(T1530-07-40) Design and Enhanced Permeability of Sublingual Tablets Containing Leuprolide Nanoparticles With or Without Permeation Enhancers

Purpose: To investigate permeability behaviors of peptide leuprolide nanoparticles in sublingual tablet in the presence of various permeation enhancers (PE).

Methods: Leuprolide (LEU)-oleic acid conjugate (LOC) was synthesized via Yamaguchi esterification method with 4-dimethylaminopyridine. Then, LOC was self-assembled into nanoparticles (LON). The size distribution and morphological images of LON were characterized using dynamic light scattering and field emission scanning electron microscopy. Sublingual tablets (flat-faced, 6mm in diameter) containing LON equivalent to 2mg of LEU and PE (sodium taurocholate, salcaprozate sodium, lauroyl-L-carnitine, phosphatidylcholine, L-arginine, and protamine) were via direct compression method using a rotary tablet press (RT-8, DCM Cube, Korea). Dissolution, disintegration time, and hardness of tablets were evaluated. The dissolution test was conducted using paddle (USP apparatus 2) at 50 rpm in 900 mL of 0.05 M phosphate buffered saline (pH 6.8) containing 0.5% polysorbate. In vitro permeation test was evaluated using Franz diffusion cells with PermeaPad^®. The PermeaPad^® is a biomimetic membrane with a layered structure that includes a phospholipid layer, enabling rapid measurement of passive diffusion characteristics. LEU concentration was quantitatively analyzed using an Agilent 1200 HPLC-UV system.

Results: The LONs showed spherical shape with approximately 206 nm in size and a low polydispersity index (PDI: 0.151), indicating uniformly distributed nanoparticle size. The sublingual tablet was optimally designed, having rapid disintegration (2 min) and suitable hardness (4 kP). Over 90% of the drug was rapidly released from sublingual tablet within 5 min. The permeability of LON from sublingual tablet was 2.9-fold enhanced via nanonization behaviors as compared to LEU alone. The incorporation of phosphatidylcholine into LON resulted in further increased permeability via deformable properties. When PEs was mixed with LON in sublingual tablet, the permeability was highly increased in the order: sodium taurocholate >salcaprozate sodium >lauroyl-L-carnitine >L-arginine ≥ protamine. This improvement was attributed to the varying deformability of the peptide drug nanoparticles and alterations in membrane structure facilitated by the PEs.

Conclusion: Design of amphiphilic LEU via fatty acid conjugation and its self-assembly into LONs could have potential to improve LEU permeability when a peptide drug was delivered noninvasively via sublingual route. Furthermore, the sublingual tablet incorporating PEs inside LON or with LON further significantly enhanced LEU permeability by imparting LON deformability and altering the membrane characteristics.

Acknowledgements: This work was primarily supported by a grant from the Korea Evaluation Institute of Industrial Technology (KEIT) funded by the Ministry of Trade, Industry, and Energy, Republic of Korea (20008840) in 2020.