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Choose Wisely

The shape of the pharmaceutical market is being moulded by a range of factors worldwide, including pressure on healthcare costs, the increasing ageing population, the shift of growth to economies in the BRIC countries (Brazil, Russia, India and China), environmental concerns and the ongoing patent cliff facing many blockbuster drugs.

Like most drug delivery formats, pressurised metered dose inhalers (pMDIs) face all of the above challenges. However, they also have several advantages in their favour, which include their robust and well-known technology – trusted by patients and training nurses – a long history in the marketplace and their attractive cost-per-dose ratios. This article will look at a range of solutions that can add value to existing drugs for innovators, as well as opportunities for market entrants, and also address the needs of emerging countries.

Investment in pMDIs

The pMDI is a complex system designed to provide a fine mist of medication for inhalation directly to the airways (see Figure 1). As the most important device for the regional and systemic delivery of drugs to and through the lungs in the past 50 years (1), the pMDI has revolutionised the treatment of respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD). The global market for inhalation products was valued at $26 billion in 2011, with the quantity of pMDIs in use estimated to be three times more than those products using the alternative dry powder inhaler (DPI) technology platform (2). Growth is set to continue in the near future, due to rising numbers of asthma sufferers (currently 300 million worldwide) and COPD patients (3).

As emerging economies increase their investment in healthcare, there will be new opportunities in the pharmaceutical market for the manufacturers of metered dose inhalers. As a result, by 2017, the value of the pMDI market is forecast to grow to $13 billion, mostly driven by COPD increase (2).

According to some experts, the choice of device, in addition to the choice of drug, is set to become a driving force behind pulmonary disease management. Improving inhaler device design can provide companies with a number of opportunities to gain market shares through product differentiation, without involving the usual time and financial investment to develop new drug formulations. For example, improved device designs may allow for a better deposition of the drug in the lungs, which could be achieved through changes to the aerosol characteristics and easier inhalation techniques.

Adding Value to Existing Drugs

Since better drug delivery is a key area for the improvement of pMDI devices, recent technological advances have now made it possible to design pMDI devices that have specific aerosol properties, particularly in terms of fine particle dose and spray velocity. Compact and convenient breath-actuated, breath-coordinated and velocity-modifying devices have also been devised to help patients to achieve a reliable lung dose. In fact, many studies comparing pMDIs with other types of inhaler systems have found that it is just as effective, or more effective, in terms of generating fine particles and ensuring accurate drug delivery (4,5).

Breath actuation devices fitted to pMDIs can be easier to use for certain types of patient – such as children and the elderly – compared to other drug delivery methods, including some DPIs, since successful use is less dependent on the inspiration rate (the continued force of breathing in). This characteristic is of benefit in developed and emerging countries with their burgeoning ageing population.

DPIs can also be highly variable in design, as the number and complexity of available devices is growing. This requires a specific set of skills to be taught to each patient, which can be time-consuming for healthcare professionals. For pMDIs, however, the same handling and inhalation technique applies to all devices. But coordination still remains an issue with pMDIs, whereas this constraint does not affect DPIs as much.

The attractive cost-per-dose ratios, compared to other drug delivery systems, have also ensured that the pMDI option is currently the method of choice for the treatment of asthma and COPD; this trend is set to continue in areas of the market where there is an increased pressure on healthcare costs.

Aerosol Propellants and Environmental Concerns

Chlorofluorocarbons (CFCs) were initially used as propellants in pMDI devices. However, following the Montreal Protocol, which called for a gradual reduction in their use due to their deleterious effects on the ozone layer, hydrofluoroalkanes (HFA) have been used as the gas propellant of choice (6). To date, all CFC pMDIs on the market in Western Europe have been replaced with HFA pMDIs. In the US, this is projected to occur by the end of 2013, whereas emerging countries such as China and Russia have yet to replace all of their CFC pMDIs with HFA equivalents.

Nevertheless, pMDI devices that use HFAs also have what is known as a global warming potential, since they still release small amounts of greenhouse gases into the environment. In fact, hydrofluoocarbons (HFCs) are the fastest-growing greenhouse gases in the US, China, India and the European Union (EU). If their levels are left unchecked, it has been predicted that emissions of HFCs could grow to nearly 20 per cent of CO2 levels by 2050. Although CO2 is not the highest contributing greenhouse gas when compared to methane (CH4) and nitrous oxides (NOx), the levels would be high enough to still be a serious concern for global warming (7).

Recently, however, China and the US signed an agreement to phase down the consumption and production of HFC gases by 2030. Since only a fraction of HFAs are used in the medicinal aerosol market (less than one per cent of the total HFA market), the implications of the ban for pMDIs is unclear (8). Researchers have highlighted the need to weigh up the minor environmental benefits gained if all HFA pMDI formulations were eliminated in the future, against the urgent need for accessible and effective drug delivery methods.

Historically, the switch from CFCs to HFA propellants has caused significant challenges in the reformulation of pMDIs (9); with hindsight, the resulting challenges were totally underestimated from a political, regulatory and technical perspective. The dramatically different solvent properties of HFAs mean that most drugs of interest have very low solubility when combined with them. In addition, many of the excipients used in historical CFC formulations are also poorly soluble in HFAs: drugs have to either be formulated as suspensions or their solubility must be enhanced.

Although ethanol has been widely used to either enhance the solubility of drugs in solution formulations, or to aid in the solubilisation of other excipients required in solution and dispersion formulations, such as surfactants, it may have undesirable effects: for example, the chemical and physical stability of the formulation may be impacted. Eliminating this extra component, via the design of highly soluble excipients, is therefore of great interest. Alternatively, research into using other more environmentally friendly propellants, with better solvent properties compared to HFAs, is also a future avenue for the expansion of the pMDI market.

Improving Compliance

The correct use of any drug delivery device is critical to ensure that a medication is being taken properly: good medicines are only effective if they are taken regularly as prescribed. Compliance not only has benefits for the patient, but it can reduce healthcare costs in the long-term. Improvements in patient compliance can therefore drive the future innovation of drug delivery devices, including MDIs and DPIs.

Healthcare providers, insurers and pharmaceutical companies can play an important role in helping to push through drug delivery technology currently available, which would improve patient compliance. However, questions remain over who will cover the costs of these new products. Although improvements in device design actually reduce overall healthcare costs, they mean extra outlay costs for pharmaceutical companies – however, investment may be feasible if insurers are willing to reimburse some of the costs.

One way for drug companies to add value to their existing portfolios and ensure patient compliance is through the use of ‘add-ons’ to a drug delivery device. A good example of this is a dose counter or indicator, either mechanical or electronic (e-device), which allows a patient to clearly see when a dose has been taken and provides an indication as to the amount of product left. The US Food and Drug Administration (FDA) currently recommends that drug manufacturers integrate a dose-counting mechanism into new pMDI drug products; therefore, devices now need to be compliant with the functional and technical requirements they define (10).

The metering valve of a pMDI is also a critical component in the effectiveness of the system: it should accurately and reproducibly deliver a measured volume of aerosol containing the dispersed drug, and form a propellant-tight seal for high pressure in the canister. The DF30 metering valve technology developed on this device has been used within the industry for more than 20 years, and the newly optimised DF30Plus model offers several key benefits, including better compatibility across a wider range of drug formulations, including ethanol-containing formulations (see Figure 2) (11).

Future Applications

The ongoing patent cliff, which will see more generic drugs entering the market, will provide opportunities for investment in drug delivery devices and new interest in novel device designs. Asthma products such as Salbutamol have now been released as generics; however, the bioequivalence of generics will need to be proven in order for regulatory approval to be granted.

Nevertheless, there will be room for new competitors to enter the market as the regulatory science underpinning this area begins to develop. 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 drugs (12). Within Europe, new guidelines and research on bioavailability and bioequivalence studies for orally inhaled drugs are also in place, as set out in Directive 2001/83/EC (13).

However, once the hurdles of proving bioequivalence are overcome, the reduced prices of generics – combined with the low dose-to-cost ration of pMDIs – mean that this drug delivery system will provide a low-cost treatment solution, which may be of particular interest for developing countries.

Evolution of pMDIs

Current research is now looking into the use of pMDIs for the treatment of diseases such as diabetes, pain management (migraine, for example), cancer and cystic fibrosis through the delivery of drugs that contain large biological molecules, such as oligonucleotides and peptides (14). While these present some technical challenges, recent research presents novel strategies (for instance the use of polymeric nanocarriers that can protect such proteins from exposure to harsh environments) and processing steps (such as high temperature or organic solvents) (15).

Combination products are becoming a new avenue of development for companies, particularly for asthma where a combination of airwayopening drugs (long-acting beta-2 agonists such as salmeterol and formoterol) and inflammation-reducing steroids (including fluticasone and budesonide) are used. Current market activities have shown how major companies are moving into the MDI arena, with double therapies being part of their business strategy. With numerous combination products leading the pMDI market, triple therapies – for example PT010 from Pearl Therapeutics – are also an innovative future development for the respiratory disease market.

Conclusion

The ease of use, well-established technology and low cost-per-dose ratios of pMDIs have made them an attractive mode of drug delivery for the past 50 years. However, in order to remain an important player, the device needs to adapt to rapid developments in the pharmaceutical market: including the rise of generic drugs, increased safety and environmental concerns, and the pressures on healthcare costs. By evolving to meet the needs of a new pharmaceutical era through recent technological advances – such as the use of e-counters to improve compliance – pMDI drug delivery systems, alongside DPIs, hold the potential to remain successful and effective modes of drug delivery for many years to come.

References
1. Bell J and Newman S, The rejuvenated pressurised metered dose inhaler, Expert Opinion in Drug Delivery 4(3): pp215-234, 2007. Visit: www.ncbi.nlm.nih.gov/ pubmed/17489650
2. Data Monitor Inhalation market report, 2011
3. World Health Organization, Global surveillance, prevention and control of chronic respiratory diseases: a comprehensive approach, Geneva: WHO Press, 2007
4. Ram, Systematic review of clinical effectiveness of pressurised metered dose inhalers versus other hand held inhaler devices for delivering β2agonists bronchodilators in asthma, British Medical Journal 323: p901, 2001
5. Dolovich MB et al, Device selection and outcomes of aerosol therapy: evidence-based guidelines, Chest 127: pp335-371, 2005
6. UNEP, Handbook for the Montreal Protocol on Substances that Deplete the Ozone Layer, 9th edition, 2012. Visit: http://ozone.unep.org/ publications/mp_handbook/ mp-handbook-2012.pdf
7. The White House, United States and China agree to work together on phase down of HFCs, 2013. Visit: www.whitehouse.gov/ the-press-office/2013/06/08/ united-states-and-china-agreework- together-phase-down-hfcs
8. OINPD News, Orally inhaled and nasal drug product news: Aptar dose indicator on newly-approved nasal aerosol, 2013. Visit: www.oindpnews.com/2012/08/ aptar-dose-indicator-on-newlyapproved- nasal-aerosol
9. de Jager D, Manning M and Kuijpers L, Safeguarding the Ozone Layer and the Global Climate System: Issues Related to Hydrofluorocarbons and Perfluorocarbons in IPCC/TEAP, Special report, Editors: Davidson O, McFarland M and Midgley P, 2006a
10. FDA, Guidance for industry: integration of dose counting mechanisms into MDI drug products, 2003
11. Aptar Pharma, Aptar Pharma Landmark® dose indicator chosen for new asthma combination therapy, 2013. Visit: www.aptar.com/pharma/ prescription-division/news/pressreleases/ aptar-pharma-landmarkdose- indicator-chosen-for-newasthma- combination-therapy
12. US Department of Health and Human Services, FDA, Center for Drug Evaluation and Research, Guidance for Industry Applications Covered by Section 505(b)(2) Draft Guidance, 1999
13. European Medicines Agency, Committee for Medicinal Products for Human Use, Guideline on the investigation of bioequivalence, 2010 14. Da Rocha et al, Science and technology of pressurized metereddose inhalers: controlled pulmonary drug delivery, Advances in Delivery Science and Technology, Chapter 8, pp165-201, 2011
15. Nyambura BK, Kellaway IW and Taylor KMG, Insulin nanoparticles: stability and aerosolization from pressurized metered dose inhalers, International Journal of Pharmaceutics, 375(1-2): pp114-122, 2009

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Dr Gerallt Williams is Director of Scientific Affairs at Aptar Pharma. After obtaining his PhD from the University of Wales, UK, in 1985, he has held various industrial positions at Monsanto Inc (UK), Fisons Ltd (UK), Valois (France) and Inhale/Nektar Therapeutics (US). He is now in charge of scientific affairs for Aptar Pharma’s Prescription Division and is involved in the development of new devices for nasal and inhaled drug products.
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