Comparative investigation of sublingual tablets containing oleic acid-conjugated leuprolide nanoparticles and permeation enhancers on disintegration, release rate, permeability and pharmacokinetics in beagle dogs

Abstract

To overcome invasive injectables and low oral bioavailability issues of peptide drug, leuprolide (LEU), sublingual tablets was challenged by forming deformable and self-assembled LEU nanoparticles with permeation enhancers (PEs). LEU–oleic acid (OA) nanoparticles (LON) was prepared via self-assembly of LEU–OA conjugates (LOC), whereas deformable LON (d-LON) was prepared by incorporating α-phosphatidylcholine (PC) into LON. Effect of LEU forms (LEU, LOC, LON, and d-LON) and seven GRAS (Generally Recognized As Safe)-listed permeation enhancers (PEs) were screened using a Franz diffusion cell with PermeaPad® membrane. The permeability was dependent on the types of LEU nanoparticles, giving d-LON was the highest followed by LON, LOC and LEU. Furthermore, PEs synergistically and consistently increased the permeability of all forms of LEU. Among seven PEs screened, lauroyl-ʟ-carnitine (LLC), sodium decanoate (SD), salcaprozate sodium (SNAC) exhibited much higher permeabilities. Then, thin and wide sublingual tablets containing LEU nanoparticles and PE were designed to undergo rapid disintegration approximately within 2 min in the order: LON (31.6 ± 3.5 s) > d-LON (79.3 ± 2.5 s) > d-LON/LLC(99.7 ± 4.0 s) > d-LON/SD(107.3 ± 2.5 s) ≥ d-LON/SNAC(109.0 ± 7.5 s). The dissolution rate was the highest in the order: LEU > LON > LOC > d-LON > d-LON/LLC > d-LON/SD ≥ d-LON/SNAC, completing release over 90 % within 10 min. Three PEs decreased the disintegration time and dissolution rate of sublingual tablet but were effective for enhancing LEU permeability, showing 28.2 ± 0.81 % (LLC), 31.7 ± 0.49 % (SD), 37.3 ± 0.76 % (SNAC), and d-LON without adding PEs (20.9 ± 0.36 %) for 2 h. In pharmacokinetic studies conducted in beagle dogs, d-LON-loaded sublingual tablets with SD exhibited the highest bioavailability followed by LLC and SNAC, whereas LON without adding PEs were under detection limit of LEU. These findings suggest that sublingual tablets simultaneously incorporating LEU nanoparticle and PEs are crucial for maximizing LEU delivery via the sublingual route.