Advancing Nose to Brain Drug Delivery: Intranasal Administration of Insulin

Background
Intranasal insulin is under exploration as a treatment for Alzheimer’s disease due to its potential to improve cognitive function and modify disease progression. This study aims to further investigate the biodistribution and brain uptake of intranasal insulin in a preclinical setting, specifically in vervet monkeys, which are considered relevant animal models for such research.

The delivery method used in this study, the Aptar Pharma’s Cartridge Pump System (CPS), is key to achieving reliable and targeted intranasal drug delivery. One of the challenges in the field of intranasal delivery is ensuring that the therapeutic agent reaches the brain in sufficient concentrations to be effective, without exposing the rest of the body to excessive doses. The biodistribution study utilized a novel radiotracer, Gallium 68-labeled NOTA-conjugated insulin ([68Ga]Ga-NOTA-insulin), to trace the movement of insulin throughout the body, focusing on its accumulation in the brain.

Study Objective
The primary objective of this study was to demonstrate the successful delivery of insulin to the brain using Aptar Pharma’s CPS intranasal drug delivery system in healthy adult vervet monkeys. The researchers also aimed to establish the safety of this method by evaluating vital signs, blood glucose levels, and overall radiation exposure during the procedure.

Methods
To visualize and measure the brain’s uptake of insulin after intranasal administration, the researchers developed [68Ga]Ga-NOTA-insulin, a PET radiotracer. Positron Emission Tomography (PET) combined with CT scans was employed to monitor the distribution of the insulin throughout the body and assess brain regional activity in real-time.

The study involved anesthetized adult vervet monkeys, which were given intranasal doses of [68Ga]Ga-NOTA-insulin through Aptar Pharma’s CPS device. PET/CT imaging was then conducted to track the radiotracer and determine which brain regions showed uptake. Additionally, safety assessments, such as monitoring vital signs and measuring glucose levels, were conducted to ensure that the insulin administration did not induce adverse effects.

Results
The study demonstrated that intranasal delivery of [68Ga]Ga-NOTA-insulin via the Aptar Pharma’s CPS drug delivery system resulted in successful insulin uptake in various brain regions. Specifically, the researchers observed significant activity in the amygdala, putamen, hypothalamus, hippocampus, and choroid plexus—all key areas associated with memory, emotional processing, and neurodegenerative diseases like Alzheimer’s.

The whole-body dosimetry revealed that no organ was exposed to more than 2.5 mSv of radioactivity, confirming the safety of the procedure. The monkeys’ vital signs remained stable throughout the study, and blood glucose levels were unaffected, indicating that the intranasal administration of [68Ga]Ga-NOTA-insulin did not disrupt systemic glucose metabolism.

Moreover, the data gathered from the vervet monkeys were used to estimate the absorbed dose of [68Ga]Ga-NOTA-insulin in humans. The study concluded that the maximum safe dose for human administration is 185 MBq, which is critical information for future clinical trials.

As intranasal insulin continues to be explored as a treatment for Alzheimer’s, the data from this research will be instrumental in guiding the development of clinical protocols and ensuring that the right dose reaches the brain effectively. This preclinical biodistribution study in vervet monkeys sets a strong foundation for future investigations into the therapeutic potential of intranasal insulin in humans, particularly in addressing neurodegenerative diseases.

Implications for Future Research
The successful targeting of insulin to the brain using the Aptar Pharma’s CPS nasal drug delivery system opens new avenues for the treatment of Alzheimer’s disease through intranasal drug delivery. Future research will focus on translating these findings to human studies, with the potential to significantly impact the management and treatment of Alzheimer’s Disease.