Nose-to-brain transport of melatonin from polymer gel suspensions: a microdialysis study in rats.

PURPOSE: Exogenous melatonin (MT) has significant neuroprotective roles in Alzheimer's and Parkinson's diseases. This study investigates the delivery MT to brain via nasal route as a polymeric gel suspension using central brain microdialysis in anesthetized rats. METHODS: Micronized MT suspensions using polymers [carbopol, carboxymethyl cellulose (CMC)] and polyethylene glycol 400 (PEG400) were prepared and characterized for nasal administration. In vitro permeation of the formulations was measured across a three-dimensional tissue culture model EpiAirway(™). The central brain delivery into olfactory bulb of nasally administered MT gel suspensions was studied using brain microdialysis in male Wistar rats. The MT content of microdialysis samples was analyzed by high performance liquid chromatography (HPLC) using electrochemical detection. The nose-to-brain delivery of MT formulations was compared with intravenously administered MT solution. RESULTS: MT suspensions in carbopol and CMC vehicles have shown significantly higher permeability across Epiairway(™) as compared to control, PEG400 (P < 0.05). The brain (olfactory bulb) levels of MT after intranasal administration were 9.22, 6.77 and 4.04-fold higher for carbopol, CMC and PEG400, respectively, than that of intravenous MT in rats. In conclusion, microdialysis studies demonstrated increased brain levels of MT via nasal administration in rats.

Effect of cyclodextrins on the complexation and nasal permeation of melatonin.

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.

Box-Behnken experimental design in the development of a nasal drug delivery system of model drug hydroxyurea: characterization of viscosity, in vitro drug release, droplet size, and dynamic surface tension.

The purpose of the research was to investigate the changes in physicochemical properties and their influence on nasal formulation performance using 5-factor, 3-level Box-Behnken experimental design on the combined responses of viscosity, droplet size distribution (DSD), and drug release. Gel formulations of hydroxyurea (HU) with surface-active polymers (hydroxyethylcellulose [HEC] and polyethylene-oxide [PEO]) and ionic excipients (sodium chloride and calcium chloride) were prepared using Box-Behnken experimental design. The rheology and dynamic surface tension (DST) of the test formulations was investigated using LV-DV-III Brookfield rheometer and T60 SITA tensiometer, respectively. Droplet size analysis of nasal aerosols was determined by laser diffraction using the Malvern Spraytec with the InnovaSystems actuator. In vitro drug release studies were conducted on Franz diffusion cells. With PEO gel, calcium chloride increased the viscosity and DSD and retarded drug release, while sodium chloride decreased the viscosity, DST, and DSD and accelerated the release of HU. With HEC gel, the addition of the above salts resulted in less significant changes in viscosity, DSD, and DST, but both salts significantly increased the release of HU. Droplet size data obtained from a high viscosity nasal pump was dependent on type of polymer, polymer-excipient interactions, and solvent properties. The applications of Box-Behnken experimental design facilitated the prediction and identified major excipient influences on viscosity, DSD, and in vitro drug release.

Evaluation of different parameters that affect droplet-size distribution from nasal sprays using the Malvern Spraytec.

The applicability of laser diffraction (Spraytec) for characterizing the droplet-size distribution (DSD) from nasal sprays was examined to understand the relationship between physical properties of nasal formulations and their spray characteristics. The impact of actuation force (3-7 kg), rheological properties from carboxymethylcellulose (CMC) and carbopol 934PNF, the influence of surfactant (Tween 80), actuation distance, and different nasal-pump designs on the aerosol DSD of nasal sprays were investigated using Spraytec((R)) with the eNSP actuation station (InnovaSystems, Moorestown, NJ). Spray-pattern analysis was performed by monitoring the emitted nasal spray containing a dye or a fluorescent marker. Parameters for DSD and spray pattern included: Dv(10), Dv(50), Dv(90), polydispersity, minimum and maximum diameters, plume area, and ovality. Increasing actuation distance from 1.5 to 6 cm from the laser beam decreased Dv(50) values by 17-27% for commercial nasal-spray products. Spray-pattern analysis revealed a power law relationship between viscosity and surface area for CMC formulations. However, this relationship could not be obtained for carbopol formulations, which was attributed to differences in their rheological behavior. The addition of surfactant (0.5-5% Tween 80) to a 2% CMC solution decreased the Dv(50) values (16-26%) and altered the rheological properties (e.g., changes in viscosity and appearance of the thixotropic system). Briefly, the characteristic of nasal aerosol generation is dependent on a combination of actuation force, viscosity, rheological properties, surface tension, and pump design. The Spraytec with the eNSP actuation station provides an efficient and reliable way of monitoring the effects of formulation variables on DSD from nasal aerosols.

Comparison of the transdermal absorption of nimesulide from three commercially available gel formulations.

Nimesulide is a non-steroidal anti-inflammatory drug (NSAID) applied topically for a variety of conditions characterized by pain and inflammation. One of the aims of this study was to compare the permeation profile of nimesulide from the commercially available transdermal gel formulations across dermatomed porcine and human skin. The in vitro transdermal absorption of nimesulide formulations across porcine skin and human skin was studiedfor 24 hr using a continuous flow-through diffusion cell. The three commercial gels used in this study were Nimulid, Nise Gel, and Orthobid. All gels contained 1% (w/w) nimesulide. An infinite dose of nimesulide gel (about 300mg) was applied on the skin over 0.636 cm2 surface area. The rank order for the drug permeation from these formulations using porcine skin was: Nimulid > Orthobid > Nise Gel. The rank order of the permeation across human skin was: Nimulid> Nise Gel> Orthobid. The permeation profiles followed zero-order kinetics without any significant lag time. The steady-state flux of nimesulide from Nimulid was significantly higher than that of Nise Gel and Orthobid in both porcine and human skin (p <.05). However, there were no significant differences in the delivery of nimesulide (24 hr) from Nise Gel and Orthobid across both human and porcine skins. The results suggest that the Nimulid gel may have a greater bioavailability of nimesulide compared to the other gels. In addition, permeation profiles of the various gels across porcine skin did show a positive profile behavior to human skin. However, the in vitro drug release of nimesulide gels across a synthetic membrane did not correlate with skin permeation profiles.