Formulation Strategies to Enhance Nose-to-Brain Delivery of Drugs (2018)

Delivery of drugs via the intranasal olfactory route is a non-invasive and practical method of bypassing the blood-brain barrier (BBB). However, targeted delivery and retention of drugs to the olfactory region is a significant challenge due to the geometrical complexity of the nasal cavity and mucociliary clearance. Formulating drugs into particulate-carriers, specifically, carriers with mucoadhesive properties can potentially overcome this challenge by enabling targeted deposition and retention of the drug onto the olfactory epithelium for subsequent nose-to-brain transport. Recent modeling data indicates that particles around 10 μm in size show maximum deposition in the olfactory region, the target site for nose-to-brain drug absorption. Therefore, the primary objectives of this thesis was to develop and characterize 10 μm-sized mucoadhesive microparticles for selective drug deposition in the olfactory region and enhanced nose-to-brain delivery. Furthermore, recently several drug delivery devices that aim to target drug formulations to the olfactory region in the nasal cavity are making their way to the market. Therefore, the second objective of this thesis was to explore if the formulative approach of making particles to a specific size and combining it with a targeting device could augment olfactory targeting and further enhance nose to brain delivery of therapeutic molecules. Consequently, the effect of particle size combined with a bi-directional delivery technique on the olfactory deposition of microparticles in the human nasal cavity was investigated.&#13;\nA naturally occurring mucoadhesive polymer, tamarind seed polysaccharide (TSP), was spray-dried with model drugs, FITC-Dextrans of molecular weight (MW) 3 to 40 kDa. The spray-drying process was optimized by the Box-Behnken experimental design to produce particles with 10 µm size. In-vitro and ex-vivo characterization demonstrated mucoadhesive potential and successful drug loading of TSP-microparticles. Particles of 10 µm in size demonstrated higher olfactory deposition compared to 2 µm sized particles in a 3D-human nasal replica, at standard inhalation airflow rate. The nose to-brain delivery efficiency of the mucoadhesive TSP-microparticles was tested in-vivo in a rodent model. An anti-epileptic drug (AED) phenytoin was loaded into TSP-microparticles and administered intranasally to rats with an insufflator. The analysis of phenytoin concentrations in the rat brain revealed a three-fold greater direct transport of phenytoin with the TSP microparticles compared to the intranasal solution at the end of 60 min. The results from this study demonstrated the potential of TSP-microparticles to improve direct transport of drugs to the brain by enhancing the nasal residence time of phenytoin due to mucoadhesion.&#13;\nIn-silico computational fluid and particle dynamics (CFPD) techniques were utilized to identify the variability in olfactory deposition of microparticles between three human subjects with the inhalational delivery technique. Three normal human nasal cavities reconstructed using computerized tomography (CT)-scans were used to study the deposition of particles. The results identified that particles around 10 µm have consistently high deposition in the olfactory regions of three human subjects without any significant inter subject variability. CFPD techniques were also used to study the effect of particle size in combination with a novel bi-directional delivery technique (used in the ‘OPTINOSE®’ targeting device) on the deposition of particles in the human nasal cavities. The deposition of particles in the olfactory region was found to be a function of particle size. The bi-directional delivery technique demonstrated significantly higher deposition of particles in the olfactory region compared to standard inhalation. The results identified a particle size range of 14 to 18 µm can significantly enhance the olfactory deposition of particles when administered with bi-directional delivery technique without any inter-subject variability. &#13;\nIn summary, this thesis demonstrated that formulation strategies can augment olfactory deposition and enhance nose-to-brain delivery of therapeutic molecules. This thesis integrated data from in-vitro, in-vivo and in silico studies to refine and optimize a size tailored mucoadhesive microparticle delivery system that has promising potential in the nose to brain drug delivery.