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Discovery & Development Drug Delivery

Sparking Innovation in Drug Delivery

According to the US Department of Commerce (1), the US is the largest medical device market in the world and is expected to be valued at over $130 billion by 2016. The same source reports that there are more than 6,500 medical device companies in the US. I am a co-organizer of the Respiratory Drug Delivery (RDD) meetings and it occurred to me that there is much that my field could teach medical device developers in other areas. For example, could some of the latest advances in inhaler technology be applied to the development of autoinjectors or influence the design of new devices? Conversely, could innovations in other medical devices affect the development of platforms to administer inhaled drugs? Ultimately, combining all of our knowledge and learning could be beneficial to both pharmaceutical development and patients.

Our RDD conferences have traditionally addressed contemporary science issues that affect combination products (hardware and drug-containing formulation packaged together), but the science we cover extends far beyond pulmonary and nasal inhalation products; in part, because the conferences showcase innovations that have applications for other pharmaceutical solid, non-aqueous and aqueous liquids, and dispersed systems – for both small and large molecules. The technologies created in the inhalation industry have enabled developments at many companies making injectors, novel parenteral formulations, biopharmaceuticals and specialty orphan products.

Stephen J. Farr described it this way when Aradigm Corporation acquired Intraject in 2003: “Adding the Intraject project to Aradigm’s portfolio extends and leverages Aradigm’s core competencies,” he stated (2). He went on to describe how both AERx (an inhalation platform) and Intraject (later commercialized as DosePro – a needleless injection system) deliver liquid formulations under pressure through specialized nozzles and involve aseptically filled, single-use drug/device combinations to optimize delivery. These commonalties have also been made apparent by Turanin et al., who have spoken at previous RDD meetings to describe the challenges faced by developers of needleless injectors (3), including bubble formation in the drug-containing cartridge, which can cause glass fracturing. Bubbles are also a problem in mechanical nasal spray pumps where they manifest as under-dosing, so clearly there is a shared interest.

As well as looking at the devices themselves, it is also useful to look at technologies, which are radically altering the way inhalers are conceived and developed. Individual inhaler components can now be designed, manufactured and evaluated in ways that were almost unimaginable back at the first RDD meeting in 1988. For example, rapid prototyping has proliferated today to allow intricate mechanical components of various materials to be made in a matter of hours. We’re also seeing more medical devices, such as heart rate and blood pressure monitors, pulse oximeters, sleep, and exercise monitoring tools, being integrated into ubiquitous personal electronics – and this trend is likely to continue and accelerate. In the inhalation area, this trend will present great opportunities to move away from simple ‘apps’ that focus on patient education and disease tracking via manually entered data, to sophisticated devices that automatically coach, monitor, report and analyze data through seamless communication with ever-more powerful mobile technologies.

In this article, I’d like to share some ideas and visions that could potentially expand the scope of inhalation technologies, platforms and concepts. I’ll focus on three areas – pressurized metered dose inhalers, dry powder inhalers and nebulizers.

Although current pMDIs are not sterile products – could they be?
Under pressure to perform

The nearly 60-year-old pressurized metered dose inhaler (pMDI) is still with us, and arguably received a scientific and commercial boost after the phase out of the predominant liquefied gas propellant – chlorofluorocarbons – in the 1990s, before which a focus on copying rather than innovating were the dominant themes in pMDI research. Indeed, new intellectual property ownership surrounding hydrofluoroalkane (HFA)-based formulations spurred innovations to address the problems that emerged – primarily, the lack of drug and surfactant solubility, and the subsequent formation of aggregates and adhesion of drug to canister walls.

One approach to the first problem was to simply omit a surfactant and thereby place more responsibility for metering a homogeneous formulation in the hands of the patient – by requiring that they shake the inhaler immediately prior to actuation. Another approach was to add ethanol to aid drug dispersion or dissolution directly, or to facilitate surfactant solubility. Ethanol was well known to increase droplet size when used at high concentrations so HFA-containing formulations sought to minimize the concentration. Safety concerns and negative patient perceptions (intoxication, throat deposition and irritation) also drove down sprayed volumes. Small-volume metering requirements propelled the need for more precision in metering valve design and manufacture, while toxicological concerns led to the development of “clean” (low extractable and leachable content) elastomeric components with exceptional functionality (4). Drug adhesion to container surfaces was addressed not just as a formulation problem, but as an opportunity to explore new canister materials (notably stainless steel) and interior wall treatments (5). Could some of these anti-adherent advances also be applied to implanted pumps, stents and prosthetics, where tube occlusion and tissue interactions can be problematic?

The spray orifice of the pMDI actuator has received much attention because of its ability to modulate the characteristics of the sprayed formulations. A range of orifice shapes and sizes have been studied (6, 7). The use of small orifice diameters in association with a dissolved drug formulation containing a low ethanol concentration and high propellant driving pressure has allowed lower drug doses, as seen in Teva’s Qvar inhaler. Could advances in nozzle design be applied to other sprayed formulations, such as sublingual, nasal or topical sprays? Could innovative nozzle design be combined with guided placement within the cross section of the nares to potentiate better coverage of the nasal mucosa or allow some degree of targeting to the olfactory region or sinuses? Could computational fluid dynamic modeling support this effort?

Spray pattern testing has also advanced for pMDIs; what once took days with TLC plates, drug visualization and crude photographic image analysis is now possible in seconds with highly automated laser imaging. Could precise spray pattern control and innovative actuator designs, combined with accurate dose metering, facilitate development of a near-invisible spray-on patch with a controlled area for drug absorption?

Our industry (and regulators) have been historically reluctant to utilize new excipients, for obvious reasons, but perhaps the formulation toolbox needs to be expanded by first gaining more experience with excipients sprayed on less sensitive targets. Despite concerns, a number of film-forming polymers have made their way into both experimental and commercialized inhaled formulations, such as AstraZeneca’s Symbicort, which contains povidone K25 USP (8). This could perhaps pave the way for spray-on patches that adhere to mucus membranes in the mouth, nose and elsewhere.

Finally, although current pMDIs are not sterile products – could they be? Could we add a microbiological preservative to a sprayed formulation that was intended for delivery into the eyes or ears? The classical advantage of sprayed products is the ‘no-touch drug delivery’ to hard-to-reach, oddly shaped surfaces – common situations in ocular and aural applications. Because we have developed low-velocity “soft” plumes in respiratory drug development, why not apply them in other routes of administration? Phospholipid sprays applied to closed eyelids for treatment of dry eyes already exist so perhaps pressurized and aqueous sprays could have an expanded role here too. We are all patients and I’m sure we’d all like to take medicines without head tilting or missing our targets...

Pre-Filled Challenges

I’ve noted that pre-filled syringe (PFS) makers are often beset with challenges that inhaler developers and their partners routinely address, including those associated with extractables and leachables in elastomers. MDIs contain metering valves with metal and elastomeric components – and the device industry has developed effective approaches for the quantification of extractables and leachables. These could be beneficial for PFS makers too. Other challenges include:

the need to better predict human in vivo injection times based on in vitro models
the need to understand the impact of protein and formulation parameters on tungsten and silicone oil compatibility
the need to improve the capabilities of analytical methodologies for the characterization of sub-visible and submicron particles in terms of size limitations and particle type discrimination.

Solutions do exist within the inhalation field; for example, there are a range of technologies that can characterize inhaled particle size and determine their chemical nature. Computational fluid dynamic modeling is now a staple at RDD meetings and has a role in the development of needleless injectors (18, 4). We have a lot of experience measuring and reproducing finger forces applied to pMDI and nasal spray pumps that might be transferable to other medical and surgical devices. Furthermore, inhalation scientists are acutely aware of the value of in vitro and in vivo correlations so there is the possibility of shared interest, regulatory overlap and an opportunity for harmonization of registration requirements. Looking in the opposite direction, PFS and autoinjector makers seem to have found ways to incorporate electronics and sophisticated human engineering into their devices, while maintaining commercial viability. In contrast, inhalation devices with onboard electronics and monitoring are rare.

Magic Powder

And what about dry powder inhalers (DPIs)? DPIs can be seen as the most diverse inhalation platform in terms of device design, but their general method of action tends not to deviate from the traditional three-step mode (open, inhale and close) because otherwise they would likely be too confusing for a patient to use. There are other pharma sectors too that could benefit from standardization, such as autoinjectors. Innovation is all very well, but patients have to be able to use medical devices intuitively and easily, if we want to ensure adherence.

I think there are other lessons that certain pharma fields could learn from the humble DPI. Looking at images of the internal workings of GlaxoSmithKline’s Ellipta inhaler (9), I was struck by the elegance with which two strips of powder-containing blisters are stored and opened, and then the way in which the empty cavities neatly recoil within the small device – all achieved just by opening and closing a mouthpiece cover. I contrast this with watching some patients struggle to extract a small tablet from a blister pack… Is it not possible to use this approach to provide a 30-day supply of one or two tablets for patients needing extra convenience? It could also create opportunities for containers that are not only convenient, but also more secure (child resistant) and able to protect their contents from the environment as effectively as individual blister packing without the use of so much plastic and foil laminate. Inhaler manufacturers have, after all, developed expertise in keeping water out of formulations through the creative use of sealing technologies (on valves and blisters) and use of desiccants.

Inhalation expertise in the mechanical handling of plastic strips could be very useful when it comes to transdermal strips (it’s often a battle to prevent the patch from adhering to the floor). What about developing something akin to the use of a sticky tape dispenser, which neatly strips away a backing layer as the patch is securely adhered to the skin?

Respiratory drug development experts also have a lot to offer in terms of knowledge regarding particle size, shape, surface morphology and charge – all of these factors play a key role in determining the efficiency with which a drug leaves an inhaler and deposits following inhalation, so there is an in-depth understanding of how to engineer micron-sized particles with specific and reproducible properties. What other fields could utilize this expertise? Could there be value in using this knowledge base to develop faster dissolving sublingual films and tablets or easier/faster to reconstitute powders in vials for injection?

But DPIs also have much to learn from other pharma sectors and there are a number of areas where I think we could perhaps see device improvements. To ensure effective DPI drug delivery, inhalation profiles are necessary – and this issue has been extensively researched and reported (10). Trainers are also often used to coach patients in achieving desired flow rates. So why then is it necessary to ask some patients to carry a separate peak flow meter to monitor their disease? Aradigm pioneered this concept with its SmartMist product using an electrically operated device. But could training and monitoring be built into DPIs using only mechanical means with a reasonable expectation of better therapeutic outcomes at moderate cost?

We also seem to be solidly in unit dose mode for most locally acting inhaled pharmaceuticals – the prescriber typically has a choice of one or two puffs unless the patient is willing to use a nebulizer and take responsibility for inhaling a partial dose. The packaging insert for Afrezza (insulin human, MannKind) Inhalation Powder makes it clear that fractional dosing is at best crudely practiced (11), but sorely needed if systemically acting biologicals are to have a future via the inhalation route.

Finally, I think that given the increasingly complex nature of DPIs using blister metering of doses, it seems wasteful that they remain single-use devices. Have environmental, economic and regulatory realities altered enough that refillable devices could reasonably be envisioned? Are there sectors that have moved in this direction that we can learn from?

Respiratory drug development experts also have a lot to offer in terms of knowledge regarding particle size, shape, surface morphology and charge.
Specialized but standardized?

Modern mesh nebulizers are small and efficient, but patient convenience is limited by the use of form–fill–seal ampoules that must be opened and emptied by patients into the reservoir. Other segments of the pharma field have standardized on fittings; for example, the Luer taper is standard for syringes, while more specialized injectors such as Merck Serono’s EasyPod autoinjector are designed to deliver a narrower range of medications (12). If we took a similar approach to the Luer Lock on form–fill–seal ampoules, we could fill any nebulizer. That said, newer nebulizers might benefit from filling with less effort or room for error by patients – and it might be possible to make the connection between the nebulizer and the solution for inhalation aseptically, so that unused formulations could be used in subsequent dosing periods.

Staccato (Alexza) seems able to deliver sufficient heat to generate a thermal aerosol from a drug-coated metal foil. We could perhaps explore using analogous technology to heat sterilize the mesh and other potentially contaminable areas of a multiuse ampoule in an ultrasonic nebulizer after each use. This could be made even more realistic if the antimicrobial properties of silver (which are the basis of some preservative-free multiple dose nasal sprays) are combined with heating (13).

There are other areas too where nebulizers could benefit from some standardization. Pressurized inhalers have enjoyed a consistent ‘look’ for a long time with common operating principles and component vendors standardizing parameters such as canister neck diameters. This has the benefit of making it relatively easy to switch a patient from one product to another. DPI manufacturers seem to be converging on the open–inhale–close approach to simplify patient training. Is it possible to also begin moving nebulizers in this direction to make them as mainstream as the other inhalation platforms?

Boehringer Ingelheim’s Respimat utilizes energy stored in a spring under tension to drive an aqueous solution into a nozzle assembly for spray generation. Could this concept be adapted to drive a drug through microneedles being developed for patch systems to yield a needleless injector, or could the high driving pressure attainable by the spring allow use of finer conventional needles than is possible when finger forces alone are used to drive a conventional plunger into the barrel of syringe? Sonophoresis had been combined with microneedle technology to enhance transdermal delivery of large biomolecules (14), so could a nebulizer mesh be modified to become a microneedle-based autoinjector?

Some developments are inevitable, such as the development of smart inhalers.
Vice versa

Numerous pulmonary and nasal products have been introduced into the world’s markets in recent years, and here I’ve speculated on how learning from these products could inform development of other medical devices and drug products. Of course, learning goes both ways, so why not look at how innovation in other fields might alter the inhalation device landscape? Some developments are inevitable, such as the development of smart inhalers (see Smarter Inhalers), but others discussed in this article may seem a little unrealistic... at first. Nevertheless, I feel it’s important to push the boundaries of innovation and to explore how innovations from one pharma field can be applied to another.

There are numerous reasons that might spur an organization to look beyond the confines of its own niche for inspiration, including the development of new products with enhanced safety, efficacy or convenience features – and the potential to lower the cost  of manufacture of existing products. Electronics and connectivity are likely to play an increasingly important role. Throughout the 25-year history of RDD meetings, reported developments in inhalation products have always reflected the work of a complex amalgam of scientists, clinicians, engineers and entrepreneurs. In the next quarter century of RDD conferences, it looks like we will also need to hear from authorities on human factors engineering, software and electronics experts, and smartphone application specialists. Perhaps it will even make a nice change from my ramblings! I am certainly looking forward to such an exciting future.

Smarter Inhalers

Electronic monitoring is widely considered to be among the best tools for medication adherence measurement because it provides the ability to record the date and time of medication use. Unfortunately, it is not without additional costs and challenges (15). While electronic monitors have been developed for portable inhalers, including the Doser (Meditrack), SmartTrack and SmartDisk (Nexus6), these technologies have yet to be incorporated (or co-packaged) into a marketed, drug-containing inhaler product, which is probably an essential step to increase their availability and realize their benefits. In contrast, several drug cartridge-containing electronic autoinjectors have been commercialized, including the Easypod platform, which provides visual signals and on-screen feedback, combined with audio cues to guide the patient through the injection process and to provide reassurance that the correct dose has been delivered successfully. To inject a dose, a patient follows a simple three-step process (an increasingly familiar concept for DPI developers).

First, a needle cap containing the needle is inserted into the device; once the needle has been automatically withdrawn into the device, the empty needle cap is removed. When the device is correctly positioned on the skin, as confirmed by a skin sensor, patients can trigger the automated injection by one press of the injection button. Finally the empty needle cap is reinserted into the device to collect the needle for safe disposal. The device features a number of adjustable injection settings that allow patients to control the speed and depth of needle insertion, injection speed and injection time. In addition, the device records an accurate and objective dosing history, including the date, time and dosage of every injection, and the comfort setting used. Innovations such as these make the reed-generated, audible warnings associated with excessively inhaled use of some inhalers seem pretty crude

Human factors engineering is instrumental in identifying and subsequently reducing or eliminating errors during the use of medical devices (16) – and played a significant role in the design and development of Sanofi’s Auvi-Q autoinjector. Auvi-Q is a single-use epinephrine autoinjector that talks a patient or caregiver through the delivery of 0.3 mg (0.3 mL) or 0.15 mg (0.15 mL) of epinephrine during allergic emergencies. Is such technology only warranted on rescue inhalers that are used infrequently? For controller (prophylactic) medications is it acceptable or prudent to design inhalers that communicate through Bluetooth to a smartphone which then does the talking as soon as the mouthpiece is opened? Would innovations such as this expand the range of inhaled drugs in commercial products to naloxone for the treatment of opioid overdose or infrequently dosed biopharmaceuticals that are currently injected?

It certainly seems feasible when you consider that a toothbrush can now deliver real-time feedback on brushing intensity, duration and technique improvements over time. Apple’s Research Kit open-source software seems aimed at encouraging companies to move in this direction, and Mount Sinai/LifeMap Solutions have already launched an Asthma Health app that is designed to “facilitate asthma patient education and self-monitoring, promote positive behavioral changes, and reinforce adherence to treatment plans according to current asthma guidelines” (17).

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  1. Select USA, “The medical device industry in the United States.”
  2. Bloomberg Business News, “Aradigm Acquires Intraject Needle-Free Technology From Weston,” (May, 2003).
  3. J. Turanin, B. Boyd, and SJ. Farr, “Overcoming critical challenges for needle-free parenterals,” in
  4. G. Brouet et al., “Developing new container closure options: A suppliers perspective,” in Respiratory Drug Delivery 2006. Volume 1, edited by R.N. Dalby et al., (DHI Publishing, 2006).
  5. C. Baron et al., “Evaluation of powder adhesion and stability of pMDIs with different canister types including plasma treated canisters,” in Respiratory Drug Delivery 2014. Volume 2, edited by R.N. Dalby et al., (DHI Publishing, 2014).
  6. J. Fachinger et al., “Nozzle design characterization of metered dose inhalers (MDI) using quality by design (QbD) tools,” in Respiratory Drug Delivery Europe 2009. Volume 1, edited by R.N. Dalby et al., (DHI Publishing, 2009).
  7. D.A Lewis, B.J. Meakin and G. Brambilla, “New actuators versus old: reasons and results for actuator modifications for HFA solution MDIs,” in Respiratory Drug Delivery 2006. Volume 1, edited by R.N. Dalby et al., (DHI Publishing, 2006).
  8. AstraZeneca, “Symbicort Prescribing Information.”
  9. A. Dundon et al., “Device design development and quality by design,” in Respiratory Drug Delivery 2014. Volume 1, edited by R.N. Dalby et al., (DHI Publishing, 2014).
  10. P.R. Byron et al., “Breath profiles for testing new DPI devices in development,” in Respiratory Drug Delivery 2014. Volume 1, edited by R.N. Dalby et al., (DHI Publishing, 2014).
  11. Sanofi, “Afrezza Prescribing information.”
  12. EMD Serono, “Rebif Prescribing Information.”
  13. N. Klöcker et al., “Antimicrobial safety of a preservative-free nasal multiple-dose drug administration system,” European Journal of Pharmaceutics and Biopharmaceutics 57(3), 489-93 (2004).
  14. T. Han, and D.B. Das, “Permeability enhancement for transdermal delivery of large molecule using low-frequency sonophoresis combined with microneedles,” Journal of Pharmaceutical Sciences 102(10), 3614-22 (2013).
  15. H.L. Figge, “Electronic tools to measure and enhance medication adherence,” US Pharm. 2011, 36(4), 6-10 (2011).
  16. J. Dixon, D. Aston-James and B.D. Cox, “Identifying and satisfying new human factors requirements through good study design,” in Respiratory Drug Delivery Europe 2013. Volume 1, edited by R.N. Dalby et al., (DHI Publishing, 2013).
  17. Biotimenic, “Icahn School of Medicine at Mount Sinai and LifeMap Solutions Launch Asthma Study for iPhone,” (March, 2015).
  18. Z. Tong et al., “Unraveling the mechanics of deagglomeration through experiments based upon complex modelling theory,” in Respiratory Drug Delivery 2012. Volume 1, edited by R.N. Dalby et al., (DHI Publishing, 2012).
About the Author
Richard N. Dalby

PhD is Professor and Associate Dean for Academic Affairs at the University of Maryland School of Pharmacy, USA.

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