Fatty acids as therapeutic auxiliaries for oral and parenteral formulations.

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.

A dicarboxylic fatty acid derivative of paclitaxel for albumin-assisted drug delivery.

Paclitaxel (PTX) is a potent chemotherapy for many cancers but it suffers from very poor solubility. Consequently, the TAXOL formulation uses copious amounts of the surfactant Cremophor EL to solubilize the drug for injection, resulting in severe hypersensitivity and neutropenia. In contrast to Cremophor EL, presented is a way to solubilize PTX by conjugation of a dicarboxylic fatty acid for specific binding to the ubiquitous protein, serum albumin. The conjugation chemistry was simplified to a single step using the activated anhydride form of 3-pentadecylglutaric (PDG) acid, which is reactive to a variety of nucleophiles. The PDG derivative is less cytotoxic than the parent compound and was found to slowly hydrolyze to PTX (≈ 5% over 72 h) in serum, tumor cytosol, and tumor tissue homogenate. When injected intravenously to tumor-bearing mice, [(3) H]-PTX in the TAXOL formulation was cleared rapidly with a half-life of 7 h. In the case of the PDG derivative of PTX, the drug is quickly distributed and approximately 20% of the injected dose remained in the vasculature experiencing a 23 h half-life. These improvements from modifying PTX with the PDG fatty acid present the opportunity for PDG to become a generic modification for the improvement of many therapeutics.