Inhaled biologics have become highly important, as it is now the preferred route of choice for delivering many drugs. This is particularly true in the treatment of respiratory diseases. Inhalation has many advantages over other routes; these include faster onset of action due to the large surface area and good vascularisation of the lung. Delivery of biologics via the respiratory route delivery also avoids the issue of degradation in the gastrointestinal tract and first-pass effect with improved therapeutic index due to targeted delivery typically requiring lower doses (with potentially fewer side-effects). It also holds to the more patient-centric approach that the industry has shifted to with improved patient adherence, convenience, and less pain or intrusiveness when compared to injections or infusions.
The majority of biologics are administered through injections or infusions due to oral bioavailability issues. This has several disadvantages; not least that approximately one in 10 of the population are apprehensive about injections. Infusions are also problematic; not only are they an uncomfortable process for the patient, but they are also expensive due to the requirement of in-patient care by skilled professionals.
Delivering biologics via inhalation offers a more patient-friendly alternative and can often be lower cost. The respiratory route also has obvious benefits for treating lung diseases, enabling better targeting and a direct pathway to the site of action.
The History of Inhaled Biologics Delivery
Early Drugs and Challenges
Biologic therapeutics have conventionally been administered via the systemic route; however, this has proven dangerous for drug delivery to the lung due to the possibility of toxicity effects in the rest of the body. In addition, biologics can accumulate in the lungs due to their molecular weight while having a significantly weakened ability to traverse the air-blood barrier. This results in heightened target site accumulation and is therefore crucial for toxicity and immunogenicity considerations.
Pulmozyme was one of the first inhaled biopharmaceuticals to make it to market, gaining approval in 1993 to treat cystic fibrosis. Since then, the field has expanded and is continuing to grow significantly. Not every inhaled biologic area has seen success, however.
Inhaled insulin was heralded by many in the industry as the next big thing. In 2006, Exubera was the first inhaled insulin approved by the FDA. While its efficacy was comparable to other delivery forms, it failed primarily due to associated side effects and patient perception. Many adverse respiratory effects were reported, including increased risks of infection, chronic coughing, pharyngitis, and rhinitis. When a study found cases of lung malignancies in patients, the drug’s safety was put into doubt, despite the results being too small to ascertain a correlation with Exubera. Nevertheless, it was enough to put off many potential patients and providers. As a result, it was discontinued after only one year on the market.
In 2014 a new inhaled insulin treatment called Afrezza was launched. It appeared to have many advances over Exubera; however, it faced many of the same safety concerns, which led the FDA to require a “black-box” warning notifying patients of a heightened risk of acute bronchospasm. The difficulties faced by these insulin drugs made many companies became wary of investing in inhaled biologics.
Current Market and Projections
Despite this, over 40 inhaled biopharmaceuticals in the public domain have passed through the discovery stage and are now in the early phase of development and testing. Moreover, total revenues increased from 17% of all prescription drugs in 2010 to 26% in 2017, with the figures predicted to reach as high as 30% by 2022. if inhaled biologics can meet the challenges ahead, they could become a much more significant presence in the global market.
Formulation: No Perfect Solution
There are two key goals when formulating inhaled biologics: making particles small enough to be inhaled and the aerosolisation of dry powders or liquids. Both have the potential to impact product quality through decreased activity or protein aggregation.
The formulation and packaging system must be optimised with the intended delivery system in mind. Therefore, critical quality attributes for the drug product are carefully defined and evaluated. Dry powder from freeze and spray drying face protein degradation issues due to the formulation’s stressful nature. Nebulised formulations are cheaper to produce and test because the manufacturing process does not require extra drying steps. However, there is currently only one drug on the market deliverable through liquid jet stream nebulisation. In addition, the requirement for prolonged storage of proteins in liquid solutions can lead to instability and degradation pathways.
Choosing The Right Drug Delivery Device
There are currently three main types of inhalation devices: dry powder inhalers (DPIs), metered-dose inhalers (MDIs), and nebulisers. While the powder formulations used in DPIs possess stability and storage advantages, the key challenge here is formulation. Both MDIs and nebulisers are challenged by the requirement of aqueous solutions, which are not ideal for protein storage. Moreover, the process of nebulisation exposes the protein to further physical pressures such as heat and shearing force which can lead to protein degradation and denaturation. Protein stability is essential when considering delivery devices for biologics. It is often a difficult choice, with each having different pros and cons. Soft mist inhalers (SMI) are a new form of device that does not require propellant and confers the highest level of stability; however, its possible usage for biologics is still unclear.
Disease Effects and Structure of the Respiratory Tract
it is not only essential to achieve high deposition rates through formulation and delivery choices; it is also important to consider targeting and the structure of the respiratory tract. For example, a therapeutic for emphysema in COPD would need to reach the lung’s small airways because emphysema affects the alveolar region. In contrast, an asthma therapeutic would have to reach the large airway, as asthma mainly affects the bronchi. The effects of diseases on respiratory structure also need to be examined, such as changes to breathing patterns, clearance mechanisms, airway diameter, and anatomy.
Looking to the Future
Inhalation-based drug delivery of biologics is a growing area in modern drug formulation and development. It has the potential to open up new treatments and lower the burden of disease management for patients. While inhalation requires extra considerations and comes with additional challenges, the potential rewards are too great to pass up. There are a considerable number of early-stage products currently in development, and the number is only expected to grow in the coming years.