Review
The inhalers of the future? A review of dry powder devices on the market today

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Abstract

International agreements to ban the use of environmentally damaging chlorofluorocarbons (CFCs) have signalled an end to the traditional CFC-propelled pressurised metered dose inhaler (pMDI) which has long been the mainstay of topical asthma therapy. The need for acceptable and cost-effective replacement inhalers, combined with opportunities to develop generic formulations of patent-expired drugs, has fuelled a lively response from the pharmaceutical industry. Improvements in pMDI design and reformulation with propellants such as hydrofluoroalkanes may offer significant advantages over CFC-pMDIs and prolong the widespread use of pressurised drug delivery systems for many years to come. In the longer term, however, another likely candidate for success in providing economical, efficient and acceptable inhaled therapies is the breath-actuated, multiple-dose dry powder inhaler (DPI). This review concentrates on the multiple-dose DPIs available within Europe today.

Introduction

Over 40 years have elapsed since the pressurised metered dose inhaler (pMDI) was first introduced as a convenient delivery system for targeting bronchodilator drugs, and later corticosteroids, directly into the lungs of patients with asthma [1], [2]. Now, at the dawn of a new era and in light of the seemingly inexorable worldwide socio-economic impact of chronic respiratory diseases, environmental concerns over the use of propellant gases have forced the pace of pharmaceutical research into suitable replacements for the CFC-pMDI [3], [4], [5], [6]. Major constraints include the need for improved patient compliance and cost-effectiveness of treatment [7], [8]. Various approaches appear to offer feasible solutions to the problem, with current developments concentrating largely in the two major areas of pMDI reformulation and innovative DPI technology. Successful reformulation with ‘ozone-friendly’ hydrofluoroalkane (HFA) propellants will permit the continued use of some drugs in the pMDI in the shorter term, and patient coordination difficulties may be resolved by means of breath-actuated pMDIs as well as spacers or valved holding chambers [6]. The reality of global warming continues to escalate, however, potentially limiting reliance on propellant-based pMDIs in the longer term. In practice, the patient-driven, propellant-free, multiple-dose DPI is most likely to emerge as the device of the future for the control and management of asthmatic disease [6], [7], [8]. These inhalers are inherently both environmentally friendly and more user friendly, holding the prospect of more effective therapy through improved compliance. This review therefore focuses on the multiple-dose DPIs which are commercially available today.

Section snippets

Profile of the traditional pMDI as historic ‘gold standard’

Since its introduction in 1956, the pMDI has been the system of choice for delivery of inhaled therapies for airway diseases such as asthma [1], [9], [10]. The chief advantage in targeting drugs directly into the lung lies in reduction of systemic bioavailability, and consequently of unwanted side-effects. The most frequently used classes of drug, β2-agonist bronchodilators and corticosteroids, both have dose-related adverse systemic effects and dosage should therefore be kept to a minimum [10]

Green—or greenhouse?

Replacement of the CFC-driven pMDI is no longer an option but a necessity. Concerns over damage by chlorine to the Earth's ozone layer, due to the accumulation of CFC gases in the stratosphere, came to light almost 30 years ago [36]. The ozone layer plays an essential role in absorbing ultraviolet-B rays, thus preventing potentially devastating over-exposure of plant and animal life-forms to short wavelength radiation from the sun. When fears of its impending destruction were confirmed by the

First phase of DPI development

In response to the need for effective asthma drug delivery alternatives to pMDIs, three multiple-dose inhaler devices were developed by multinational pharmaceutical companies AstraZeneca (Turbuhaler/Turbohaler) and GlaxoSmithKline (Diskus/Accuhaler and Diskhaler), for their own bronchodilator and corticosteroid treatments. Other bronchodilator therapies have since been made available via the Turbuhaler device.

Turbuhaler

The AstraZeneca Turbuhaler (Fig. 1) is made up of 13 plastic components and a steel

Diskus versus Diskhaler

Interpretation of comparative studies is problematic in that not only the device, but often a different drug and a different formulation must be taken into account. This holds true irrespective of DPI/pMDI or DPI/DPI comparisons. At the same time, more sophisticated techniques of in vitro assessment have become the norm [33], [34].

The results obtained by Srichana et al. [60] caution against extrapolation of in vitro performance data from one drug/device combination to another: the salbutamol

Conclusion

A summary outlining the major design and performance features of the six DPI devices detailed in this review (based on the published information) is presented in Table 2. One of the main disadvantages associated with single-dose DPIs, in addition to patient handling issues involved with capsule reloading, is poor efficiency of lung delivery, with as little as 10% of the dose reaching the lung. Deposition of the inhaled aerosol from DPIs is influenced by both the patient and the physical

Acknowledgements

We gratefully acknowledge the contribution made by Patsy Riley in producing this review.

References (185)

  • S.P. Newman et al.

    Terbutaline sulphate Turbuhaler: effect of inhaled flow rate on drug deposition and efficacy

    Int J Pharmaceutics

    (1991)
  • L. Borgström et al.

    Total and regional lung deposition and effect of terbutaline sulphate inhaled via a pressurised MDI or Turbuhaler

    Int J Pharmaceutics

    (1993)
  • L. Agertoft et al.

    Effects of long-term treatment with an inhaled corticosteroid on growth and pulmonary function in asthmatic children

    Respir Med

    (1994)
  • S.S. Chatterjee et al.

    Beclomethasone dipropionate in asthma: a comparison of two methods of administration

    Br J Dis Chest

    (1980)
  • T. Freedman

    Medihaler therapy for bronchial asthma: a new type of aerosol therapy

    Postgrad Med J

    (1956)
  • Double-blind trial comparing two dosage schedules of beclomethasone dipropionate aerosol in the treatment of chronic bronchial asthma

    Lancet

    (1974)
  • Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC

    Lancet

    (1998)
  • (1987)
  • Chlorofluorocarbon propellants in self-pressurized containers; determinations that uses are no longer essential; request for comments

    Federal Register

    (1997)
  • A.J. Hickey et al.

    A new millennium for inhaler technology

    Pharm Technol

    (1997)
  • F.W. Dekker et al.

    Compliance with pulmonary medication in general practice

    Eur Respir J

    (1993)
  • H. Bisgaard

    Drug delivery from inhaler devices. Lung deposition, clinical effect, and cost-effectiveness vary

    Br Med J

    (1996)
  • C.G. Thiel

    From Susie's question to CFC free: an inventor's perspective on forty years of MDI development and regulation

    Respir Drug Delivery

    (1996)
  • British Thoracic Society guidelines on asthma management. Thorax, 52 (1997)...
  • B.J. Lipworth

    Risks versus benefits of inhaled β2-agonists in the management of asthma

    Drug Safety

    (1992)
  • D.M. Geddes

    Inhaled corticosteroids: benefits and risks

    Thorax

    (1992)
  • M. Phillip et al.

    Integrated plasma cortisol concentration in children with asthma receiving long-term inhaled corticosteroids

    Pediatr Pulmonol

    (1992)
  • O.D. Wolthers et al.

    Controlled study of linear growth in asthmatic children during treatment with inhaled glucocorticosteroids

    Pediatrics

    (1992)
  • L. Agertoft et al.

    Effect of long-term treatment with inhaled budesonide on adult height in children with asthma

    N Engl J Med

    (2000)
  • B.J. Lipworth

    New perspectives on inhaled drug delivery and systemic bioavailability

    Thorax

    (1995)
  • S. Pedersen

    Aerosols and other devices

  • R. Pauwels et al.

    Airway deposition and airway effects of antiasthma drugs delivered from metered-dose inhalers

    Eur Respir J

    (1997)
  • G.K. Crompton

    problems patients have using pressurised aerosol inhalers

    Eur J Respir Dis

    (1982)
  • S. Hilton

    An audit of inhaler techniques among asthma patients of 34 general practitioners

    Br J Gen Pract

    (1990)
  • S. Newman et al.

    Effect of add-on devices for aerosol drug delivery: deposition studies and clinical aspects

    J Aerosol Med

    (1996)
  • M. Farrer et al.

    Morning serum cortisol concentrations after 2 mg inhaled beclomethasone dipropionate in normal subjects: effect of a 750 ml spacing device

    Thorax

    (1990)
  • J.H. Toogood

    Complications of topical steroid therapy for asthma

    Am Rev Respir Dis

    (1990)
  • A.J. Frew et al.

    Poor inhaler technique may be perpetuated by clinical staff

    Practitioner

    (1984)
  • D. Taylor et al.

    Metered dose inhalers: a system for assessing technique in patients and health professionals

    Pharm J

    (1991)
  • E. Dompeling et al.

    Treatment with inhaled steroids in asthma and chronic bronchitis: long term compliance and inhaler technique

    Fam Pract

    (1992)
  • Devices under discussion

    (1997)
  • Document CPMP/QWP/158/96

    (1998)
  • Document 2180

    (1998)
  • European Pharmacopoeia—Supplement;...
  • Pharmacopeial Forum

    (1998)
  • H. Buck et al.

    Discriminating measures of bronchodilator drug efficacy and potency

    Br J Clin Pharmacol

    (2001)
  • M.J. Molina et al.

    Stratospheric sink for chlorofluoromethanes: chlorine atom-catalysed destruction of ozone

    Nature

    (1974)
  • J.C. Farman et al.

    Large losses of total ozone in Antarctica reveal seasonal ClOx/NOx interaction

    Nature

    (1985)
  • Handbook for the international treaties for the protection of the ozone layer

    (2000)
  • G. Bentham

    Health in the global greenhouse

    Biologist

    (1999)
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