Evolution of nasal aerosol products with focus on pain management

Dr. Gerallt Williams

Although nasal aerosol products to treat pain have been around for a number of years, recent developments have brought renewed interest to this market. In addition, estimated at over $1.2 billion in 2011, the world market for nasally administered systemic drugs has seen strong growth in the last few years. This article will look at the past, present and future of this particular aerosol application with a focus on some of the devices used to deliver the aerosolised drug.

Potential advantages of the nasal route of administration compared with parenteral or oral administration include a non-invasive approach removing any associated pain or anxiety related to injection, rapid onset of action, good bio-availability, and hence high levels of acceptability resulting in improved comfort and compliance for patients. As compared to oral forms of pain management treatments, intranasal delivery also benefits from the avoidance of first pass metabolism. From a managed care perspective, reduced medical staff supervision or intervention is needed to administer the medication, leading to potentially significant cost savings which is a very strong driver for over burdened health care system worldwide.

The applications of nasally administered treatments for management of severe pain, as opposed to OTC pain killers, are numerous and include in-hospital treatments such as post-operative pain management, burns and breakthrough pain associated with cancer, multiple sclerosis and other types of pain episodes. Out of hospital applications include amongst others, palliative care, paramedic retrieval medical services and anti-migraine treatments. Some of these treatments will use potent drugs and may be managed under the controlled substances regulations.

A review1, 2 of the pharmacokinetic (PK) properties of intranasal, intravenous and oral treatments in three classes of drugs (opioids, benzodiazapines and anti-migraine agents) which are potentially suitable for intranasal delivery reveals the attractive PK benefits for this mode of delivery, see Table 1.

A typical PK profile for a nasally administered drug as compared to an intravenous formulation clearly demonstrates the potential of this drug delivery mode. The PK properties of intra-nasally administered drugs lie between those of intravenous and orally administered drugs with the added advantages of self administration versus intravenous and avoidance of first pass metabolism versus oral administration.

Nasal spray device evolution

Figure 1 – Early generation of anti-migraine nasal spray devices

One of the first generation of devices used to deliver pain medication via a specifically designed nasal spray system were the anti-migraine treatments Diergospray/ Migranal and Imigran (Imitrex) products in the early 90s. The device for the Diergospray / Migranal was an adaptation of a standard nasal spray pump coupled to a glass ampoule containing the product. The glass ampoule was opened just before use, the nasal spray pump dip tube was inserted in the drug solution, the product was primed several times and the dose was then delivered into the nasal cavity (Figure 1). The Imigran device used a specifically developed ready to use unidose system which did not need priming before use (Figure 1). These kinds of devices are very effective for acute treatments such as migraine attacks. Other devices that followed later appeared with a more customised and patient oriented designs such as Zomig (Figure 1).

Figure 2 – Recent multi-dose nasal treatments introduced to the marketplace

Evolving needs for drug delivery systems for use in treatments for chronic pain management where numerous doses have to be taken over a prolonged period of time has given rise to the development of nasal multidose delivery systems for pain management. One of the first to reach the marketplace was Stadol NS where the active ingredient is Butorphanol which can deliver up to 14 or 15 doses per container. Two recent examples to reach the marketplace in Europe are PecFent from Archimedes Pharma and Instanyl from Nycomed, where the active ingredient is Fentanyl (Figure 2). Here the delivery devices can deliver multiple doses and can be self-administered by the patients thus meeting two of the requirements for improved delivery devices to meet these needs, a reduced cost per dose as compared to unidose systems and the possibility for self administration thus reducing healthcare professional supervision costs.

New developments, challenges and future opportunities

An evolving regulatory landscape has brought its own challenges and opportunities with regulatory authorities both in EU3, US4 and further afield5 (e.g. Brazil) increasing their regulatory requirements around nasal aerosols products with the issuance of several guidance documents. Some of these are focused on usability (& avoidance of misuse) and chemistry, manufacturing and control (CMC) activities which require increased understanding of product performance such as dosing, droplet size distribution, spray pattern and plume geometry.

Increasing regulatory requirements mean that devices have been obliged to evolve to meet the more stringent demands put on the CMC aspects of the drug delivery systems. As a result there has been a lot of activity in these areas over the last few years, for example, the development of sophisticated techniques for controlling extractables and leachables from nasal spray devices. Device manufacturers have reacted by improving the quality, robustness and their understanding of key quality attributes that impact aerosol spray performance. This has resulted in a quality by design approach being applied systematically to the development of new generation of nasal spray delivery devices.

More frequent use of potent molecules as well as controlled substances in nasally administered products means that more scrutiny is being placed on issues such as potential overdosing or side effects. As a result more attention will be paid to any potential risk for aerosol particles to pass through the nasal cavity and into the lungs inadvertently. Particles greater than 10µm will be deposited in the nasal cavity, however, particles less than 10µm could potentially be inhaled into the lungs. As a consequence product developers need to monitor and minimise the amount of particles less than 10µm in such products using suitable aerodynamic particle sizing methods.

Other innovations in the device area include the novel Optinose device currently in development for anti-migraine treatments6 amongst others, where the patient delivers the dose using a unit-dose device (containing either a liquid or powder dose) by blowing from the mouth into the nasal cavity.

Another challenge for device manufacturers related to the use of powerful pain management treatments are potential misuse, diversion and overdosing. These issues can largely be negated by using tamper or child resistant packaging solutions and using lock-out mechanisms on the delivery devices and these features can be electronically or mechanically based.

Patient compliance is another challenge during product development and with increased pressure on health care costs more focus is being placed on getting the patients to use the devices correctly according to the correct dosing regime and in the prescribed way. New innovations in devices to tackle the above challenges could either be mechanically based or electronically based and many ideas are emerging in these areas. Dose counters will be another feature of future nasal drug delivery devices in this treatment area as they will assist patients in identifying when their products are about to run out and that they need to renew their prescriptions. Lockout systems will become obligatory where potent molecules or controlled substances are to be used to ensure against overdosing or diversion. The ultimate advantage of using electronic solutions is that they could be integrated in future into a telemedicine approach where the healthcare professionals can monitor virtually how the patients are using the devices and make necessary adjustments for maximum efficacy and efficiency on a patient by patient basis, this approach could also significantly reduce associated healthcare costs.

Summary

Managing pain using nasally administered treatments has many benefits that will surely be exploited in the coming years. Administrating aerosols nasally provides numerous opportunities to introduce innovative drug delivery devices that can meet the increasing pressure on healthcare costs coupled with improved patient compliance and comfort. Nasal drug delivery devices have advanced over the years in line with evolving regulatory requirements and to meet the needs of the current products either already marketed or in development. Many opportunities lie ahead in this aerosol application and the best maybe yet to come with a new generation of electronically or mechanically based devices meeting the needs of the evolving market for pain management.

References:
1. Clinical Therapeutics, 31(12):2954-2987, 12/2009, Veldhorst-Janssen, N.M.L.; Fiddelers, A.A.A.; van der Kuy, P.H.M.; Neef, C.; Marcus, M.A.E., A review of the clinical pharmacokinetics of opioids, benzodiazepines, and antimigraine drugs delivered intranasally
2. Current Drug Delivery, 5(1):55-58, 1/2008, Paech, Michael James; Shelley, Katherine, The Clinical Applications of Intranasal Opioids
3. EMEA-Heath Canada: Joint Guideline on the Pharmaceutical Quality of Inhalation and Nasal Products EMEA/CHMP/QWP/49313/2005
4. Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products Chemistry, Manufacturing and Controls Documentation, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), May 1999
5. Guidance for Pharmaceutical Equivalence and the Bioequivalence of Nasal Sprays and Aerosols, Agência Nacional de Vigilância Sanitária [National Health Surveillance Agency], Brasil, 2008
6. Intranasal sumatriptan powder delivered by a novel breath-actuated bi-directional device for the acute treatment of migraine: A randomised, placebo-controlled study, PG Djupesland, P Docekal, 50th Annual Scientific Meeting of the American Headache Society, Boston, US, June 2008.