Let’s makeinhalers better

Let’s makeinhalers better

OCCORIS®

The contextThe global pulmonary drug delivery market continues to grow at a rapid pace1. Beyond the traditional market sectors of asthma and COPD, research is underway to develop therapeutic drugs for systemic delivery via the pulmonary route for applications including pain relief, migraine relief, insulin delivery and vaccinations2. Dry powder inhalers (DPIs) are seen as promising delivery solutions for many of these therapies, as shown in the array of applications in which they are employed.

Existing DPIs can be broadly classified as either ‘passive’ or ‘active’ devices depending on the energy source used for drug entrainment and dispersion3. Currently marketed DPIs are all passive devices and rely solely on the patient’s inspiratory effort to disperse and deliver drug to the lungs. Active devices use mechanisms other than the patient’s inhalation to disperse the formulation such as pneumatic, mechanical or piezoelectric mechanisms. These devices offer improved performance but are often more expensive to produce, and there are currently no active device products on the market. Until now there has not been a device that offers the performance of active delivery together with the low cost and simplicity of passive delivery.

A new way forwardOccoris® creates a new class of active DPI: high performance yet low cost. It enables the systemic delivery of drugs to the deep lung and, as a platform technology, can be integrated into a range of inhaler configurations. As a result, Occoris® opens up new therapy markets previously unattainable for DPIs.

This report includes preliminary performance data and highlights some of the potential applications that the Occoris® inhaler engine could address.

This is a significant developmentOccoris® is an active, API (Active Pharmaceutical Ingredient) only, ultra-low cost, high-performance dry powder aerosolisation engine. It consistently achieves a Fine Particle Fraction in excess of 70%, and can be integrated into a breath-actuated inhaler costing no more than 20 US cents.

The Occoris® inhaler engine concept was introduced at Respiratory Drug Delivery 2012. Since then, we’ve continued to develop the technology as we had some exciting ideas for its potential use. In May 2013 we were awarded a feasibility grant from the UK’s Technology Strategy Board to engineer a proof-of-principle device and to further understand the science behind the concept.

03EXECUTIVE SUMMARY

Pulmonary drug delivery continues to grow

The global pulmonary drug delivery market is mature, large, and growing – it reached $22.5 billion in 2011, and it is expected to reach $44.4 billion in 20161. Much of this growth is attributed to the rise in asthma and COPD worldwide, especially in the BRICS countries, and it is these diseases that are typically managed through the use of inhaled pharmaceuticals. However, there is another projected area of growth within this market as research is underway to develop therapeutic drugs for delivery via the pulmonary route for other applications, such as pain relief, migraine relief, insulin delivery and vaccinations2. With the right delivery technology, there is a wealth of opportunity to deliver novel therapies via the inhaled route.

$44.4 bi l l ion

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$22.5 bi l l ion

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THE GLOBAL PULMONARY DRUG DELIVERY MARKET

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Pulmonary drug delivery offers significant and unique benefits

Local or systemic delivery to lungsInhalers have been used for many years to deliver drugs to the lungs to treat airway diseases such as asthma, COPD and more recently cystic fibrosis. Inhalation allows direct delivery of microgram drug quantities to the site of action with fewer systemic side effects than oral therapy3. The lungs may also be used as a portal of entry to the body, enabling delivery of drug via the airways into the bloodstream. Increasingly, companies are developing inhaled formulations for systemic delivery, taking advantage of the optimal permeability to macromolecules provided by the lungs.

Rapid onset of actionThe large surface area of the lung, combined with the extensive blood flow and extremely thin alveolar-capillary membrane, means that small molecules in particular are absorbed within seconds, making inhaled delivery particularly suitable for conditions in which the patient would benefit from a rapid response.

Non-invasive self-administrationInhalers offer patients a non-invasive method of delivering drug directly to the site of action, reducing systemic side effects, and enabling lower doses than might otherwise be required.

Improved bioavailability over orally delivered drugsThe liver and gut wall metabolise many drugs when delivered orally and therefore greatly reduce their concentration and bioavailability (the first-pass effect). For such drugs, inhalation offers a non-invasive route almost directly into the bloodstream. Some of the most exciting therapies include peptides and smaller proteins, where bioavailability is 10 to 200 times greater by the pulmonary route compared to other non-invasive routes4, and which must otherwise be injected.

DPIs offer unique benefits over other types of inhaler

The inherent and potential benefits of dry powder inhalation has resulted in this delivery route being investigated for a wide range of therapies far beyond asthma and COPD, including inhaled insulin, oxytocin, antibiotics, vaccines, opioids, and drugs for neurological disorders.

No coordination requirementsDPIs avoid the well-known misuse issues associated with pMDIs, namely the significant hand breath coordination and timing required to depress the canister whilst inhaling, which results in a high proportion of users not receiving the correct dose5. Typically, extensive training is required for patients to master this.

Propellant freeUnlike pMDIs, DPIs do not require propellant to be mixed with the drug.

PayloadDPIs can deliver high doses, whereas 1 mg is the maximum dose for pMDIs.

Stability of the formulationFormulating the drug as a dry powder offers inherent stability.

Generally low cost due to simplicityThe simplicity of passive DPIs enables relatively low cost production, especially when compared to electro-mechanical, technically complex nebulisers.

05THE MARKET

1Low cost with limited performanceAll DPIs currently on the market are passive devices, and are well suited to the treatment of asthma and COPD. However, systemic delivery requires high dose consistency, which is difficult to achieve with the passive approach, largely due to its dependency on the patient’s inspiratory effort. New technology could overcome both this and a range of other fundamental limitations:

Limited pressure differential results in only 20-40% efficiencyIn the majority of commercially available devices, the micronized drug (API) particles are generally blended with larger carrier particles such as lactose. The DPI must detach the pure drug from the carrier during inhalation. In the majority of cases this is achieved by impacting the carrier particles, typically on an internal wall of the device, and the energy for these impacts is provided by the inspiratory effort of the patient. The energy available is therefore limited by the negative pressure that the patient is able to generate. Even if they could generate a perfect vacuum, the 1 atmosphere of pressure differential still may not be sufficient to fully detach and aerosolise all of the API. Due to this inefficiency, typically only 20-40% of the pure drug detaches from the carrier and is delivered to the lung. The majority of the pure drug delivered from these devices (up to 80%) remains attached to the larger carrier particles and impacts in the mouth and throat, which is not only a waste of drug but can lead to unpleasant side effects.

Limited deep lung performanceFor systemic delivery, particle sizes of around 1-3µm are required in order to reach the deep lung. The deagglomeration approaches of existing passive inhalers, however, are not efficient enough to break all the agglomerates down into primary particles, and so the majority of the drug does not reach the deep lung.

Existing DPI technologies are limited by the underlying physics

PassiveWhere power is provided by the user’s inhalation, and the drug is usually blended with a carrier particle fraction. Passive devices tend to be simple and cheap to produce but offer limited performance.

ActiveWhere power is provided by another means, such as a battery or from compressed air, and which are generally more suitable for the delivery of pure API. Active delivery can provide consistently high delivery efficiency, but the devices are complex in their design and expensive to manufacture, and as a result are costly for both companies and patients.

The DPI market is therefore split accordingly

Existing DPIs fit into one of two types

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Inconsistent delivered doseBecause the deagglomeration and aerosolisation of the powder is powered by the inspiratory effort of the patient, the Fine Particle Fraction (FPF; the quantity of fine, respirable particles delivered to the lung) may vary depending on their inspiratory characteristics6, resulting in an inconsistent dose between patients, and even between uses by the same patient.

API is typically blended with a carrierTo improve the metering and handling of low doses, a carrier fraction comprising larger particles is commonly used to dilute the API. For higher doses, a carrier is still beneficial as it is challenging to aerosolise cohesive API particles using only the power from the patient’s inhalation. For pharmaceutical companies the formulation and process development can be expensive and time consuming as the particles have to be made smaller than necessary to account for incomplete deagglomeration by the device engine. Additionally, the drug-carrier mix must be engineered to be homogenous and have a suitable balance of adhesive and cohesive forces to ensure the stability of the carrier API mix.

Cannot use a spacerSpacer devices are often recommended for use with pMDIs, providing a chamber into which the aerosol is fired; the drug becomes suspended in the air within the chamber, and then the aerosol is inhaled from the chamber. Spacers prevent the jet of drug / propellant mixture hitting the back of the throat (especially helpful with steroids), and when combined with a facemask can be used with very small children. However, as passive DPIs are breath powered, a spacer becomes impractical, and so its primary benefits cannot be realised and the DPI cannot be used with very small children.

2High performance but expensiveInhalers in this category do not necessarily require a carrier fraction and can deliver pure API. This avoids the time and expense associated with developing a stable, homogenous formulation and optimising the drug-carrier detachment forces for a particular DPI device.

By using an alternative power source to the lungs, deagglomeration and aerosolisation performance can be increased whilst dose-to-dose variability is reduced, and therefore these systems have been shown to produce aerosols that are largely independent of the way in which the user inhales.

However, the known active systems are complex, often electro-mechanical, and as such are expensive and unsuitable for disposable use. Active DPI technologies have been in development for almost twenty years, but to date there is no active DPI product on the market.

The DPI market is therefore split accordingly

THE MARKET

High performance at an ultra-low cost

As Occoris® is a platform technology it can be used across a variety of device designs depending upon the dosing regimen. Notably, the high performance of the Occoris® technology, combined with the very low device cost, means that drugs of higher payloads requiring systemic delivery to the deep lung can be self-administered by untrained users in a highly efficient, breath-actuated, single-use disposable device. Never before has an active delivery device been feasible at such low cost that single-use is economically viable.

In 2013 we ran a technical feasibility project, funded by the UK’s Technology Strategy Board, in which we aerosolised and delivered pure API. Additionally, we developed a concept for a single-use, breath-actuated disposable device that uses the Occoris® engine.

Occoris® is an active, API only, ultra-low cost dry powder aerosolisation engine. The simple, non electro-mechanically powered technology is small enough to enable its use in a multi-unit dose device, thereby delivering all the benefits of active delivery at the same cost as the most inexpensive of passive devices.

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“This is an innovative and exciting technology

with great potential. It could enable pulmonary delivery of drugs in many

different areas, for example in therapies requiring higher

payloads such as inhaled antibiotics and systemic

drug delivery.”

09WHAT IS OCCORIS®?

Professor Peter J Barnes FRS, FMedSciMargaret Turner-Warwick Professor of Medicine

Head of Respiratory Medicine, Imperial College London

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Figure 1

Figure 1 Delivery performance of the Occoris® inhaler engine, showing high Fine Particle Fraction (percentage mass <5 µm of the emitted dose) and low mouth/throat deposition. Occoris® data shown is of delivery of 1.5 mg unformulated micronized salbutamol sulphate, with performance measured using a Next Generation Impactor at 90 LPM. (Cyclohaler® data source8,9)

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Figure 2

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Figure 2 Deagglomeration performance of the Occoris® engine, showing that Occoris® deagglomerates salbutamol sulphate on par with a Sympatec RODOS system

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Fine Particle Fraction Fine Particle Fraction (FPF) is the percentage mass <5 µm of the delivered dose and represents drug particles that are sufficiently small to travel deep into the lung and to provide therapy. Figure 1 shows the delivery performance of the Occoris® aerosolisation engine and demonstrates the percentage of FPF exceeding 70%. Typical dry powder inhalers achieve a FPF of 20-40%.

Breaks particles down to primariesThe particle size distribution of the salbutamol was analysed using the industry standard Sympatec RODOS dry dispersing unit and HELOS laser diffractometer. Occoris® was shown to deagglomerate the powder on par with the Sympatec system, as can be seen in Figure 2.

Throat retention dataIn current DPIs, a significant issue is the amount of drug that, having exited the device, is deposited in the mouth and throat, typically 40-70%10. The Occoris® test rig achieves typical mouth and throat deposition of approximately 20% (as shown in Figure 1), with the lowest recorded being 14%. The low throat and mouth deposition achieved by Occoris® is primarily because it does not use lactose carrier particles, the majority of which impact on the mouth and throat whilst still holding API.

Benefits of active deliveryAs highlighted in the earlier section, being an API only, active DPI technology, Occoris® brings with it the benefits of:

— no lactose-blend formulation time and expense— high aerosolisation efficiency and FPF— good delivery to the deep lung— user-independent, consistent aerosolisation— high dose-to-dose consistency

How Occoris® works The core of the Occoris® engine is simple and small. Accurate and reproducible delivery of the API is achieved using a straightforward mechanism that releases the powder from a sealed container containing a defined unit dose in a single, coordinated action. Upon the release of the powder, the internal energy source accelerates and separates the pure API particles generating a fully deagglomerated aerosol in a way that is not possible with passive devices. Actuation of the Occoris® engine is performed by a unique, low-cost breath-actuation mechanism (BAM). The feasibility study determined that the BAM can be triggered at a pressure drop of 1.4 kPa at low flowrates, although this mechanism can be easily tuned to suit a particular patient’s needs.

The Occoris® engine ensures that each dose is identical and is delivered completely independently of the inspiratory characteristics of the user. The result is an API-only platform DPI engine producing very high FPF with low throat deposition. All the benefits of an active device at the cost of a passive device.

Team Consulting has patents pending on the construction and manufacture of the Occoris® engine technology.

How much does Occoris® cost?In the technology feasibility study a concept for a breath-actuated, single-use disposable device utilising the Occoris® engine and containing fewer than five injection-moulded components was developed. Using comprehensive cost-models, it was estimated that such an inhaler could be produced for under 20 US cents per device (not including drug), based on 50 million units per year, with the potential for further reduction to 15 US cents per device. At lower volumes, the estimated production cost was 25 US cents per device, based on 10 million devices per year. Due to the low part count, capital expenditure can be kept to a minimum.

These figures are dependent on economies of scale but demonstrate the potential of the device as a low cost, high performance inhaler.

PERFORMANCE DATA

How Occoris® performsThe pharmaceutical performance of the Occoris® technology using unformulated micronised salbutamol sulphate as a model powder was determined in Team Consulting’s Respiratory Physics Laboratory, using a Next Generation Impactor (NGI, without pre separator) and in accordance with USP 29 <601>7.

Single dose — disposable

A single-use device, breath-actuated, designed to be used by an untrained user and thrown away after a single dose. Potential markets and applications include developing nations, drugs for pandemic response, delivery of antibiotics, vaccinations and antidotes, and migraine relief.

Occoris® as a platformOccoris® is a DPI engine. As such, it can be incorporated into a number of device designs aimed at different dosing regimens, user groups and therapies. Three such devices are:

1 2 3Multi-unit dose

The small space envelope of the Occoris® technology means that it could be incorporated into a small multi-unit dose device.

Single dose — reusable

Potential applications include non-routine therapies such as migraine relief, insulin delivery and break-through pain relief.

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THE APPLICATIONS 13

Oxytocin deliveryOxytocin is routinely prescribed in the treatment of post-partum haemorrhage; it is delivered by needle and syringe and hence requires access to trained medical staff. In developing nations, especially in remote villages, there is often no access to medical staff and sadly many women die during childbirth due to lack of oxytocin.

Dry-powder oxytocin intended for inhaled delivery is currently being developed. A breath-actuated, single-use, disposable device would enable the self-administration of oxytocin without a needle and syringe, and would be ideal for contexts where a lack of trained medical staff can prevent access to this life-saving drug.

Pandemic response / vaccinationsDuring a pandemic, rapid drug formulation and distribution is vital. Occoris® could enable the mass distribution of essential vaccines directly to patients who could then self-administer the correct dose without the compliance issues or risks associated with a needle and syringe. This could significantly reduce the workload for healthcare professionals and allow them to focus on those who cannot self-administer. As Occoris® uses pure API, there is no need for the drug to go through the time consuming and expensive carrier / drug formulation process.

Yearly flu vaccines could follow a similar model; with no need for the patient to receive an injection; instead they could receive a single-use inhaler from a pharmacist and self-administer a precise dose.

Pain reliefOral analgesics taken for the relief of headaches or migraines typically take half an hour or so to provide therapeutic effect; systemic delivery of specially formulated analgesics via the pulmonary route could provide relief within seconds. However, the limitations of current DPI technology, together with its relatively high cost, mean that this isn’t currently an option. Occoris® opens up a potential new market segment for inhalable over the counter analgesics.

Clinical trialsNCEs (New Chemical Entities) intended for delivery using DPIs would typically have to be blended with lactose before being tested in vivo (following successful in vitro trials). This requires significant formulation development time (and expense) to ensure that the ratio of the blend is correct, that the blend is homogeneous, and that the resulting particle size is in the correct respirable range following aerosolisation.

As Occoris® is capable of aerosolising and delivering pure drug powder, it could enable NCEs to be tested without the need to go through the process of lactose blending and particle size engineering, thus saving development time and cost, also removing the variable of formulation device performance from drug performance results.

And beyond...The Occoris® technology could be used to deliver drugs for a wide variety of additional therapies. The systemic delivery of antibiotics and higher payload drugs is one particularly interesting area which could be explored, as well as the use of Occoris® in the delivery of analgesics, opioids for break-through pain relief, antidotes, and drugs for bio-defence.

Occoris® enables new therapy areas for DPIs

What next?Respiratory drug delivery has the potential to not only improve the treatment of asthma and COPD but many other conditions. Until now, inhaler technology has been a limiting factor in new market growth, but Occoris® has the potential to challenge this by providing market-leading performance at low cost for a wide range of conditions that require rapid onset, ease of use and safety. There is further work to be done, but as can be seen from the initial data, it is an encouraging platform on which to build.

We’ve touched on a number of potential applications in this short document and we are now looking to engage with industry and academia to explore ways in which the platform could be used with new or existing APIs.

We are actively looking for partners to continue the development of the Occoris® inhaler engine and all enquiries should be directed to:

David Harris Head of Respiratory Drug Delivery

+44 1799 532767

david.harris@team-consulting.com

Philip Canner Senior Consultant

+44 1799 532761

philip.canner@team-consulting.com

References1 Pulmonary drug delivery systems: technologies and global markets. BCC Research (2012) 2 Hickey, A.J. Back to the future: inhaled drug products. J. Pharm. Sci. 1024, 1165-72 (2013) 3 Newman, S.P. Respiratory drug delivery: essential theory and practice. RDD Online / Virginia Commonwealth University, Richmond (2009)

4 Patton, J.S. Mechanisms of macromolecular absorption by the lungs. Adv. Drug Deliv. Rev.19, 3–36 (1996)

5 Dolovich, M.B., Ahrens, R.C., Hess, D.R., Anderson, P., Dhand, R., Rau, J.L., Smaldone, G.C., Guyatt, G. Device selection and outcomes of aerosol therapy: evidence- based guidelines, Chest 127, 335-371 (2005)

6 Clark, A.R. Medical aerosol inhalers: past, present and future. Aerosol Sci. Technology 22, 374-391 (1995)

7 Aerosols, nasal sprays, metered dose inhalers and dry powder inhalers, United States Pharmacopeia 2012, Chapter <601>. Rockville: US Pharmacopeial Convention (2012)

8 Hoe, S., Young, P.M., Traini, D. Dynamic electrostatic charge of lactose-salbutamol sulphate powder blends dispersed from a Cyclohaler®. Drug Development and Industrial Pharmacy 37 (11), 1365-1375 (2011)

9 Adams, W. P., et al. Effects of Device and Formulation on In Vitro Performance of Dry Powder Inhalers. The AAPS Journal, Vol. 14, No. 3 (2012)

10 Son, Y.J., Longest, P.W., Tian, G., Hindle, M. Evaluation and modification of commercial dry powder inhalers for the aerosolization of a submicrometer excipient enhanced growth (EEG) formulation. European Journal of Pharmaceutical Sciences 49(3), 390-99 (2013)

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