How Evolving Patient Needs Have Fuelled the Development of Nasal Drug Delivery

Next Breath

HOW EVOLVING PATIENT NEEDS HAVE FUELLED THE DEVELOPMENT OF NASAL DRUG DELIVERY

In this article, Julie Suman, PhD, President of Next Breath, considers how the needs of the patient have driven advances in nasal drug delivery and looks at the latest developments and benefits of this method of drug delivery.

The development programme for every by the method of drug delivery. Intravenous new drug or medical device is driven by routes of administration, for example, may one overarching objective: creating safe provide advantages in terms of rapid and and effective medications that improve accurate dosing, but less-invasive alternatives, patient outcomes. such as oral or nasal drug delivery, are more However, while this might be the clear readily accepted by patients and are also easier aim that guides pharmaceutical partners on to administer by healthcare professionals their path of continuous improvement and (HCPs) and patients alike. Innovation by development, achieving it in practice is far drug device development partners such from easy. The notion of patient outcomes as Aptar Pharma is therefore crucial to is recognised as a complex construct that the continued success of pharmaceutical can be measured in various ways, and companies in delivering better outcomes via success is dependent on several interlinked more patient-friendly techniques. elements being correctly aligned.1 Pharmaceutical companies are challenged A BRIEF REVIEW OF THE BENEFITS to deliver this alignment by delicately OF NASAL DRUG DELIVERY balancing their primary goal − achieving a desired therapeutic effect − with several From the patient’s perspective, research other factors, including patient adherence has demonstrated a preference for less- and compliance, which are heavily influenced invasive drug delivery methods such as intranasal administration. In a study examining patients’ responses between epinephrine delivered via a nasal spray “Innovation by drug or via an autoinjector, it was found that device development patients – all of whom suffered from severe Dr Julie Suman President of Next Breath allergies – reported a significant preference partners such as Aptar and Manager of Scientific Affairs for nasal epinephrine, specifically citing for Aptar Pharma Pharma is therefore factors including ease of learning and T: +1 (443) 538 8373 crucial to the continued use, device portability, safety and comfort E: [email protected] success of pharmaceutical within their responses.2 As an accessible, non-invasive route to Next Breath, companies in delivering rival the pharmacokinetic profile of some an Aptar Pharma company better outcomes via intravenously administered drugs, nasal 1450 Rolling Road drug delivery is increasing in profile and Baltimore more patient-friendly MD 21227 potential. Advances in intranasal drug United States techniques.” delivery technologies mean the benefits of this method are being brought to bear in an www.nextbreath.net

expanding range of therapeutic treatments, local-acting compounds. Nasal drops, for continue on this contested subject, there has both local acting and systemic. example, typically demand that the patient undoubtedly been a growing momentum This is all made possible as a result of adopts a rather unorthodox head position, behind preservative-free formulations, the biology of the nasal cavity, a highly such as Mygind or Kaiteki, to achieve encouraged by the EMA’s advice that the vascularised area of approximately 160 cm2 the gravitational conditions to support threshold for BAC should be zero for all in size.3 This large surface area provides the improved coverage in the nasal cavity. routes of administration, including nasal.6 basis for relatively rapid drug absorption However, the discomfort and complexity In response, device manufacturers have rates, leading to a fast onset of drug action. associated with such manoeuvres can developed innovative preservative-free Unlike oral administration routes, nasal understandably lead to poor compliance intranasal spray systems. Aptar Pharma is drug delivery also offers the advantage among patients. no exception, with examples including its of bypassing the gastrointestinal tract, Such weaknesses have paved the way for CPS technology platform and Advanced thus avoiding the risk of bioavailability metered-dose spray pumps to emerge as the Preservative-Free (APF) system, which being reduced as a result of first-pass dominant option for nasal drug delivery. incorporate a filter membrane in the metabolism. Equally appropriate for drugs targeting ventilation channel to prevent the ingress Exploiting the benefits of nasal drug local action as well as systemic absorption, of any microbiological contamination with delivery is not new. In fact, the nose has and compatible with formulations venting air. This ventilation channel is long been recognised for its characteristics in suspension as well as solution, these combined with a spring-loaded tip seal as a drug-administration pathway, as devices provide a platform for accurate, mechanism to eliminate the need for any exemplified by the nasal insufflation of repeatable dosing and targeted delivery. preservatives or additives, such as silver powders for local and systemic disorders A specified volume of liquid, between 50 ions or surface coatings. Rigorous integrity in medieval Persia (Nofookh).4 Modern, and 140 µl, is contained within the device’s tests have proved that both the tip seal Western medicine accelerated its interest metering chamber and then aerosolised via and ventilation channel protect against any in the mid-20th century, when early nasal compression of the actuator – following ingress of bacteria from either air or liquid. drug delivery products were dominated by initial priming of the device. Releasing local-acting treatments for conditions such the actuator causes a pressure imbalance ENHANCING PATIENT CARE as nasal congestion and allergic rhinitis. that triggers the refilling of the metering Product examples include fluticasone chamber via the dip tube. For a growing number of applications, propionate (Flonase) (GlaxoSmithKline) During the spraying manoeuvre, make- multi-dose nasal sprays are being replaced and oxymetazoline hydrochloride (Afrin) up air enters the bottle, which potentially by devices that can deliver a controlled single (Bayer Healthcare). exposes the formulation to bacterial dose (Unidose (UDS), Figure 1a) or two contaminants. As aqueous formulations doses (Bidose (BDS), Figure 1b). Through DEVELOPMENTS IN NASAL may support bacterial growth, antimicrobial their intuitive design, ease of use and no need DEVICE TECHNOLOGY preservatives may be included within the for priming, such products allow for needle- formulation to maintain stability and free administration (or self-administration) As these products evolved into over- prevent contamination throughout the of potentially life-saving emergency the-counter (OTC) remedies from their product’s shelf life. The use of preservatives medicines where there is urgent need. prescription origins, the convenience and such as benzalkonium chloride (BAC), Examples include naloxone (NARCAN®) ease of use of aerosolised delivery made however, has led to concerns over their (Opiant) for treatment of opioid overdose them highly marketable to patients, potential role in causing undesirable side and midazolam (Nayzilam®) (UCB) and particularly when contrasted with effects such as damage to the ciliated tissue diazepam (Valtoco®) (Neurelis) for alternative methods for administering in the nasal cavity.5 While discussions treatment of seizures.

(A) (B)

Figure 1: Unidose liquid (UDS) spray (A), and Bidose liquid (BDS) spray (B).

(A) (B)

Figure 2: Nasal Powder Unidose device (UDSp) gives higher deposition than Liquid Unidose device.

Further breakthroughs in recent form of sumatriptan (Onzetra®) (Avanir that play a more “active” role in supporting years include esketamine nasal spray Pharmaceuticals). Such products exploit the greater adherence. By monitoring, recording (Spravato®) (Janssen Pharmaceuticals) for unique advantages of nasal powders, which and communicating data on usage via the treatment-resistant depression. In addition, include their suitability for accommodating internet, connected devices represent a diabetic patients have benefited from the larger doses and supporting compounds potent opportunity for establishing an introduction of glucagon nasal powder lacking aqueous stability. In addition, ecosystem where pharmaceutical company, (Baqsimi®) (Eli Lilly and Company), a study of in vitro deposition has also shown patient and healthcare practitioner are more which can be used in the event of a severe that, when compared with an aqueous closely integrated (Figure 3). Apps can hypoglycaemic episode. Portability, ease of spray, nasal powder may improve targeting prompt patients to take their medication, use and reliability of dosing are critical to the olfactory region (Figures 2). healthcare professionals can accurately qualities in an application such as this, and track progress and pharmaceutical a single-use nasally administered powder EMERGING OPPORTUNITIES companies can receive anonymised data on device represents significant advantages FOR NASAL DEVICES real-world medicines use. In this scenario, over the alternative option of a glucagon injection, which also requires refrigeration. As well as their intuitive design, nasal This is a clear example of nasal drug inhalation devices are subject to continued delivery’s potential in the sphere of drug innovation by pharmaceutical companies repurposing, where the reformulation of and device partners to enhance the care existing compounds can bring significant and support provided to patients. With new advantages in terms of patient and emergency therapies, for example, caregiver accessibility. training kits have been developed In addition to the treatment of diabetes, that closely mirror the real-life nasal powder also provides a delivery experience of using a nasal spray platform for migraine sufferers in the with a view to optimising compliance and decreasing the mortality risk. Patient safety is also being addressed through “As well as their intuitive the inclusion of lock-out design, nasal inhalation mechanisms on devices, while the development of laterally devices are subject to actuated nasal sprays provides continued innovation greater levels of comfort and by pharmaceutical simplicity for certain patient populations. companies and device Dose counters have long partners to enhance the been recognised as benefiting care and support adherence, and rapid advances in technology have built on provided to patients.” this platform to create an Figure 3. Connected devices are ecosystem for connected devices the future for digital healthcare.

interaction with immune modulators in the “At the other end of the spectrum, nasal drug delivery nasal cavity and dendritic cells in the nasal epithelium. With vaccines in development is demonstrating success at treating neurological for conditions including anthrax, conditions via the central nervous system (CNS). HIV and Hepatitis B, among others, It has been shown that targeting drugs at the roof of further opportunities exist in this area, where sufficient activity can be achieved by the nasal cavity enables molecules to be transported overcoming challenges in drug absorption, to the CNS via the olfactory or trigeminal pathway.” mucociliary clearance, the mucus barrier and enzymatic degradation at the nasal mucosa. avoiding medicines wastage is an obvious It has been shown that targeting drugs Today, the more immediate potential benefit, but it also represents a fundamental at the roof of the nasal cavity enables for nasal drug delivery concerns treatments opportunity for delivering better long-term molecules to be transported to the CNS via for covid-19, which has rapidly emerged health outcomes. the olfactory or trigeminal pathway.8 Many as the most urgent healthcare challenge of Further high-value opportunities exist existing therapies targeting these conditions modern times. Promising treatments are in the OTC space, where there is growing suffer from poor bioavailability due to the currently in development that eradicate evidence of the benefits of nasal saline in blocking effect of the blood-brain barrier the virus from the upper respiratory promoting well-being and addressing the (BBB). In bypassing the BBB, intranasal tract while blocking the ACE-2 receptor, symptoms of air pollution, which causes the delivery methods can be used with targeting essential for the virus to infect cells. deaths of an estimated seven million people strategies to increase the level of drug Examples of nasally administered treatments worldwide every year.7 reaching the intended site of action. include antibodies such as immunoglobulin As research into this important area G (IgG) and immunoglobulin Y (IgY). OVERCOMING THE continues, nasal devices continue to be According to the WHO, at least five nasal BLOOD-BRAIN BARRIER deployed in a prophylactic capacity through spray vaccines are now in early clinical the delivery of vaccines. In the 2019–20 trials. In tandem with mass vaccination At the other end of the spectrum, nasal season, over three million children were programmes, nasal devices may enable drug delivery is demonstrating success at vaccinated against flu across the UK with therapies such as these to play an important treating neurological conditions via the the live attenuated influenza vaccine (LAIV)9 part in our protection against covid-19 in its central nervous system (CNS) (Figure 4). nasal spray. Immunity is achieved through various forms in the years to come.

Figure 4. Unmet CNS disease states span across all demographics. The size of the bubble represents the size of the market for the disease state.

Nasal drug delivery has evolved into a REFERENCES Rhinol, 2008, Vol22 (2), pp 125–129. highly versatile method of administration 6. “Questions and answers on for locally acting and systemic drugs; 1. Liu Y et al, “Patient outcomes benzalkonium chloride used as an for administering emergency doses and in the field of nursing: A concept excipient in medicinal products for managing long-term conditions; and, in the analysis”. Int J Nurs Sci, 2014, human use”. PDF, EMA, 2013. case of preventative vaccines or breaking new Vol 1(1), pp 69–74. 7. “Air Pollution”. Web Page, ground, in challenging therapeutic areas. 2. Beckman S, “Patients prefer epinephrine WHO. (www.who.int/health-topics/ Central to all these diverse applications is nasal spray over auto-injector”. air-pollution, accessed April 2021). the fact that patient outcomes have been Healio.com, November 5, 2019. 8. Gänger S, Schindowski K, enhanced by delivering medicines and 3. Gizurarson S, “Anatomical and “Tailoring Formulations for therapies in a way that is more accessible and Histological Factors Affecting Intranasal Nose-to-Brain Delivery: acceptable to the patient, smoothing their Intranasal Drug and Vaccine A Review on Architecture, Physico- access to the care they need. With continued Delivery”. Curr Drug Deliv, Chemical Characteristics and innovation, driven by pharmaceutical 2012, Vol 9(6), pp 566–582. Mucociliary Clearance of the Nasal companies and their drug delivery partners, 4. Zarshenas MM et al, “Nasal Drug Olfactory Mucosa”. Pharmaceutics, nasal administration is poised to play an Delivery in Traditional Persian 2018, Vol 10(3), p 116. ever-more important role in tackling unmet Medicine”. Jundishapur J Nat Pharm 9. “Nasal Flu Vaccine”. Web Page, patient needs in the future. Prod, 2013, Vol 8(3), pp 144–148. Vaccine Knowledge Project 5. Ho C-Y et al, “In vitro effects of (Oxford Vaccine Group). All images courtesy of Aptar Pharma. preservatives in nasal sprays on (vk.ovg.ox.ac.uk/vk/nasal-flu-vaccine, human nasal epithelial cells”. Am J accessed April 2021.) ABOUT THE COMPANY

Next Breath is a speciality company of Aptar ABOUT THE AUTHOR Pharma, and a full-service cGMP compliant laboratory specialising in analytical testing Dr Julie Suman is the President of Next Breath, an Aptar Pharma company, and manager of a range of drug delivery systems, from of Scientific Affairs for Aptar Pharma. Dr Suman holds a BSc in Pharmacy and a PhD early stage to commercialisation. Next in Pharmaceutical Sciences. Dr Suman is co-editor for Respiratory Drug Delivery Breath provides comprehensive solutions Proceedings, and an Affiliate Assistant Professor in the Department of Pharmaceutics, for the product development process from Virginia Commonwealth University, VA, US. A Past-Chair of the AAPS Inhalation formulation and CMC support, to finished Technology Focus Group, Dr Suman has published in several peer-reviewed journals and batch release and post-approval stability, presented at numerous international meetings. to regulatory agencies worldwide.

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