SMI TECHNOLOGY - How Soft Mist Inhalers Support Improved Biopharma Drug Delivery

INTRODUCTION

Worldwide, rising cases of chronic lung conditions, such as asthma, cystic fibrosis, pulmonary arterial hypertension (PAH), and chronic obstructive pulmonary disease (COPD), are driving demand for inhalation drug delivery devices.

Some 262 million people were living with asthma and 212.3 million with COPD globally in 2019, and case rates for these con­ditions are expected to rise by 7% and 23% respectively over the next 20 years.^1-3 It is estimated that up to 50-70 million individuals, almost 1% of the world’s population, are affected by PAH worldwide — a figure that is expected to rise over the next few decades as the global population grows and ages.⁴ According to estimates, 162,428 people are living with cystic fibrosis worldwide.⁵

Inhalation is the ideal route for delivering drugs to the target site within the lungs to tackle these pulmonary conditions. It is no surprise, then, that the inhalation drug delivery market is forecast to reach a value of $18.6 billion by 2029, growing at a compound annual growth rate (CAGR) of 3%.⁶

This is not the only factor in the growth of inhalation as a delivery route. One of the most significant factors is the rapid rise of the biopharma segment — expected to enjoy a CAGR of 7.8% from 2022 to reach $719.84 billion by 2030.⁷

Traditionally, biologics have been delivered parenterally to avoid the gastrointestinal route. However, an intravenous injection can be unpleasant for patients, as 20%-50% of adults have a fear of needles, leading to a high rejection percentage of needle-based therapies. Administration of these treatments is often limited to a clinical setting, further increasing patient burden while impacting the limited resources of healthcare professionals (HCPs).⁸

Developments in inhalation delivery technologies, such as soft mist inhalers, mean that inhalation is now a viable alternative delivery method for many biologic formulations.⁹

MARKET OPPORTUNITIES FOR BIOPHARMA

As the biopharmaceutical industry grows, it is becoming increasingly competitive. Several blockbuster biologic therapies are due to lose their exclusivity in the next few years, including four of the best- selling biopharmaceutical drugs of 2020: Humira, Revlimid, Eliquis, and Keytruda.¹⁰ These patent expiries are, in part, driving the expansion of the biosimilars market — the segment is expected to reach a value of $75 billion by the end of the decade, with a CAGR of 15% between 2020 and 2030.¹¹

Faced with the possibility of new rivals entering the market, product originators need to reconsider the life cycle of their therapies to maximize the value of their in­vestments. Reformulation into inhaled treatments can offer the potential to sup­port drug developers in extending their product life cycle while enhancing the lives of the patients using the therapies.

NASAL ADMINISTRATION RISING UP THE BIOPHARMA AGENDA

The nasal administration route is also being considered increasingly for the re­formulation of biologics. Recent studies have highlighted the benefits of the nasal route for a wide range of biopharmaceu­tical formulations compared with the tra­ditional parenteral route.¹²

There are unique advantages to using the nasal cavity for the systemic de­livery of a variety of protein and peptide drugs, thanks to its large, 150 cm² ab­sorption area, which is highly vascularized, with a similar permeability to the small in­testinal mucosa. Nasal inhalation is also easy and non-invasive to administer, offers rapid onset of action and avoids gastroin­testinal degradation and hepatic first-pass effects.¹¹

Studies have shown that the delivery of insulin from the nose to the distal re­gions of the brain is enhanced via nasal administration.¹¹ In addition, mucosal de­livery of vaccines has been found to offer a more pronounced and longer-lasting ef­fect than traditional injection.¹³ Harnessing this route triggers a strong protective im­mune response at the principal sites of pathogen infection. The induction of adaptive immunity at mucosal sites, involv­ing secretory antibody responses and tis­sue-resident T cells, can prevent an infec­tion. This is particularly the case for vaccines against viruses, such as influenza and coronavirus, that can stop establishing infection in the first place, rather than only curtailing infection and protecting against the development of disease symptoms. For these reasons, the nasal vaccine segment is expected to grow particularly well in the next few years to reach $250.91 million by 2029, up from $122.29 million in 2021.¹⁴

In addition, nasal delivery offers an exciting advantage for the reformulation of biologics about to lose their exclusivity. It opens up a new avenue for drug devel­opers to breathe new life into their prod­ucts, providing a distinct new format for their intellectual property that also offers enhanced convenience for patients. The nasal route also has regulatory advan­tages for reformulated products compared with parenteral administration. Due to its non-invasive nature and target delivery with fewer side effects, the path to regula­tory approval can be significantly stream­lined.

The Resyca. Soft Mist Inhaler.

OVERCOMING THE CHALLENGES OF NASAL DRUG DEVELOPMENT

With all of these benefits in mind, it is clear nasal delivery offers a unique alter­native route for biopharmaceutical inno­vators to consider. Nevertheless, developing an effective final nasal drug product does pose challenges that need to be overcome.

For example, biologic formulations can be fragile and prone to damage from delivery devices during nebulizing or spraying. Lipid nanoparticles of the kind used in mRNA vaccines can be damaged by nebulizers for oral inhalation, accord­ing to a study by the University of Amster­dam.¹⁵

Preservatives traditionally used in nasal devices, such as benzalkonium chlo­ride, also cannot be used in biological for­mulations as they are incompatible with the actives. This complicates the develop­ment of nasal biopharmaceutical treat­ments, mandating delivery devices that can ensure sterility of the biopharmaceuti­cal during use.

In addition, the area of the nasal cav­ity that needs to be dosed, as well as the dose volume, are critical for drug efficacy. This makes the selection of the nasal in­halation device vitally important. For in­stance, a traditional nasal spray often features a swirl nozzle with a spray cone angle of between 60° and 90°. Rather than allowing the treatment to penetrate deep into the nasal cavity, this can result in most of the formulation being deposited on the walls of the nose, undermining dose uni­formity.

The need for an effective turn-key nasal delivery device platform for biophar­maceuticals is another challenge that needs to be addressed. An appropriate platform would not only address the issues around the sensitivity of the active to shear forces during administration and the re­strictions on preservatives — it would also be easy to source and use with minimal time-consuming customization.

Nasal spray design has evolved sig­nificantly in recent years, overcoming many of these challenges for biopharma­ceutical developers. Partnerships between specialist device developers have been in­tegral in spearheading this innovation, helping to establish nasal delivery as a vi­able option for biopharmaceutical devel­opment.

THE ROLE OF PARTNERSHIPS IN INHALED & NASAL DEVICE INNOVATION

A network of strategic collaboration partners is fast becoming an important el­ement of many device developers’ strate­gies to meet the needs of the pharmaceutical industry and address drug delivery trends in healthcare. Working to­gether, device experts can share knowl­edge and technology to create new inhalation and nasal device platforms that offer improved performance for biologics and enhance patient convenience. Due to this collaboration, there has been an in­crease in the variety of inhaled and nasal spray technologies available to drug de­velopers in recent years.

Each device has unique benefits that make it suitable for particular applications. However, many devices often require con­siderable design customization to ensure they are effective at delivering biologic for­mulations at the required dose. This can add time and cost to any inhaled or nasal biologic reformulation project.

COLLABORATION ENABLES DEVICE DEVELOPMENT EFFICIENCIES

A new generation of inhaled and nasal devices has recently entered the market due to collaboration between spe­cialist developers — soft mist inhaled and nasal sprays. They offer unique design ad­vantages both for new biologics projects and for the reformulation of existing drugs. They can significantly reduce the cus­tomization required to ensure the device is suitable for the formulation, minimizing the time and cost of development.

Related to the soft mist inhaler (SMI) for oral delivery, the soft mist nasal spray is a liquid sprayer that creates a slow-mov­ing aerosol cloud designed to optimize drug delivery to the nasal cavity while min­imizing the inspiratory effort required by the patient.

Partnerships between device special­ists have enabled further enhancement to the design of soft mist nasal spray devices that have made them ideal for the delivery of sensitive biologic formulations.

Large suppliers that offer full integra­tion of device development, pharmaceuti­cal product development, and manufacturing can enable collaboration between internal experts in each aspect of the development journey. Supporting every aspect of a project, from the sourcing of clinical material to simultaneous formula­tion and device development, to commer­cial manufacturing, such a single supplier can help pharmaceutical companies min­imize the need for complex and time-con­suming technical transfer. In doing so, it can reduce the risk of costly delays and speed up project delivery.

PERFORMANCE BENEFITS ARISE FROM EXPERT PARTNERSHIPS

Another example of collaboration is the sharing of new, more targeted nozzle designs with soft mist nasal spray develop­ers by nozzle manufacturers. These can create a narrower spray cone that ad­dresses dosing problems posed by the wide-cone nozzles traditionally used in nasal devices, allowing more of the dose to reach the nasal cavity. Next-generation spray nozzles allow the fine-tuning of the spray cone angle, from 0° to 30°. Together with a significantly reduced spray velocity, this reduces the amount of formulation being deposited at the front of the nose. In doing so, it increases the dose reaching the upper turbinates and the olfactory re­gions of the nasal cavity. When used in a soft mist nasal spray, such a nozzle can evenly distribute a soft mist into the nasal cavity, resulting in uniform dosing, a longer residence time for the formulation in the nose, and potentially enhancing drug performance.¹⁶

The new nozzle formats used in soft mist nasal sprays are particularly benefi­cial for the delivery of sensitive formula­tions, such as many biologic products. They aerosolize the drug on delivery in a unique way, which limits the shear forces imposed on formulation particles, mini­mizing damage to the formulation itself and ensuring optimum effectiveness.¹⁴ The customization of the spray cone of soft mist nasal sprays further simplifies develop­ment, as it can be easily adjusted to suit the unique needs of the biologic formula­tion without needing to invest the time to rework the whole device design.

SHARING INNOVATION UNLOCKS THE BENEFITS OF INHALED & NASAL BIOLOGICS

Inhaled and nasal administration of­fers an exciting alternative approach to both biologics development and the refor­mulation of existing treatments. New de­livery technologies, such as the soft mist nasal spray, have made nasal a viable route for biopharma products. They can minimize development and regulatory time frames and optimize manufacturing efficiency. At the same time, they can help create a more convenient and easier-to-use end product for HCPs and patients.

Knowledge sharing through partner­ships between device specialists has played a key role in enabling the develop­ment of these technology platforms. With ongoing collaboration, the industry will be able to see further innovations that will transform biologics development and open up new routes of administration. As a result, drug developers will be able to launch new biopharmaceutical drug prod­ucts or give their blockbuster biologic for­mulations a new lease of life and continue to address the self-administration needs of patients.

REFERENCES

1. https://www.who.int/news-room/fact-sheets/detail/asthma#:~:text=Asthma_affected_an_estimated_262,lead_a_normal%2C_ac­tive_life.
2. https://www.bmj.com/content/378/bmj-2021-069679.
3. “The Global Asthma Report 2018” http://globalasthmare­port.org/.
4. https://journals.physiology.org/ doi/full/10.1152/ajplung.00098.2020.
5. https://www.sciencedirect.com/ science/article/pii/S1569199322000315.
6. HealthcareAnalyst, “Global Inhalation Drug Delivery De­vices Market $17.6 Billion by 2027” (October 25, 2021) https://www.ihealthcareanalyst.com/global-inhalation-drug-delivery-devices-market/.
7. Precedence Research, “Biologics Market Size to Worth Around US$ 719.84 Bn by 2030” (April 2022) https://www.globenewswire.com/en/news-release/2022/04/20/2425668/0/en/Biologics-Market-Size-to-Worth-Around-US-719-84-Bn-by-2030.html.
8. https://pubmed.ncbi.nlm.nih.gov/30109720/.
9. J.O. Morales, et al., AAPS J., 19 (May) 652–668 (2017) [and references therein].
10. Fierce Pharma, “The top 15 blockbuster patent expira­tions coming this decade” (July 2021).
11. IQVIA, “Biosimilars to continue rapid growth over the next decade” (Jan 2022) https://www.iqvia.com/blogs/2021/12/biosimilars-to-continue-rapid-growth-over-the-next-decade#:~:text=According_to_IQVIA’s_Forecast_Link,bn_within_the_next_decade.
12. Darshana S, June S, “Nasal Delivery of Proteins and Pep­tides”. Glob J Pharmaceu Sci, (2017), Vol 1(4), 555569.
13. Mucosal vaccines — fortifying the frontiers, Ed C. Lavelle & Ross W. Ward, 2021.
14. https://www.databridgemarketresearch.com/ reports/global-nasal-spray-vaccine-market.
15. Klein D, Poortinga A, Verhoeven F, Bonnet S, van Rijn C, ‘Degradation of lipid based drug delivery formulations during nebulization’, medRxiv, March 24 2021.
16. Mucosal vaccines — fortifying the frontiers, Ed C. Lavelle & Ross W. Ward, 2021.

Dr. Nicolas Buchmann is Chief Technology Officer at Resyca®. He has experience in the development of smart nebulizer and inhalation devices and has worked in this industry for most of his career. He has extensive knowledge in medical device development and managing complex development programs and portfolios for inhalation drug-device-combination products. Before joining Resyca, he held roles at Vectura (Chippenham, UK) as Program Manager and at Pari GmbH (Starnberg, Germany) as Technology Manager. He earned his PhD in Biomedical Engineering and is a certified senior project manager (IPMA).