The future of inhalation therapy

Dr Gerallt Williams

Pressurised metered-dose inhalers (pMDIs) are devices that deliver a specific amount of medication to the lungs by releasing an aerosol which is inhaled by the patient. Today, pMDIs are the most widely used drug delivery devices used to treat asthma and chronic obstructive pulmonary disease (COPD) with an estimated 600 million units sold every year. Their story began more than fifty years ago, at the time when asthma medication was administered using a glass squeeze bulb nebulizer, which was fragile and unreliable. By March 1956, the first pMDI products were launched: the Medihaler-Iso and the Medihaler-Epi. These devices contained the drugs isoprotenerol and epinephrine respectively and were formulated with alcohol, ascorbic acid and the chlorofluoro carbon (CFC) propellants Freon 12 and Freon 114. Asthma treatment was revolutionised as a result.

Excellence in engineering

The basic design of the pMDI system has changed very little in fifty years. It consists of a container, which holds the active drug formula; the metering valve, which helps to deliver the correct aerosolised dose of drug; the actuator, usually a single entity that includes the mouthpiece, the body of the device and nozzle [See Figure 1]. The entire formulation is made up of the drug, the propellants and often contains surfactant and other excipients. The interaction of the formulation with the other pMDI components defines the final dosage form and characteristics 1.

Figure 1: Schematic of typical pressurised metered-dose inhaler

Although parts of the pMDI system have been significantly improved over the past five decades, a user of pMDIs in 1956 would probably know how to use a modern pMDI. This familiarity is also one possible reason why the average time required for regulatory approvals is less than for dry powder inhalers (DPIs). The operation mode of the pMDI is also well-understood by regulators.

One of the main benefits of using pMDIs, as recognised by patients and healthcare providers, are their convenience and ease of use. A pMDI typically contains 120 to 200 doses (but there are products with between 60 and 300 doses marketed) in a small, pocket-sized portable device, unlike nebulizers and DPIs. The large number of doses available from a device means that pMDIs are a cost-efficient option which can reduce healthcare costs.

The phase-out of CFC propellants

Despite the basic components of the pMDI remaining unchanged, there has been a great deal of innovation in pMDI technology. In the 1970s, it was recognised that traditional CFC propellants were responsible for the depletion of the stratospheric ozone2. As a result, hydrofluoroalkane (HFA) propellants were developed to replace CFC gases. The phase-out of CFC-based pMDIs has occurred at different times for various countries. In the US, most of the CFC products have been transitioned, although a couple of products will remain in the market until end of 2013. In certain developing countries, CFC-based pMDIs continue to be sold to provide low-cost inhalers according to article 5 of the Montreal Protocol, an international agreement that controls the production and consumption of substances causing ozone depletion. The development of HFA pMDIs in the late 1980s, and changing regulatory requirements in the 1990s, led to a significant increase in the number of patents being filed in the pulmonary delivery technology area. Between 1991 and 2000 over 1300 patents were filed, in comparison with 240 from 1981-19903. The market dynamics for pMDIs began to shift, as several leading manufacturers began developing DPIs; the majority, however, continued to research new technologies to improve existing pMDI designs4. The surge in innovation opened up the pulmonary drug delivery market and resulted in a range of new therapies, some for treating systemic diseases, as well as diseases of the lung.

Industry challenges, technical hurdles

The pressure to find solutions to the technical hurdles encountered by pMDI manufacturers during the switch from CFC to HFA propellants drove innovations in pMDI design with a focus on drug formulation and metering valve designs. Surfactants, used to prevent particle aggregation and lubricate the valve mechanism, as well as other excipients, have different solubilities in HFAs. One option was to find a low-volatility co-solvent, such as ethanol.

Traditionally, a two-stage filling process was used to fill pMDIs, whereby the active ingredient, low-boiling liquids and other excipients are filled into the empty canister, valve sealing or crimping takes place and then the high boiling propellant is pressure filled through the metering valve. This filling process works well for CFCs as some have a boiling point lower than room temperature, thus facilitating the first stage of the formulation and filling process at room temperature while other CFCs had higher boiling points and were used for the second stage of the manufacturing process. However, since HFAs do not have such a low boiling point, it was necessary to redesign the filling process. A single stage filling process was therefore developed, where the concentrate is pre-mixed with the HFA under pressure and the whole formulation is then pressure filled through the metering valve, into the canister, following valve sealing or crimping.

The sealing components (elastomers/gaskets) of the metering valve used within the CFC pMDIs were not compatible with the new HFA propellants: different swell characteristics led to propellant leakage and the introduction of moisture into the device, impacting on product performance. Increased valve friction was also caused by the absence of the traditional surfactants which were present within the original CFC products. Following the phase out of CFC propellants, novel metering valve designs were developed, which minimised these effects.

Key innovations

To improve compatibility of the formulation with the valve components, a new generation of elastomer sealing gaskets have been developed. Increased regulatory standards with a strong focus on ‘extractables and leachables’ forced technical improvements to elastomers/ gaskets, in order to reduce the levels of extractables and leachables that could potentially enter into the drug formulations5. New generations of sealing gaskets have been developed to replace the traditional black sealing gaskets, which contained carbon black fillers and therefore potentially high levels of polynuclear aromatics (PNAs). Most of these black gaskets (e.g. Nitrile) have now been replaced with cleaner white gaskets which incorporate alternative fillers. The development of one particular new generation of gaskets i.e. ethylene propylene diene monomer (EPDM), has greatly reduced the extractables and leachables burden [See Figure 2].

Figure 2: The reduction in extractables levels as new elastomer varieties are developed

Generics and changing market dynamics

Until recently, the pulmonary drug delivery market has not been subject to a significant amount of generic product substitution, contrary to other therapeutic areas and dosage forms. This is largely a result of the complex technical, regulatory, and commercial processes required to develop and commercialise a pharma product for inhalation6.

The intellectual property rights on intricate formulation and delivery device design, plus pioneering manufacturing processes, have helped to protect products. However, opportunities do exist for generic players to enter the market as the regulatory standards evolve. For example, in the field of establishing bioequivalence for certain types of drugs, the introduction of the FDA’s Federal Food, Drug, and Cosmetic Act section 505 (b) (2) (which describes the new drug application route for development of inhaled clinically equivalent products) may help to overcome some of the technical and regulatory hurdles involved in establishing therapeutic equivalence for generic drugs7. Within Europe, new guidelines and research on bioavailability and bioequivalence studies for orally inhaled drugs are also in place8. Opportunities to introduce lower cost inhaled medicines to the market will continue to arise as pressure grows to reduce healthcare costs across the US and Europe.

Improving patient compliance

The industry also faces a drive towards improving patient drug adherence, which has driven innovations in the design of pMDIs and new developments appearing on the marketplace. Improving the ease of use and effectiveness of pMDIs has been paramount: coordination of the inhalation and dose actuation can be challenging, particularly for elderly or very young patients. The development of Breath Actuated Inhalers (BAI) devices, have improved inhaler usability and compliance, however the cost and added complexity implications associated with such devices has led to minimal take-up within the market place. The use of ‘Spacer devices’, attachments to pMDI actuators, which can increase the amount of drug reaching the lungs and also eliminate the need for a coordinated actuation and inhalation of the device are also useful to the patient. Nevertheless, the drawbacks are that spacers make pMDI’s larger and less convenient to use. In addition to these mechanical improvements, novel formulations have been developed, which enable a more consistent dose delivery for low-dose suspensions or for the delivery of multiple drugs (e.g. reliever and prophylactic drug combined in one single pMDI).

‘Smart’ devices

Technical progress has resulted in integral dose counters and external ‘add on’ devices that are able to provide patients with dosage information and feedback, such as drug quantities remaining in a device and timing of next dose.

The development of ‘smart’ devices with integrated electronic systems (‘e-devices’) that can feed information back to healthcare providers about patient use of inhalers may help unravel the question of how patient adherence could be improved and lead to improved health outcomes. A good example of this ‘telemonitoring’ approach to drug taking is the Nexus6 ‘Smartinhaler’, a device credited with helping patients to self monitor and adhere to their asthma or COPD medication.

Improving pMDI design: The role of Aptar Pharma

The metering valve is a critical component of the pMDI system. It should accurately and reproducibly deliver a measured volume of propellant based formulation containing the dispersed drug, and also form a propellant-tight seal under high pressure with the canister. Aptar Pharma, a leader in innovative and proven inhalation drug delivery devices for asthma and COPD, has developed metering valves that have been selected by major branded pharma companies and generic producers across the globe. Each year, several hundred million metering valves are produced in Aptar Pharma GMP ISO7 clean rooms. Aptar Pharma is the only metering valve manufacturer that designs, develops and manufactures its own elastomer formulations and rubber gaskets – a key component of the valve – within its unique in-house and dedicated Elastomer Center.

Aptar Pharma’s DF30 metering valve technology platform has been the industry gold standard for more than 20 years. The new optimised DF30Plus model offers several key benefits, including better compatibility across a wider range of drug formulations, including ethanol-containing formulations. The cost-effective solution has an ultra-low extractible level and its robust design enables accurate and consistent performance with an excellent pressure filling capability.

Future directions for pMDIs

Figure 3: The DF30Plus: the new optimised metering valve from Aptar Pharma

If the past success of pMDIs is anything to go on, the future for this mode of drug delivery looks very bright indeed. It is predicted that innovative solutions will continue to be found which will reduce dosing variability and increase dosing and aerosol efficiency. Improvements in formulation, such as the development of new surfactants to improve drug solubility; and technical improvements to device design, to improve ease of use and ensure consistent and reliable drug delivery, will drive innovation in the application of new therapies other than asthma and COPD. An example of pMDIs being used in other therapeutic areas is the recent renewed interest and market launch of several pMDI products to deliver medication via the nasal route in order to treat ailments such as allergic rhinitis, congestion etc.

Recent research and development has also focused on improving patient compliance, once specific area of activity has been the development of mechanical dose counting devices which are now an integral part of the pMDI system. Although such devices are only mandatory for new products destined for sale in the US, the inclusion of dose counting devices can now be found within pMDI products in Europe, Latin America and India.

Aptar Pharma is striving to ensure that pMDI technology reaches its full potential. So, in addition to its work on metered valves, the company has collaborated with key partners in inhalation therapy to produce innovative solutions for pulmonary drug delivery. Local state-of-the-art manufacturing facilities have also been introduced in order to streamline logistics and costs towards local market needs, e.g. manufacturing sites in China & India.

References:

1. Oliveira, R.F., Teixeira, S., Silva, L.F., Teixeira, J.C. and Antunes, H. Study of a Pressurized Metered-dose Inhaler Spray Parameters in Fluent™. Proceedings of the World Congress on Engineering 2010 Vol II.
2. Molina, M.J. and Rowland, F.S. (1974) Stratospheric sink for chlorofluoromethane: chlorine atom catalysed destruction of ozone. Nature: 5460; 810-812.
3. Clark, A.R. (2005) Pulmonary Delivery Technology: Recent Advances and Potential for the new Millennium. In Hickey, A.J. (ed.) Pharmaceutical Inhalation Aerosol Technology. Marcel Dekker, New York, USA: pg 514.
4. Fradley, G. 2006 Fifty Years of the Pressured Metered Dose Inhaler – Building on a Golden Heritage. Future Drug Delivery. Available online at http://www.touchbriefings.com/pdf/1859/3M_tech_proof.pdf
5. Guidance for Industry Bioequivalence Recommendations for Specific Products U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) June 2010.
6. Oliver, MJ (2012) Developing Inhaled Branded Generic Products: A Review of Successful Past Practices. Respiratory Drug Delivery 1: 299-304.
7. US Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) (1999) Guidance for Industry Applications Covered by Section 505(b)(2) Draft Guidance. Center for Drug Evaluation and Research (CDER), Rockville, MD, USA.
8. Dissanayake, S. (2010) Application of the EU Guidelines for Pharmacokinetic Studies of Locally Acting Orally Inhaled Drug Products. Respiratory Drug Delivery 1: 293-304.