Effect of Cyclodextrins on the Complexation and Nasal Permeation of Melatonin

Abstract

The inclusion complexation of melatonin (MT) with modified cyclodextrins (CDs) was studied with an objective of improving the solubility and nasal absorption of MT. The formation of inclusion complex of MT with Hydroxypropyl β CD (HPβ CD) and randomly methylated β CD (RMβ CD) was characterized in solution and solid states by phase solubility and differential scanning calorimetry analyses. The phase solubility data indicate a linear increase in the solubility of MT with CDs demonstrating Higuchi's AL-type phase solubility profiles. The effect of CDs on the permeation of MT across EpiAirwayTM-100 cultures was studied using a modified nonstatic diffusion setup. CDs were employed at different concentrations with 1% w/v micronized MT suspension in hydroxypropyl methyl cellulose (HPMC) vehicle. At low CD concentrations (1% w/v), the permeation of MT from HPMC formulation was significantly increased (125%,p < .001). However, the permeation was significantly reduced when CDs were used at relatively high concentrations (5 to 10% w/v concentration for HPβCD and 10% w/v concentration for RMβCD,p < .001). All the tissues were viable with good tissue integrity at the end of permeation experiments, as measured by methylthiazoletetrazolium assay and transepithelial electrical resistance measurements. In conclusion, formation of inclusion complex of MT with HPβCD and RMβCD was demonstrated in solution and solid state. Both HPβCD and RM βCD at 1% w/v concentration were found to improve the nasal permeability of MT from HPMC gel formulations.