Abstract
Therapeutic peptides can treat a wide variety of diseases with selective and potent action. Their oral bioavailability is strongly limited by an important proteolytic activity in the intestinal lumen and poor permeation across the intestinal border. We have evaluated the capacity of solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) to overcome both oral bioavailability limiting aspects, using leuprolide (LEU) as model peptide. Lipidization of LEU by formation of a hydrophobic ion pair (HIP) with sodium docusate enables a significant increase of peptide encapsulation efficiency in both SLN and NLC. The nanocarriers, obtained by high-pressure homogenization, measured 120 nm and were platelet shaped. Regarding the protective effect towards proteolytic degradation, only NLC maintained LEU integrity in presence of trypsin. Intestinal transport, evaluated on Caco-2 (enterocyte-like model) and Caco-2/HT29-MTX (mucin-secreting model) monolayers, showed nanocarriers internalization by enterocytes but no improvement of LEU permeability. Indeed, the combination of nanoparticles platelet-shape with the poor stability of the HIP in the transport medium induces a high burst release of the peptide, limiting nanoparticles capacity to transport LEU across the intestinal border. Stability of peptide lipidization needs to be improved to withstand biorelevant medium to benefit from the advantages of encapsulation in solid lipid nanocarriers and consequently improve their oral bioavailability.
Highlights
Therapeutic peptides can treat a wide variety of diseases with selective and potent action
Solid lipid nanocarriers refers to two types of nanoparticles: solid lipid nanoparticles (SLN), composed of solid lipid excipients at room and body temperature and stabilized by surfactants, or nanostructured lipid carriers (NLC), in which the solid lipid excipients is supplemented by a liquid lipid fraction (Müller, 2011)
The results showed that EE of 10.7 ± 2.2% and 84.7 ± 2.0% were reached when hydrophobic ion pair (HIP) of Desmopressin and Leuprolide were respectively encapsulated in NLC (Dumont et al, 2019b)
Summary
Peptides display high specificity and selectivity for some drug targets, offering pharmacological advantages over small molecules by increasing the capacity of action while reducing secondary effects (Craik et al, 2013). On a physico-chemical point of view, these molecules are generally hydrophilic and exhibit a high molecular weight, between 500 and 5000 kDa. Most therapeutic peptides are delivered through parenteral administration. Depending on the administered drugs, these injections may be painful and frequently repeated to overcome the poor viability of therapeutic peptides in human physiological fluids (Morishita and Peppas, 2006). Administrating these drugs would considerably improve patients’ comfort and compliance to medications as well as reducing the costs of treatments. 60 peptides were approved by the FDA in 2016, only 12 peptides are currently marketed as oral dosage forms (2 being approved in 2019 and 2020 respectively) and, among them, only 6 peptides are intended to reach the systemic circulation, even if their oral bioavailability barely exceeds 1%. (Aguirre et al, 2016; Richard, 2017)
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