The aim of the present study was to develop hydrophobic H-bond pairs (HHPs) of leuprolide (LEU) with non-ionic surfactants to improve its membrane permeability. LEU was lipidized via hydrophobic H-bond pairing (HHP) with the sucrose esters (SEs) sucrose laurate HLB 15 (SLA-15), sucrose palmitate HLB 16 (SPA-16), sucrose stearate HLB 11 (SST-11) and sucrose stearate HLB 15 (SST-15). HHPs were evaluated regarding precipitation efficiency in water, zeta potential, log Pn-octanol/water and dissociation behavior at various pH over time. Cytotoxic potential of HHPs of LEU with SST-11 was investigated on Caco-2 cells. Subsequently, ex vivo permeation studies were carried out across freshly excised Sprague-Dawley rat intestinal mucosa. At a molar ratio of LEU to SEs of 1:≥1 a precipitation efficiency of above 50% was achieved. Zeta potential of complexes was neither influenced by the type nor the amount of added surfactants. Log Pn-octanol/water of LEU was up to 250-fold increased due to HHP utilizing SST-11. Dissociation studies showed that HHPs of LEU with SST-11 dissociate up to 20% in gastrointestinal (GI) pH conditions within 4 h. Moreover, HHPs of LEU with SST-11 exhibited no cytotoxicity. Ex vivo permeation studies revealed 2-fold improved membrane permeation of HHPs of LEU with SST-11 compared to free LEU. Findings of this study show that HHP can be considered as a promising strategy to improve membrane permeation.
Keywords: Hydrophobic H-bond pairs (HHPs); Leuprolide; Membrane permeation; Mucosal drug delivery; Oral drug delivery; Peptide drugs; Sucrose esters.
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