Fatty acids as therapeutic auxiliaries for oral and parenteral formulations

Abstract

Many drugs have decreased therapeutic activity due to issues with absorption, distribution, metabolism and excretion. The co-formulation or covalent attachment of drugs with fatty acids has demonstrated some capacity to overcome these issues by improving intestinal permeability, slowing clearance and binding serum proteins for selective tissue uptake and metabolism. For orally administered drugs, albeit at low level of availability, the presence of fatty acids and triglycerides in the intestinal lumen may promote intestinal uptake of small hydrophilic molecules. Small lipophilic drugs or acylated hydrophilic drugs also show increased lymphatic uptake and enhanced passive diffusional uptake. Fatty acid conjugation of small and large proteins or peptides has exhibited protracted plasma half-lives, site-specific delivery and sustained release upon parenteral administration. These improvements are most likely due to associations with lipid-binding serum proteins, namely albumin, LDL and HDL. These molecular interactions, although not fully characterized, could provide the ability of using the endogenous carrier systems for improving therapeutic outcomes.

Keywords: Albumin; Drug absorption; Drug delivery; Drug formulation; Endogenous drug carriers; Fatty acids; Lipid prodrugs; Protein binding; Reversible lipidization; Triglycerides.

Figure 1

A schematic presentation of the hydrophobic and electrostatic interactions involved in fatty acid-albumin binding (A). The addition of a drug, or surrogate such as fluoresceinamine (blue), may utilize only the hydrophobic interaction (B) or both hydrophobic and electrostatic (red) interactions (C) depending on the modification chemistry.

Figure 2

Artwork depicting the LDL particle. The outer shell contains mostly triglyceride and free cholesterol while the internal core contains mostly cholesteryl ester with some triglyceride. The particle is held together by Apo-B100 which wraps around the particle equatorially. SM, sphingomyelin; PC, phosphatidylcholine; TG, triglyceride; CE, cholesteryl ester; UC, unesterified cholesterol. [Reprinted from, Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 1488, Tiia Hevonoja, Markku O Pentikäinen, Marja T Hyvönen, Petri T Kovanen, Mika Ala-Korpela, Structure of low density lipoprotein (LDL) particles: Basis for understanding molecular changes in modified LDL, 189–210, Copyright (2000), with permission from Elsevier]

Figure 3

The serum pharmacokinetics of a cholesterol derivative of ³²P-labeled siRNA and various ¹²⁵I-labeled serum components that are known to bind cholesterol. Note that the relatively weak binding of the cholesterol-esterified siRNA to the serum components resulted in a significantly different profile compared to the carriers alone. [Reprinted by permission from Macmillan Publishers Ltd: Nature Biotechnology [82], copyright (2007)]