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 beta CD (HPbeta CD) and randomly methylated beta CD (RMbeta 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 A(L)-type phase solubility profiles. The effect of CDs on the permeation of MT across EpiAirway(TM)-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 HPbetaCD and 10% w/v concentration for RMbetaCD,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 HPbetaCD and RMbetaCD was demonstrated in solution and solid state. Both HPbetaCD and RM betaCD at 1% w/v concentration were found to improve the nasal permeability of MT from HPMC gel formulations.

FIG. 1

The picture shows six-well plates with six culture tissue inserts containing EpiAirway-100^™ cell cultures placed in a rotary bath maintained at 37°C. The adjacent diagram depicts the culture insert in the culture well showing tissue at the air–liquid interface. The top surface of tissue is exposed to air allowing for direct application of test formulation.

FIG. 2

Phase solubility diagram of MT with HPβCD and PM-βCD in water at room temperature (~25°C).

FIG. 3

Differential scanning calorimetric analysis of various MT/HPβCD systems. (1) MT-HPβCD complexed, (2) MT, (3) HPβCD, (4) physical mixture of MT and HPβCD at molar ratio 1: 1.5, (5) physical mixture of MT and HPβCD at molar ratio 1:1, (6) physical mixture of MT and HPβCD at molar ratio 1:0.75, and (7) physical mixture of MT and HPβCD at molar ratio 1:0.25.

FIG. 4

Differential scanning calorimetric analysis of various MT/RMβCD systems. (1) MT-RMβCD complexed, (2) MT, (3) RMβCD, (4) physical mixture of MT and RMβCD at molar ratio 1:1.5, (5) physical mixture of MT and RMβCD at molar ratio 1:1, (6) physical mixture of MT and RMβCD at molar ratio 1:0.75, and (7) physical mixture of MT and RMβCD at molar ratio 1:0.25.

FIG. 5

Effect of support material (collagen matrix) on the permeation of MT (1% MT in HPMC vehicle + 0.1% Tween 80) through the human-derived tracheal/bronchial epithelial tissue (EpiAirway^™-100).

FIG. 6

Effects of different concentrations of HPβCD on the permeation of MT (1.0% MT in 2% HPMC + 0.1% Tween 80) across EpiAirway^™-100 tissue.

FIG. 7

Effects of different concentrations of RMβCD on the permeation of MT formulation (1.0% MT in 2% HPMC +0.1% Tween 80) across EpiAir way^™-100 tissue.

FIG. 8

Effect of CDs on the cell viability (A) and transepithelial electrical resistance (B) after the permeation experiments with MT (1% w/v) from various formulations. (A) MTT assays showed no toxic effects caused by mucosal application of the polymers and CD formulations in comparison with the control. (B) Symbol (*) represents statistically significant (p < .05) differences in TEER measurements compared to the control.