What pharmaceutical leaders should know about non-invasive drug delivery
Stuart Madden, chief scientific officer at neuroscience company Neurelis, examines the drug delivery sector and the opportunities non-invasive methods present to the industry and patients.
Non-invasive drug delivery is a broad term typically referring to routes other than parenteral administration, such as oral, intranasal, buccal/sublingual, pulmonary, and transdermal routes. For pharmaceutical leaders and decision-makers on the manufacturing side of the industry, it’s important to understand available delivery methods, their unique benefits and use cases and innovations which are making some methods attractive solutions for boosting available therapeutics.
Pros and Cons of Parenteral Administration
Parenteral administration (typically injections via intravenous, intramuscular, subcutaneous, and intrathecal routes) has numerous disadvantages, including required administration by a trained health care professional (for IV), inconvenience of administration, injection site pain, and potential needle-stick injury. These aspects can lead to poor patient compliance, especially for chronic treatments, and can have a negative impact on quality of life.
Notwithstanding these issues, parenteral administration does have benefits, for example rapid systemic distribution, avoidance of first pass metabolism, by-passing potential gastro-intestinal adverse effects, and 100% bioavailability of the dose delivered. The delivery of biologics is one area where parenteral administration is still the leading route. Peptides and proteins are inherently difficult to deliver by non-parenteral routes. Their characteristic instability in the GI tract rules out traditional oral administration. Further, their high molecular mass results in lower permeability across biological barriers such as the skin, mucosal membranes, and cell membranes, making non-oral routes sub-optimal as well. Instability of biologics leads to structural changes that are either physical (aggregation, confirmational changes etc.) or chemical (deamination, hydrolysis, oxidation) resulting in the loss of therapeutic efficacy. When indicated for use in specialised dosage forms, these products also present significant challenges to pharmaceutical manufacturers.
Innovations & Opportunities within Non-Invasive Delivery
However, over the past few decades, non-invasive routes of administration have become more sophisticated in their delivery mechanisms. In many cases, these solutions have reduced the potential advantages of parenteral administration to the point that they can routinely be considered as the preferred option.
As many working in pharmaceuticals and manufacturing are aware, oral drug delivery is the most ubiquitous route for non-invasive systemic drug delivery. Oral delivery has numerous advantages over other routes, including ease of administration, convenience, ability to deliver high drug loads, and ease of manufacturing at a relatively low cost. There are disadvantages, however. Extensive first-pass metabolism, unfavourable physicochemical drug properties (low solubility and/or low permeability resulting in poor bioavailability, poor stability, enzymatic degradation) can be difficult to overcome and other non-invasive routes may be more attractive.
If oral delivery is not suitable, even with enhanced delivery technologies to address some of the potential issues described above, then strategies to pursue other non-invasive routes for systemic delivery can be developed. The therapeutic indication is a key driver in this process. For example, if rapid onset of drug action is a pre-requisite for an indication, then nasal, and to some extent sub-lingual or buccal, administration are attractive options.
Moreover, nasal administration has the potential for direct nose to brain delivery - this is especially attractive where ease of administration and rapid onset are of paramount importance. For example, treating drug overdoses or CNS disorders such as epilepsy, anxiety, or panic attacks. One of the limiting factors of using drugs to treat neurological conditions is their inability to cross the Blood Brain Barrier (BBB).
However, nasal delivery does have limitations as well. This includes dose volume typically being restricted to no more than 100 µL to prevent potential leakage through dripping back out the nostril or going past the upper reaches of the nasal passages to be swallowed via the oesophagus. The dosage form also has a limited residence time in the nasal passages before being removed by mucociliary clearance, and the nasal passages themselves can be sensitive to irritation from the drug product. Thus, adequate solubility to provide the required dose in one administration that is rapidly absorbed in a formulation and doesn’t provoke significant irritation presents formulation challenges. In addition to these challenges, the dose must be delivered in a consistent and reliable manner so that the patient gets a reproducible dose with each use. Nasal delivery is an established route for many seasonal disorders (the common cold, allergies, etc.) so this aspect of the drug product is well established.
Similarly, other non-invasive forms of drug delivery have advantages and disadvantages. Dry powder inhalers and pressurised metered-dose inhalers are useful for pulmonary delivery of powders where long-term stability in solution does not provide for a commercially viable shelf-life under room temperature conditions. However, the development of these types of formulations and delivery systems are not straightforward. Transdermal delivery systems offer numerous advantages for drug delivery, including the potential to deliver biologics with appropriate permeation enhancers, sustained release of drugs over prolonged periods (days) and facilitating patient compliance with ease of administration. Buccal or sublingual dosage forms offer rapid onset, ease of administration, and avoid first pass effect but require drugs that are easily and rapidly absorbed by the mucosa and have appropriate organoleptic properties.
In summary, non-invasive routes can offer an attractive alternative to parenteral drug administration for many drugs and leaders in the pharmaceutical industry should stay educated on the various options available in this space. The biggest challenge lies with biologics, but recent advances in non-invasive delivery of proteins and peptides show promise. The preferred and optimal route choice is dependent on a variety of factors encompassing clinical needs, physicochemical attributes of the drug substance, manufacturing requirements, patient needs and preferences, and regulatory considerations. There is a no cure-all that will meet all these needs and each development program will have a unique set of requirements and challenges. Despite these challenges, the technologies for non-invasive drug delivery are sufficiently mature that a systematic approach can be taken in every instance to develop and produce an optimised drug product that meets its target product profile.