Developing robust formoterol-containing suspension pMDIs with enhanced shelf lives

Oct 01, 2009
Volume 21, Issue 10

Formoterol is increasingly viewed as the long-acting β2-agonist (LABA) of choice by pharmaceutical companies wishing to participate in the dynamic inhaled corticosteroid (ICS) plus long-acting β2-agonist (ICS + LABA) combination therapy segment of the asthma and chronic obstructive pulmonary disease (COPD) market. Although GlaxoSmithKline's fluticasone + salmeterol combination (Advair) dominates the segment, the more recent approval and marketing of formoterol containing pressurized metered dose inhaler (pMDI) systems, such as Symbicort (AstraZeneca, UK) and Foster (Chiesi, Italy), signal a major change in market dynamics.

Formulating and manufacturing pMDI products containing formoterol, however, is a challenge for the industry, given the low dose of the API, its inherently moisture-sensitive and unstable nature, and the resulting difficulties experienced in achieving dose reproducibility after storage. These difficulties have been attributed to both physical and chemical stability challenges.1

Current European marketed pMDIs contain formoterol fumarate in solution. However, one of the associated risks of solution based products is the greater propensity for chemical degradation upon storage when compared with suspension based formulations,1 hence degradation of the API during storage is a concern. As a result, these products must be kept refrigerated prior to dispensing and, once dispensed, are allocated a 3 month shelf life by the pharmacist.

Dominating the market

The market for asthma and COPD products is the third largest pharmaceutical category in the world2 and, although well established, is still growing ahead of the pharmaceutical market overall.2 The largest therapy segment is ICS + LABA combination therapies.3

ICS products are prescribed to control disease symptoms and to avoid the use of 'rescue' medication in the form of a short acting β2-agonist. A LABA inhaler is often prescribed alongside an ICS inhaler for those patients whose symptoms are not controlled by an ICS inhaler alone. Combining a LABA and ICS into one product, therefore, provides convenience and ease of use for patients, simplifying disease management and improving compliance. This benefit is widely recognized, thus combination ICS + LABA inhalers are becoming the mainstay of treatment for those patients whose symptoms are not controlled by an ICS alone.4,5

The author says...
Formoterol is the best-selling LABA globally6 owing to its remarkably fast onset (1–3 min) and long duration of action (up to 12 h of bronchodilation); by contrast, salmeterol, the LABA in the market leading Advair, also provides 12 h of bronchodilation, but needs up to 30 min after inhalation to take effect.7

Both mono and combination pMDI and dry powder inhaler (DPI) products containing formoterol are successful in the marketplace, however, multiple benefits can be gained by administering the agent in a pMDI:

  • This established dosage form is familiar to regulators, smoothing the product registration process.
  • It is recognized and accepted by patients, prescribers and payers, thus enabling fast product adoption.
  • It presents the manufacturer with the possibility of achieving lower costs than with a DPI device.

The industry has responded to these benefits by developing new pMDI products combining formoterol with corticosteroids, such as Symbicort (formoterol + budesonide [AstraZeneca]), which was approved by the FDA for asthma in July 2006 and COPD in February 2009; Foster (beclomethasone + formoterol [Chiesi]), which is widely marketed within Europe and is on track to become the company's best seller; and pipeline products, such as Flutiform (formoterol + fluticasone [Skyepharma, UK]), which was accepted by the FDA for review in May 2009, and a combination of formoterol + mometasone [Schering Plough, USA], for which the company announced on 22 July 2009 it had filed, and had had accepted for review, a New Drug Application with the FDA.8

Figure 1: Comparison of market share of LABA + ICS pMDI products, by LABA.
As a result of this interest, formoterol-containing products now account for 25% of the world's ICS + LABA combination market and are growing at 390% year on year, in comparison with salmeterol containing pMDIs, which are growing at a more modest 11%.9 A comparison of market share of ICS + LABA pMDI products, by LABA, is illustrated in Figure 1.

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