(T0930-12-78) Preparation and Evaluation of Dexamethasone Phosphate-Encapsulated Liposomal Gel Formulation for Intratympanic Delivery

Purpose: The aim of this study is to investigate ultradeformable lipid nanoparticles (UDL) containing dexamethasone phosphate (DexP) for enhanced permeability, and mix UDL with hyaluronic acid gel (HA gel) for extended maintenance time inside the tympanum during intratympanic delivery by delaying the time of drug elimination through Eustachian tube

Methods: DexP-UDL was prepared by lipid membrane hydration and extrusion methods using egg phosphatidylcholine (egg PC) and Tween 80 (TW80) as edge activators. The physicochemical properties of the nanoparticles were characterized in terms of particle size, zeta potential, polydispersity index, encapsulation efficiency, loading capacity, and deformability. DexP-UDL-HA gel was prepared by mixing DexP-UDL and HA gel as the ratio of 1:1 (v/v ratio). The physicochemical properties of DexP-UDL-HA gel was descried in terms of water content, swelling ratio, morphology, and rheological properties. In vitro release study and in vitro skin permeability study of DexP-UDL HA gel was evaluated using Franz diffusion cell. In vivo intratympanic delivery test was evaluated by Department of Otorhinolaryngology, Seoul National University Hospital, Republic of Korea. After intratympanic injection of both DexP-UDL-HA gel and DexP solution in each ear of hearing impairment rat model, micro CT Images were taken with in vivo micro CT (NFR Polaris-G90, NanoFocusRay, Jeonju, Republic of Korea) to verify the residence time of the residual amount in the tympanum just after the injection and at Day 0, 4, 7 and 14.

Results: In rheology study, DexP-UDL-HA gel was confirmed to have a semi-solid formulation as it shows a shear thinning characteristic which the viscosity decreases as the shear rate increases, as well as a high storage modulus (G’) and loss modulus (G’’). As the result of in vitro release study, DexP-UDL HA gel slightly retarded the release of DexP in comparison with DexP-HA gel in which the drug simply dispersed. Drug permeability from DexP-UDL-HA gel was 3.1 times higher than that of DexP solution, and 1.5 times higher than that of DexP HA gel. From the result of in vivo intratympanic injection study, it was confirmed that more residual amount remained in the tympanum in which HA gel was injected, than the one that solution formulation was injected. The presence of residual amount was confirmed when signal attenuation was detected in the tympanum where air was supposed to be found.

Conclusion: Thus, enhanced permeability and sustained drug elimination was confirmed by in vitro and in vivo studies. DexP-UDL-HA gel could be a promising strategy for improved intratympanic drug delivery.

Schematic diagram of intratympanic administration: (a) DexP solution and (b) DexP-UDL-HA gel

Skin permeation profile of DexP from DexP solution, DexP-HA gel and DexP-UDL-HA gel across the skin for 24h.
Data are expressed as mean ± S.D. (n = 3).

Micro CT Images were taken with in vivo micro CT (NFR Polaris-G90, NanoFocusRay, Jeonju, Republic of Korea) to verify the residence time of the residual amount in the tympanum just after the injection and at Day 0, 4, 7 and 14. The presence of residual amount was confirmed when signal attenuation was detected in the tympanum where air was supposed to be found. Checked points (★) showed the presence of residue.