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Optimization of Chitosan Microparticles for Nose-to- Brain Delivery of Peptides

Background: The intranasal route is useful for the delivery of drugs to the brain via the blood brain barrier and/or the olfactory nerve. The purpose of this research was to investigate drug carriers for nasal administration by optimising the formulation of mucoadhesive polymeric microparticles. Chitosan (low, medium and high molecular weight) and trimethyl chitosan (TMC) were selected due to their biocompatibility, mucoadhesiveness and non- toxicity. Two important parameters for nasal application are particle size, where the diameter should be above 10 μm to prevent inhalation to the lungs, and mucoadhesiveness. Mucoadhesion can be evaluated by measuring changes in charge that occur upon bonding due to electron transfer between the polymeric system and the mucus membrane epithelium. Methods: The microparticles were prepared by spray drying. Solutions (0, 5% acetic acid) of high, medium and low molecular weight chitosan and mixtures with TMC were prepared at concentrations of 0, 5%, 1% and 2%. The solutions were spraydried and solid microparticles were obtained. The size and morphology of the microparticles were determined by SEM analysis. Moisture content was determined using thermogravimetric analysis. The charge and the mucoadhesive properties were evaluated using a mucin particle method, developed by Takeuchi et al. In brief, the mucin powder (Mucin type II) was suspended in phosphate buffer (pH 6.5) at a concentration of 1% w/v. Then, 1ml of this suspension was mixed with different volumes (1, 2, 3 and 4 ml) of a suspension of MPs 0.1% in phosphate buffer (pH 6.5) under mild magnetic stirring (200 rpm) and the Zeta potential of the mixtures was evaluated. All experiments were performed in triplicate. Results: Microscopic analysis of the chitosan MPs showed that they had a very different size range (5.06 um-29.87 μm). The particles were spherical, with a rough and wrinkled surface. As usual in spray dried chitosan formulations, the moisture content was shown to be relatively high, with a range between 4.8 and 10.7%. The optimal parameters to prepare MPs with the appropriate size (>10 μm) for nasal drug delivery were determined. The mucoadhesion test showed that the charge of the microparticles, correlating to the bond strength between the mucin particles and the MPs, was proportional to the chitosan concentration in the mixtures, changing from negative to positive with the addition of higher quantities of the MP suspension. The molecular weight of the chitosan did not make a significant difference in the bonding between the MPs and the mucin particles. The prepared MPs containing TMC and LMwCh in different ratios were less mucoadhesive compared to LMwCh MPs. Conclusions: Chitosan microparticles were successfully prepared by spray drying. The molecular weight of chitosan did not make a significant difference in the mucoadhesive properties of the microspheres, while the addition of the TMC reduced the mucoadhesion.

spray drying ; chitosan microparticles ; nose-to-brain drug delivery ; mucoadhesion

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