Local delivery of drugs has been well established as the primary method of treating and managing many respiratory diseases, such as asthma, chronic obstructive pulmonary disease (COPD) and allergic rhinitis. Beyond the traditional classes of long-acting beta agonist (LABA) / long acting muscarinic agonist (LAMA)and inhaled corticosteroid(ICS) molecules however, inhaled and nasal delivery of drugs presents unique opportunities for the delivery of other classes of drug as treatments for both traditional and non-traditional respiratory targets.
Repurposing existing active ingredients for inhaled or nasal delivery is a growing trend in the industry, offering reduced costs and time compared to new chemical entity (NCE) / new biologic entity (NBE) development and there are obvious benefits in lifecycle management of existing marketed products. Some reduction in clinical effort is offered through special registration pathways (such as the 505(b)(2) pathway) aimed at reducing unnecessary studies or duplicating existing work.
Even within clinical development of new products, shifting to respiratory delivery can also make sense, potentially addressing issues in efficacy, side effects, or commercial viability that parenteral or oral delivery may demonstrate during development.
Nasal Delivery
Delivery of drugs via the nasal route has seen significant growth in recent years, with the different tissue types in the nasal cavity allowing for systemic delivery, possible nose to brain delivery and access to the lymphatic system – of particular interest for vaccines. Respiratory vaccination is already present in the market with the nasal flu vaccine a popular option for school vaccination programmes, and the covid-19 response has obviously increased focus in this area.
There are a number of ways of describing the various areas, properties and attributes of the nasal anatomy but as a general guide we can focus on three primary areas of interest, the olfactory region, the turbinates and the nasal associated lymphoid tissue (NALT).The olfactory region, at the top of the nasal cavity is responsible for our sense of smell and is of interest as a route for direct delivery of treatments to the brain, avoiding the blood brain barrier, to treat conditions such as Parkinson’s and Alzheimer’s disease.
The turbinates are responsible for warming, humidifying and filtering the air we breathe, and provide a large surface area target for drug absorption for systemic delivery. Towards the anterior of the nasal cavity there is the NALT, which is connected to the lymphatic system and can induce a mucosal and systemic immune response. It is therefore a key target for delivery of vaccines and biologics.
Nasal delivery as an alternative to needle based administration offers relatively rapid absorption that also has the benefit of avoiding the hepatic first-pass effect, where the therapeutic agent is rapidly metabolised by the liver into inactive components. Actuating a device into the nose is also seen as preferable to most people when compared to administering themselves an injection, improving ease of use and compliance for patient administered treatments.
There are however some disadvantages, such as inconsistent absorption caused by infection blocking the nasal passageways, the natural nasal cycling of the nose, where one side then the other of the nose is more congested than the other, as well as the variation between different individual’s nasal geometry. The deposited drug is also rapidly removed from the nose by mucociliary clearance, where the small hairs covering the nasal mucosa, direct mucus and deposited material from the front of the nose back towards the throat where it is eventually swallowed. The nasal mucosa also contains enzymes which, particularly for peptides and proteins, can cause a pseudo first-pass effect where the peptides are partially metabolised in the nose prior to absorption.
Addressing these challenges can be met by a combination of device and formulation technologies to provide optimal, targeted delivery as well as excipient design that can maximise absorbance, activity, and stability once deposited; and the increasing importance of nasal delivery in the industry continues to drive innovation for this route of administration.
Inhaled Delivery
Inhaled delivery offers similar opportunities for systemic delivery, even potentially more rapid PK profiles than subcutaneous injection, however it comes with more complexity than the nasal route. The physiology of the respiratory system has evolved to keep particulates out of the lungs and so delivery of drug to the lungs requires specialised device and formulation technologies working together to achieve effective delivery.
Nebulisers are often the first option explored, as they provide an accessible translation from existing parenteral formulations, using aqueous solutions and suspensions. The formulations are delivered by a nebuliser device which generates an aerosol of droplets of sufficiently small size to be breathed into the lungs. These devices are bulkier and time consuming to use as the drug is taken over several minutes making them less ideal both for patient preference and commercial positioning for chronic disease management, when compared to other inhalation devices. However, where rapid solutions are needed to address urgent needs, as well as treatment of acute conditions in smaller populations, especially in a hospital setting, nebulisers are often the most cost and time efficient route for development. Many newer device technologies are also coming to the market which offer targeted delivery to specific regions of the lungs, connectivity to patient applications via Bluetooth, more portability, and modern designs. The downside is that these features result in a higher cost per product.
Dry powder inhalers (DPIs) require additional development work to engineer the drug substance to an appropriate size distribution and also require careful optimisation of the formulation and device technology for optimal performance, however they provide a more convenient user experience, usually taking a single dose in a single inhalation. The solid state of the formulation can also provide stability advantages for the drug which can be a significant consideration for the range of large molecule therapeutics which are increasingly dominating drug development pipelines. Finally, cost of goods (COGs) is generally much lower for this class of product when compared with a nebuliser.
Pressurised metered dose inhalers (pMDIs) also offer a patent convenient dosing process although require formulation of a solution or suspension in a propellant that can restrict the achievable dose range and limit compatibility with biologic drugs. Nevertheless, pMDI products are generally the lowest cost product per dose and a major part of the current Asthma/COPD landscape.
Summary
Respiratory delivery of drugs has already moved beyond the traditional Asthma/COPD space with new therapeutics including antibiotics and anti-viral treatments, pulmonary hypertension, diabetes management, narcotic overdose, and other CNS and mental health treatments at various stages of development and marketing.
The global covid-19 response within the industry raised the profile of repurposing drugs for respiratory delivery and has significantly stepped up momentum in this area. Driven also by the challenge of delivering biologics, significant development of formulation, device and analytical technologies continues within the industry. This opens up significant opportunities to deliver cost and time efficient programmes for the repurposing of existing drugs to greatly improve treatment options across a wide range of indications.
