forename: Dennis H
authors.initials: DH
authors.lastname: Leung
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D001682:Biological Availability; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D004339:Drug Compounding; D008055:Lipids / Q000737:chemistry*; D008297:Male; D008954:Models, Biological; D053758:Nanoparticles; D010316:Particle Size; D011804:Quinolines / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D017208:Rats, Wistar; D012995:Solubility; D013696:Temperature
chemical_list: D000924:Anticholesteremic Agents; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D008055:Lipids; D011804:Quinolines; C483909:torcetrapib
keywords: anti-solvent precipitation; controlled release; formulation; nanoparticles; solid lipid