Historically, direct delivery of drugs to the nose or lungs has been used for management of asthma, COPD and allergic rhinitis, using the recognisable inhalers and nasal sprays, but applications are now extending to vaccines and anti-infectives, rescue medications, diseases of the CNS, and management of other chronic pulmonary diseases. There is growing interest in exploiting this delivery route for a number of reasons; including targeted delivery to the affected region to enhance local bioavailability and minimising off-target effects, potential for rapid systemic delivery and thus pharmacological onset, and avoiding first pass metabolism – particularly for sensitive molecules such as biologics. Since the trend in the pharma industry is for innovator products to be developed by biotech companies with limited internal resources and expertise in formulation development, there is an increasing reliance on CROs to do the formulation and analytical development during preclinical and clinical development and choosing the right CRO is critical to success, particularly in the niche area of inhalation.
Despite the clear pharmacological benefits, there are additional complexities associated with developing orally inhaled and drug products (OINDP) – not least because delivery requires a temporary change in the state of the formulation to create an aerosol that has to travel from a delivery device through the air(ways) before depositing in the nose or lungs. This complexity often stumps formulation scientists since control of this aerosolisation process is driven by interconnecting factors such as the physicochemical characteristics of the formulation, the choice of delivery device, and the behaviour of the patient when using the product – including how well they can coordinate their inhalation manoeuvre with activation of the device.
The first challenge is that the amount of formulation that can be delivered to these regions is far more limited than an injection or a tablet – delivering more than 100-200mcl to each nostril is arguably wasteful since it is likely to either drip down out of the nose or back to the throat to be swallowed, and similarly trying to deliver too much to the lungs too quickly may also activate the cough reflex, resulting in expulsion of the drug from the body. This means that the required drug concentration / loading per dose is often at least an order of magnitude higher than other dosage forms, so if your drug has solubility or stability challenges at higher concentrations, you need to be smart with your formulation strategy. With increasing popularity, this strategy involves considering formulating the drug as a dry powder rather than a more traditional liquid formulation, since particle engineering technologies such as spray drying or lyophilisation allow for preparation of formulations that could be up to 100% drug (depending on the drug properties).
Beyond ensuring you can deliver enough drug, formulating an OINDP also requires careful selection of buffers and excipients in order to ensure local tolerability of the formulation in the nose or lungs (such as pH and osmolality) which may not always be complementary to the inherent properties of the drug itself. Furthermore, there can be a balancing act between achieving optimal aerosolisation and ensuring optimal residence time in the nose or lungs, particularly since these organs are designed to efficiently prevent foreign matter (which includes drugs!) from entering the mainstream circulation. Both aerosolisation and retention time can be modulated by the viscosity and surface tension of the formulation in the case of a liquid, and by density, cohesive-adhesive-balance and particle size for a powder – not to mention the mechanics of the drug delivery device – all of which need to be determined and characterised during the formulation development process.
To add further complexity, there are certain functional excipients that can be added to OINDP which can enhance bioavailability of your drug, particularly if you are targeting onward delivery into the systemic circulation or even the brain, including permeation enhancers to help drugs get through the cell barriers between the nose and bloodstream, and mucoadhesives to help retain your drug in situ for long enough for it to have its pharmacological effect. However, it’s not a one-size fits all and each excipient has a different mechanism of action, so understanding what is right for your drug and indication is critical to achieving optimal performance – alongside knowing what these new excipients might do to your overall drug and formulation stability.
Naturally, the more components you add to a formulation, the more risk there is of counteracting one thing with another – so having a solid foundation of knowledge around which constituents are compatible with each other, and what fundamental effect they have on both a formulation and the local environment following deposition, will save a lot of time and avoid common mistakes. This will allow the formulator to focus on the particulars of your drug and use their past experience to start off on the right path. There are few CROs with experience in orally inhaled and nasal drug product development, so make sure to validate their experience early on to avoid wasting time and money. If the formulator doesn’t understand how to manage these nuances in a holistic way as a formulator, you or your CRO could be repeatedly taking one step forward and two steps back, with no clear vision as to where the finish line is.
