ABSTRACT
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228 Definitions and Concepts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228
Lipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228 Emulsifiers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230 Cosolvents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 SEDDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 Microemulsion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
Marketed Oral LBDDS Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 Design and Characterization of Lipid-Based Drug Delivery Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
Processing In Vivo and Classification of LBDDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235 Feasibility Assessment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237 Phase Behavior and Complex Fluid Structures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239 Solubilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 Characterizing Dispersibility and Dissolution/Dispersion Behavior of LBDDS . . . . . . . . . . . . . . 242 Lipolysis and Lipid Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243 Final Dosage Forms of Lipid-Based Drug Delivery Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245
Challenges with LBDDS Formulations for Drug Solubilization and Delivery . . . . . . . . . . . . . . . . . . . 247 Physical Stability and Gelatin Compatibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247 Chemical Stability: Typical Mechanisms of Oxidation and Gelatin Cross-Linking. . . . . . . . . . . 247 Toxicological Considerations for Oral Lipid-Based Drug Delivery Systems. . . . . . . . . . . . . . . . . . 248
Conclusions and Future Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
9644: “9644_c011” — 2007/11/21 — 11:54 — page 228 — #2
Owing to the large increase in the number of water-insoluble drugs in clinical development, lipids have come to the forefront as a formulation and drug delivery tool, particularly for drugs that exhibit dissolution rate-limited absorption. Most frequently lipid-based drug delivery systems (LBDDSs) for oral use are designed to present a poorly soluble drug in a solubilized form to eliminate dissolution of crystalline material as the rate-limiting step to absorption (Pouton, 2000). For poorly aqueous soluble drugs, the dissolution rate can be extremely low under physiological conditions leading to poor oral bioavailability and nonlinear exposure with increasing dose (Hörter and Dressman, 1997). Many of these lipophilic drugs will also exhibit a strong food effect where the bioavailability increases due to the solubilizing effects of ingested food and concomitant excretion of bile (Charman et al., 1997; Fleisher et al., 1999). By introducing the drug in solubilized form, lipid-based formulations have the potential to increase bioavailability and eliminate the food effect.
