Using intranasal delivery for drug repositioning: a compelling proposition for lifecycle management.

Drug repositioning - the delivery of an approved drug via a different route and/or for purposes outside the original therapeutic indication - typically reduces the drug development timeline by 6 – 9 years and attracts average costs of ~$1.6 billion, a fraction of the ~$12 billion estimated for new drugs^i,ii. For pharma, drug repositioning is a powerful lifecycle management tool capable of delivering attractive returns over a relatively short timescale. For healthcare practitioners and patients, it can bring new therapies in an abbreviated timeframe.

Intranasal delivery is a valuable tool for drug repositioning with an established and growing track record of success. This article considers issues along the route to commercialization highlighting the support provided by Aptar Pharma at every stage, from device design and manufacture through formulation to patient training.

Why choose nasal drug delivery?

From a patient perspective nasal drug products are rapidly acting, non-invasive and easy-to-administer. Clinical efficacy may be achievable with a lower dose, relative to tablets, reducing the side effect profile, and first pass metabolism and enzymatic degradation in the gastrointestinal track are avoided.

Recent examples of FDA approved repositioned nasal drug products includeⁱⁱⁱ:

This list highlights the suitability of the nasal route for peptides and biomolecules, rescue medications and for the treatment of disorders of the brain and central nervous system (CNS).

Caregivers, rather than healthcare professionals are increasingly administering life-saving drugs intranasally, outside of the clinical setting, allowing patients to live more confidently with challenging disorders. However, it is arguably the potential for nose-to-brain drug delivery to treat, for example, depression and Alzheimer’s that is most exciting.

Targeting nasal drug delivery

Nasal drug delivery typically targets either the turbinates or olfactory regions (see below).

The turbinates are richly vascularized with a large surface area that is attractive for systemic delivery, despite the complicating issue of mucociliary clearance. The trigeminal nerve is embedded within the nasal epithelium of the turbinates with neurons protected by tight junctions, inhibiting transport to the brain.

The surface area of the olfactory region is much smaller and less accessible but hosts exposed neurons enabling rapid bulk transport along the olfactory nerve. Furthermore, although there is a mucus layer in this region there are no motile cilia. These features make the olfactory region appealing for nose-to-brain delivery.

Switching an existing drug to nasal delivery

For repositioned drugs, approval typically proceeds via an abbreviated route, such as the 505(b)(2) pathway, leveraging existing toxicology and clinical study data. Preclinical animal testing to establish proof of concept (POC) for nasal drug delivery is therefore often the starting point for a project, facilitated by specific actuators for animal research.

Along the subsequent path to commercialization product developers have three main goals: deposition in the desired location, retention within the nasal cavity, and achieving a therapeutic effect. Attaining these goals relies on understanding and effectively manipulating properties of the device and formulation while at the same time recognizing the importance of patient behavior in securing successful outcomes.

Focusing on the device: a range of options for rapid commercialization

The range of devices available for intranasal delivery has increased steadily in recent years with Aptar Pharma now offering an extensive portfolio of that extends to unit dose, two-dose and multidose solutions for liquid and powder formulations. Nasal drug devices differentially target specific areas of the nasal cavity so optimal selection may be helpful in boosting performance, depending on intended application.

For emergency use or high reliability products, devices must successfully administer the dose 99.999% of the time but there is already a choice of commercial solutions in place to meet this requirement. Aptar Pharma’s Unidose Liquid is a good example. By implementing process controls and quality specifications to align to the highest reliability requirements for FDA combination products, the system is manufactured to deliver the dose to the patient when assured performance is required.

Formulation practice: achieving efficacy with powder or liquid

The ‘combined’ nature of nasal drug products makes formulation equally important for successful development, a key decision being the choice between liquid or powder. Powders offer an extended shelf-life, longer retention times and opportunities for higher drug loading. We also find that they tend to be superior for targeting the olfactory region. Our ability to optimize aerosol properties via the use of manufacturing techniques such as spray drying is growing. On the other hand, liquid formulation minimizes in vivo dissolution constraints, and provides access to a greater portfolio of devices and more established manufacturing practice.

Aptar Pharma has emerged as the ‘go to’ partner for nasal drug delivery because its extensive portfolio of device platforms is matched with cutting-edge expertise in liquid and powder formulation, and indeed patient training solutions. Below you’ll see some examples of the work we do to help customers with each factor that contributes to successful nasal drug delivery.

Aptar Pharma in action: From deposition analysis to training devices

Aptar Pharma’s Aeronose Nasal Cast, Unidose Powder and Training devices

Deposition data for artesunateⁱⁱⁱⁱ, an antimalarial drug, show delivery of a powder formulation using Unidose Powder (Aptar Pharma), an easy-to-use, portable device, offering single-handed actuation. The results indicate relatively high deposition in the olfactory region, a positive outcome for nose-to-brain delivery.

This data was generated using a nasal cast Aeronose^® (shown). Aeronose is a 3D printed in vitro tool, validated nasal cast that is representative of the physiology of a male adult, that we now use extensively for nasal drug product development.

The Nayzilam training device image is for a midazolam nasal spray product to support patient practice. The nasal trainer is provided by Noble, an Aptar Pharma company. It includes Instructions for Use, and a resettable device that closely replicates the actual product, allowing users to become confident with administration.

In conclusion

Drug repositioning via nasal drug delivery has a growing track record of success. On the horizon lie a wider range of nasal vaccines, patient-friendly solutions for anaphylaxis and new treatments for anxiety and depression. Aptar Pharma has the expertise and products to help customers to realize this valuable potential. We know how to target different regions of the nasal cavity and how to optimize formulations to maximize bioavailability. Why not talk to us about your drug repositioning project?

i. H. Xue, J. Li, H. Xie, Y. Wang ‘Review of Drug Repositioning Approaches and Resources’ Int J Biol Sci 2018; 14(10): 1232–1244

ii. G. Jin and S. Wong ‘Towards better drug repositioning: prioritizing and integrating existing methods into existing pipelines’ Drug Discov. Today 2014 May 19(5) 637 – 644

iii. United States Food and Drug Administration, FDA-Approved Drugs, https://www.accessdata.fda.gov/scripts/cder/daf/.

iiii. Yobouet Ines Kouakou, Aurelien Millet, Elodie Fromentin et al. Pre-referral intranasal artesunate powder for cerebral malaria: a proof-of-concept study

Contact us: info.pharma@aptar.com

Learn more: https://www.aptar.com/pharmaceutical/delivery-routes/nasal-device-drug-delivery-oindp/nasal-drug-repositioning/

Dr Julie Suman
Vice President Scientific Affairs
Aptar Pharma

Reenal Gandhi
Business Development
Aptar Pharma