Abstract
The intranasal route of drug administration is widely known to be a non-invasive route that has the potential to carry a drug directly to the central nervous system (CNS). Drugs with low solubility and large molecular weight are two common problems encountered which interfere with the delivery of potent drugs to a target. The purpose of this project was the preparation, characterization, in vitro and in vivo testing by intranasal administration to hamsters for various formulations of a hydrophobic small molecular weight drug- dibenzoylmethane (DBM) and a hydrophilic large molecular weight drug- oxytocin to study their bioavailability following inhalation into the nasal cavity (NC). The goal is to improve the delivery of drugs to the brain.
The poorly soluble drug, DBM was formulated in brain homogenate (BH), in HPMC polymer suspension and as drug-loaded nanoparticles and characterized in solid and suspension states. DBM was loaded into a novel lipid- and cyclodextrin-based nanoparticle formulation and characterized by various methods. In addition, oxytocin was formulated in BH and in normal saline. In vitro cell culture-based studies, histological characterizations of nasal cavities for glial fibrillary acidic protein (GFAP) protein and in vivo biodistribution studies after intranasal administration were carried out.
DBM loaded nanoparticles were observed to be thermostable and amorphous in nature. The final particle size for the DBM loaded nanoparticles was 163.8±3.2nm. The entrapment efficiency and percentage drug loading of DBM-loaded nanoparticles was 86.4±0.6% and 9.20% respectively. Invitro release studies showed about 95.80% of drug was released from the nanoparticles within 8 days. Oxytocin formulations were characterized by visual evaluations, pH, viscosity and stability. Invivo biodistribution studies after intranasal administration of oxytocin showed presence of 1.7445 ± 0.5714 and 1.895.2 ± 0.4626 ng/mL of oxytocin in the blood after 30 minutes of administration. No drug was detected in blood samples of animals treated with DBM in BH. However, about 40.77171 ± 4.9340 and 44.44912 ± 5.3666 ng/mL of DBM was detected in blood samples of animals administered DBM in HPMC polymer suspension and DBM nanoparticles respectively. Histological studies on the NC confirmed the presence of inoculum within the cavity of lymphatic vessels for both drugs.
Thus, formulations of hydrophobic small molecular weight drug- DBM and a hydrophilic large molecular weight drug- oxytocin were successfully designed and characterized. These were inhaled intranasally by hamsters to determine relative effectiveness and biodistribution.