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 have 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.

Basics and Recent Advances in Peptide and Protein Drug Delivery

“…Compared with free sCT, the reversible aqueous lipidization sCT reported increased absorption and a 19-times higher AUC value [46]. Caprates, medium-chain fatty acids, promote paracellular diffusion of Class III (highly soluble, low permeability) molecules such as peptides [47]. In addition, triglycerides can be used to evade first-pass metabolism [47].…”

“…Caprates, medium-chain fatty acids, promote paracellular diffusion of Class III (highly soluble, low permeability) molecules such as peptides [47]. In addition, triglycerides can be used to evade first-pass metabolism [47]. While irreversible methods of lipidization allow for increased membrane permeability, the activity of such modified proteins may be diminished due to steric issues with the fatty acid chain [47].…”

“…In addition, triglycerides can be used to evade first-pass metabolism [47]. While irreversible methods of lipidization allow for increased membrane permeability, the activity of such modified proteins may be diminished due to steric issues with the fatty acid chain [47]. …”

Oral films as breakthrough tools for oral delivery of proteins/peptides

“…Lipidization was also a breakthrough mean to obtain detemir (Levemir®) and degludec insulin modifications. Detemir was obtained by myristoylation of the penultimate lysine residue in position B29 and removal of the terminal threonine resulting in an increased affinity to albumin and consequent half-life and stability increase [90]. Degludec results from an addition of a palmitoyl group to the B29 -lysyl amino group using a -glutamic acid spacer with an additional removal of terminal threonine, resulting in a more stable insulin analogue, with a longer lasting glycemic control.…”

Lipid-Based Drug Carriers for Prodrugs to Enhance Drug Delivery

“…While hydrophilic compounds are quickly excreted, lipophilic drugs tend to be easily reabsorbed across the tubular epithelium back into circulation, thus prolonging their circulation time (1). Renal clearance of lipophilic drugs is further reduced by the increased binding to plasma proteins, mainly albumin (2,3). Lipid modification also has the advantage of increased absorption across biological barriers, most importantly the gastrointestinal epithelium and blood-brain barrier.…”