Studies on Curcumin Loaded Microemulsion-based in Situ Gelling for Intranasal Administration
|Keywords||curcumin microemulsion in situ gelling ion-activated|
Curcumin, a yellow polyphenolic compound extracted from turmeric, has many biological activities such as anti-inflammatory, anti-tumor, antioxidant, treatment of Alzheimer’s disease, Parkinson’s disease. However, the characteristics of poor water solubility and low bioavailability of curcumin greatly limit its clinical application.Microemulsion, the thermodynamically stable colloidal system can be used as the carrier of hydrophobic drugs to improve their stability and increase their solubilities. Gels can promote drug absorption because of their adhesion for mucosal administration. Combining the advantages of the two formulations of microemulsion and in situ gelling, microemulsion-in situ gelling can change its form from liquid to gel at the site of action. Gellan gum, a cation-sensitive gel matrix, can form the gel in the nasal cavity, thereby increasing the adhesion and extending the drug residence time. Microemulsion in situ gelling with gellan gum as matrix of curcumin made for intranasal administration can improve the solubility of curcumin and the bioavailability.The solubility of curcumin in different media and the pseudo-ternary phase diagram were used to screen the microemulsion compositions. The formulation of microemulsion was optimized by a simplex lattice experiment design with the mean particle size and curcumin solubility as evaluating factors. The concentration of deacetylated gellan gum was chosen by its viscosity. So the formulation of microemulsion-in situ gelling based on the weight ratio was obtained as follows: Capryol905.6%, Solutol HS1531.5%, Transcutol HP32.9%and0.3%deacetylated gellan gum solution30%. Observed under the scanning transmission electron microscopy, the particles presented spherical or similar spherical with no adhesion. The mean particle size and Zeta potential of curcumin-loaded microemulsion-in situ gelling were54nm and-0.38mV, respectively. Franz diffusion cells were used to study the drug release behavior in vitro. The results showed that the cumulative release drug amount was more than80%at24h after administration of curcumin-loaded microemulsion-in situ gelling and the preparation displayed sustained-release effect.The rat nasal mucosa slices after HE staining were observed by optical microscopy to evaluate the irritation of the obtained preparation to nasal mucosa. The results of pathological sections revealed that the rat nasal mucosa treated by curcumin formulation showed no significant lesions comparing to the control group treated by saline.The pharmacokinetic experiments of curcumin-loaded microemulsion-in situ gelling by nasal administration and curcumin injection by intravenous administration were carried in rats. The results showed that the pharmacokinetics processes of curcumin-loaded microemulsion-in situ gelling via nasal administration and curcumin injection via intravenous injection were both fitted two-compartment model. In contrast to curcumin injection, the AUC of curcumin-loaded microemulsion-in situ gelling was55.82%and the peak concentrations significantly decreased, while the mean residence time and biological half-life time were markedly increased.The brain homogenate method was used to study the distribution of curcumin in the brain tissue via intranasal administration. The results showed that the AUC value in brain of curcumin-loaded microemulsion-in situ gelling via intranasal administration was more3times than that of curcumin injection via intravenous administration. The AUC brain/AUC blood values of curcumin-loaded microemulsion-in situ gelling after intranasal administration was higher than that after intravenous administraton, indicating that the formulation might facilitate direct brain delivery of curcumin; the brain targeting index of the formulation via intranasal administration was6.50, indicating curcumin-loaded microemulsion-in situ gelling has the brain targeting.