TC DRUG DELIVERY
Directly targeting the difficult-to-access olfactory region of the nasal anatomy is key to successful nose-to-brain drug delivery.
TRANSCRIBRIAL DRUG DELIVERY EXPLAINED
Rocket Science Health has developed medical devices to support a non-invasive method of transcribrial (TC) drug delivery to the central nervous system by deploying novel fluidics to achieve precise delivery of a bolus to the olfactory mucosa – avoiding usage of a spray or atomized droplets.
Once the bolus is delivered to the olfactory mucosa, capillary bridging enhances residence time during which an active pharmaceutical ingredient (API) is transported to the CNS along the olfactory nerve tract via extracellular, and possibly intracellular, mechanisms.
Targeted delivery to the olfactory epithelium is necessary for efficient therapeutic uptake into central nervous system by olfactory (and possibly trigeminal) nerve projections. Transcribrial drug delivery is a novel method of precision therapeutic delivery to the CNS that is distinct from systemic intranasal drug delivery.
The Olfactory Region of the Nasal Anatomy
The human nasal cavity is essential for respiration and olfaction. A complex maze of narrow and convoluted bony, cartilaginous and mucosal structures serves to humidify and warm inhaled air, filter airborne particles before they reach the lungs, and serve as the first line of immunogenic defense.5 The nasal cavity is separated into two halves by the nasal septum. It can be broken down into three anatomically distinct sections: the nasal vestibule, the respiratory region, and the olfactory region.
The nasal vestibule is the most anterior region and contains hairs to filter inhaled particles as a first line of defense.
The respiratory region comprises nearly 85% of the total surface area of the nasal anatomy (including nasal turbinates) and has a high level of vascularization that makes it amenable for systemic drug absorption into the bloodstream.1The surface layer of the nasal mucosa in the respiratory region is called respiratory epithelium and is covered in small ciliated, “hair-like”, cells that augment the surface area of the nasal cavity and help stop microbes, pathogens, and debris from continuing into the lungs.
The little-explored olfactory region is distinct from the lower regions. It is located in the well-protected, upper-most region of the nasal anatomy, adjacent to the bony cribriform plate. It makes up only about 8-10% of the total surface area 1,3 and about 3% of the total volume of the nasal cavity3. Importantly, the olfactory region is the only place in the human body where the central nervous system (CNS) is in contact with the external environment. The specialized olfactory epithelium that lines this region consists of millions of olfactory sensory neuron axons projected from the olfactory bulb (part of the brain) through tiny holes in the cribriform plate to the olfactory region of the nasal cavity. These specialized neurons respond to chemosensory stimuli to enable olfaction but can also be utilized for drug delivery directly to the central nervous system.1
The little-explored olfactory region can be utilized for drug-delivery to the central nervous system.
ADVANTAGES OF TC DRUG DELIVERY
Right on target.
Typical intranasal devices aren’t optimized for direct-to-brain drug delivery. These spray-based devices can result in extremely low delivery efficiency to the olfactory mucosa – as low as 0.5-1% of the originally dispensed volume.7 Our delivery device precisely delivers a bolus to the olfactory region and achieves up to 92.3% delivery efficiency to the olfactory region.6
Reduced side-effects and systemic toxicity.
Targeted drug delivery to the olfactory region limits systemic toxicity and side-effects associated with other methods of CNS drug administration. Due to the low permeability of the blood brain barrier (BBB), achieving a therapeutic effect in the CNS requires other methods to flood the circulatory system with large doses of drugs1-2. This is the case of conventional intranasal drug delivery that coats large swaths of the highly vascularized lower nasal cavity. In addition to systemic toxicity and side-effects common to all of these other methods, oral administration further exposes drugs to gastric degradation and hepatic first-pass metabolism.
Non-invasive and suitable for self-administration.
We avoid the high risks associated with intrathecal administration and therapies that require physical or chemical disruption of the BBB.
Supports delivery of fragile biologics and cell therapies.
The RSH TC delivery platform is capable of delivering shear-susceptible mammalian cell lines with similar efficacy to pipette control devices6. Combining this ability with advanced human factors implementation and targeting accuracy of our delivery platform, we can deliver high-value biologicals to the olfactory region.
Beyond intranasal drug delivery.
We are not another intranasal spray or atomizer device. Our technology doesn’t require propellants or complicated breathing techniques for use. We utilize laminar flow and our custom cannula to overcome complex structures of the nasal anatomy for precise and reliable transcribrial drug delivery to the olfactory region.
1. Crowe TP, Greenlee MHW, Kanthasamy AG, Hsu WH. Mechanism of intranasal drug delivery directly to the brain. Life Sciences. 2018;195:44-52. doi:10.1016/j.lfs.2017.12.025 https://pubmed.ncbi.nlm.nih.gov/29277310/
2. Erdő F, Bors LA, Farkas D, Bajza Á, Gizurarson S. Evaluation of intranasal delivery route of drug administration for brain targeting. Brain Research Bulletin. 2018;143:155-170. doi:10.1016/j.brainresbull.2018.10.009 https://www.sciencedirect.com/science/article/pii/S0361923018303678
3. Keustermans W, Huysmans T, Danckaers F, et al. High quality statistical shape modelling of the human nasal cavity and applications. Royal Society Open Science. 2018;5(12):181558. doi:10.1098/rsos.181558 https://royalsocietypublishing.org/doi/10.1098/rsos.181558
4. Rygg A, Longest PW. Absorption and Clearance of Pharmaceutical Aerosols in the Human Nose: Development of a CFD Model. Journal of Aerosol Medicine and Pulmonary Drug Delivery. 2016;29(5):416-431. doi:10.1089/jamp.2015.1252 https://pubmed.ncbi.nlm.nih.gov/26824178/
5. Sanford M Archer MD. Nasal Physiology. Overview, Anatomy of the Nose, Nasal Airflow. Published April 17, 2020. Accessed July 27, 2020. https://emedicine.medscape.com/article/874771-overview
6. Unpublished Rocket Science Health data on file
7. Xi J, Zhang Z, Si XA. Improving intranasal delivery of neurological nanomedicine to the olfactory region using magnetophoretic guidance of microsphere carriers. Int J Nanomedicine. 2015;10:1211‐1222. Published 2015 Feb 10. doi:10.2147/IJN.S77520 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334328/