Developing robust formoterol-containing suspension pMDIs with enhanced shelf lives

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.

(DICK LURIA/GETTY IMAGES)

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

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

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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

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.

Figure 1: Comparison of market share of LABA + ICS pMDI products, by LABA.

Improving dosing consistency

Two types of MDI formulation exist: a solution and suspension; there are advantages and disadvantages to both. For example, a solution based MDI homogeneously disperses the formulation and the dose delivery is consistent throughout the life of the unit so long as the valve functions acceptably. Adequate chemical stability of the drug, however, may be difficult to attain.¹ In addition, solution based formulations typically contain co-solvents (e.g., ethanol) to solubilize the API, therefore, susceptible molecules may be more prone to degradation. Chemical stability is usually improved with suspension-based formulations; however, dose reproducibility and physical stability may be an issue, particularly for low dose/high potency APIs.

3M has developed a suspension based pMDI product of similar strength to the current marketed mono-formoterol product, Atimos (Chiesi), which has been demonstrated to minimize chemical degradation and enhance the chemical stability of formoterol (Figure 2), when compared with the marketed monotherapy. The 3M system studied in this article does not require refrigerated storage prior to dispensing and, based on current data (Figure 2), will have a greater than 1 year shelf life at room temperature. Thus the shelf life (15 months refrigerated at 2–8 °C; 3 months in use/ambient) exceeds that of the current marketed product.

Figure 2: Graph showing formoterol fumarate content assay data after storage at 40 °C/75% RH.

To alleviate through-life dosing inconsistency that might be expected with the low dose, highly potent formoterol fumarate, the novel excipient, submicron lactose, was used as a bulking agent to give improved dose consistency as this agent has been previously demonstrated to give enhanced dosing characteristics.¹⁰ Dosing data from this study can be seen in Figure 3.

Figure 3: Graph showing previous study data comparing submicron lactose bulked (left) and unbulked (right) formoterol formulations.

Our study

In our study, a batch of 500 formoterol fumarate suspension pMDIs was manufactured using a laboratory scale cold filling facility under low humidity conditions and containing formoterol fumarate (12 μg per dose), submicron lactose, ethanol and propellant 227.

Whilst under continuous agitation, the bulk formulation was dispensed into individual 3M canisters and capped and crimped with a 3M valve. Following manufacture, the units were allowed to stand in the valve up orientation for more than 7 days prior to testing, to allow the system to equilibrate.

The submicron lactose was produced by processing micronized lactose in ethanol using an Avestin emulsiflex C50 high shear homogenizer as described by Jinks.¹⁰

Following system equilibration, units were stored in the stem down orientation at 40 °C/75% RH for a period of time. During this study, units were taken from the stability cabinets after 1, 3, 4 and 6 months and tested for content assay. Additional units were taken following 13 months' storage at 40 °C/75% RH and tested for through life uniformity of delivered dose (TLUoDD).

Results

Shelf life analysis

Formoterol fumarate content assay analysis was performed at day 0 and after 1, 3, 4 and 6 months' storage at 40 °C/75% RH. The results of this testing can be seen in Figure 2. Individual datum is expressed as a percentage of the mean of the initial data.

As can be seen in Figure 2, there was no significant change in the level of formoterol fumarate during the time period assessed. In all cases, individual formoterol fumarate content assay results are within ± 5% of the mean of the initial data. Based on the FDA guidance concerning the development of pMDIs, these data meet the FDA requirements.¹¹ By extrapolating these data to predict room temperature shelf life, a shelf life in excess of 1 year will be achievable.

Performance analysis

Testing of TLUoDD was performed at day 0 and after 3, 6 and 13 months' storage at 40 °C/75% RH in the stem down orientation. Testing was performed on five units, which were subjected to testing at the start, middle and end of life by firing two shots per dose into an USCA apparatus and assaying the recovered dose. The 13 month data is representative and is shown in Figure 4.

Figure 4: Graph showing formoterol fumarate TLUoDD data after 13 months' storage at 40 °C/75% RH.

The data in Figure 4 shows all doses assayed for a 100 dose product were within ± 20% of the mean of the dataset. Furthermore, low RSD values were noted during testing. The data also showed consistent dosing throughout the life of the product; this performance was achieved even after 13 months' storage at 40 °C/75% RH and did not significantly change with time.

The above data, when compared with FDA type acceptance criteria,¹² demonstrates acceptable performance.

In conclusion

Formoterol is the LABA of choice, as a monotherapy and in combination with inhaled corticosteroids. It will increasingly be a feature of the asthma and COPD marketplace, being used in combination with various corticosteroids in currently marketed, fast-growing products and promising pipeline products. However, the low dose susceptibility to moisture and inherent instability of formoterol presents formulation and manufacturing challenges in producing a robust product with a simple supply chain and acceptable shelf life. 3M's novel excipient, submicron lactose, has been shown to answer the dose consistency challenges and achieves a robust suspension product with reproducible dosing characteristics and an enhanced shelf life.

Alex Slowey is Formulation Specialist, 3M Drug Delivery Systems Division, UK. Morley Street Loughborough LE11 1EP UK Tel. +44 (0) 1509 613913 aslowey1@mmm.com

Louise Righton is Global Market Development Manager, 3M Drug Delivery Systems Division, UK.

Paul Bainbridge is Senior Formulation Scientist, 3M Drug Delivery Systems Division, UK.

References

1. P. Bainbridge and P. Jinks, "Room Temperature Stable Formoterol Metered Dose Inhaler Systems with Consistent Delivery Characteristics," in Drug Delivery to the Lungs XIX Conference Proceedings (10–12th December 2008, Edinburgh, UK), pp 124–127

2. IMS Health, Top Ten Global Therapeutic Classes — 2008.

3. IMS Health MIDAS Database, Global Retail Sales by Value, year to December 2008.

4. National Heart, Lung and Blood Institute, National Asthma Education and Prevention Program, Expert Panel Report 2: Guidelines for diagnosis and management of asthma, National Institutes of Health, publication No. 97–4051.

5. National Heart, Lung and Blood Institute, Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma, National Institutes of Health, publication No. 02–3659, revised 2002.

6. IMS Health MIDAS Database, Global LABA Category Retail Sales by Value, year to December 2008.

7. J.A. van Noord et al., Eur. Respir. J., 9(8), 1684–1688 (1996).

8. Schering-Plough Corporation press release, 22 July 2009. www.schering-plough.com

9. IMS Health MIDAS Database, LABA + ICS pMDI Category Retail Sales by Value in the Big 5 European markets, US, Canada and Japan, year to December 2008.

10. P. Jinks, "Preparation and Utility of Sub-micron lactose, a novel excipient for HFA MDI suspension Formulations," in Drug Delivery to the Lungs XIV Conference Proceedings, p 119, 11–12 December 2003, London, UK.

11. FDA Guidance for Industry, Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products, p 42, October 1998.

12. FDA Guidance for Industry, Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products, p 18, October 1998.