The Future of Metered-Dose Inhalers

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Pharmaceutical Technology Europe

Pharmaceutical Technology Europe, Pharmaceutical Technology Europe-09-01-2005, Volume 17, Issue 9

IAdvances in pressurized metered-dose inhalers (pMDIs) in terms of formulation capability and the performance of the container closure system enable products to be developed faster and with less technical risk. Despite new delivery devices for new molecules breaking into the pMDI market, pMDIs have the ability to gain regulatory approval significantly faster than a novel device, which could save a company many hundreds of millions of pounds.

In the 1970s, Molina and Rowlands raised concerns over the possible detrimental effect of chlorofluorocarbons (CFCs) on levels of stratospheric ozone.1 Confirmation of ozone depletion was first reported over the Antarctic in 1985 and 2 years later, a great many (now over 150) nations signed the Montreal Protocol on Substances that Deplete the Ozone Layer.2 Specific exemptions were granted for defined "essential uses" where there were no technologically or economically viable alternatives; at that time this included pressurized metered-dose inhalers (pMDIs).

However, these exemptions are reviewed annually by the Technical and Economic Assessment Panel of the United Nations Environment Programme, with a background that all economically feasible steps have been taken to minimize the "essential use." Faced with this requirement, plus a diminishing supply of CFCs, the pharmaceutical industry has committed large resources to the development of CFC-free pMDIs and alternative delivery systems.

At the outset, the challenge was mainly to identify safe alternative propellants that did not contain chlorine, often referred to as hydrofluoroalkanes (HFAs). A specialist conference hosted by The Management Forum in 1992 concluded that the easiest products to reformulate would be launched in the US by 1997, with the most difficult following approximately 2 years later.3 Even in 1998, the Commission to the Council and the European Parliament envisaged that "essential use" status would be lost for most common inhaled drugs by 2002.4

The reality has proven much harder, with many technical challenges to overcome. Witness the fact that the New Drug Application (NDA) for the original isoprotenerol pMDI contained only 34 pages covering the chemistry, manufacturing and controls, whereas that for 3M's CFC-free salbutamol pMDI was a staggering 1130 pages. Nevertheless, GlaxoSmithKline was proud to announce in February this year that it is now in position to complete its transition away from CFC-containing products in the US.

Technical Advances

A pMDI is a complex assembly of formulation, metal, plastic and elastomeric components (Figure 1). Replacement of the CFCs was not just a change in the propellant, but required significant development of novel components and excipients.5 Indeed, with a lack of a suitable HFA propellant that is liquid at room temperature, new manufacturing processes were

also required.

Figure 1 Schematic diagram of a pMDI.

Formulation. Most currently marketed CFC products contain drug particles suspended in the fluid. To generate a stable homogeneous dispersion, surfactants are normally added. However, none of the surfactants that had been used in CFCs are directly soluble in HFAs, prompting the development of a new class of surfactants suitable for use in HFAs.6 Another approach has been to add a cosolvent, usually ethanol, for the surfactant.7 This may also offer the opportunity to premix part of the formulation before adding propellant. Furthermore, some drugs are soluble in ethanol, so it may be feasible for these products to add sufficient ethanol to make a solution formulation of the drug.

Container Closure System


Less obvious is the way in which propellants interact with the materials of construction of the canister and metering valve. First, drug can be adsorbed onto or absorbed by these surfaces. As these are processes that are likely to increase (in amount) through storage and as the can empties through use, it can lead to unacceptable variation in dose. This has led to the development of coatings, such as fluorinated polymers, to reduce this effect.8

The metering valve is required to retain and protect the contents of the canister at the same time as delivering a fixed volume of the formulation in a reproducible manner. There have been many design advances to improve dosing uniformity.9 Seals are used to prevent leakage around the site of the crimp between valve assembly and can, together with the moving parts of the valve itself. The solvency properties of the propellant affect the degree of swelling (or shrinkage) of elastomeric components that, in turn, can affect propellant leakage.10 Elastomer developments required for compatibility with HFAs have included the use of novel materials, removal of sources of polynuclear aromatic compounds and avoidance of sulfur-based curing processes.11,12

Actuator. The design of the actuator will influence the size and velocity of the drug particles, and propellant droplets emitted from the mouthpiece.13 By using actuators with small orifice diameters, it is possible to produce a relatively slow and warm spray from HFA pMDIs, compared with the CFC products, which may make it easier for a patient to coordinate the act of firing the pMDI with onset of inhalation.14

Accelerating Inhaled Drug Development

With the ever-spiralling costs of drug development, the pharmaceutical industry is looking at new ways to arrive at key go/no go decision points as early as possible in the drug development cycle. However, compromises often have to be made; the fastest route to get an inhaled drug into humans for the first time is not necessarily the quickest to ultimate approval, because of the complexities of the pharmaceutical development process. Nonetheless, it is usually more cost-effective to weed out drugs with undesirable safety or efficacy profiles early to focus resources on those that are most likely to surmount these hurdles. The challenge, therefore, is to choose a delivery system for Phase I studies that will minimize the subsequent risks in full development.

Feasibility assessment. Because of the technical complexity associated with developing pMDIs, it has proven difficult to begin Phase I trials until development of the container closure system and formulation is almost finalized.1

As a consequence, during the last decade, the pMDI has been the slowest route into humans. However, with increased understanding, the technology has now matured to the point that experience, backed by computer-based expert systems,15 can give a good guide at an early stage as to the likelihood of being able to successfully develop a product containing the formulation used in Phase I. Using an approach of accelerated candidate evaluation, 3M can potentially provide data to support an investigational new drug (IND) or clinical trial application (CTA) within 80 working days.16 This makes it as fast as any other type of inhaler development when it comes to decision making on the drug, with the added benefit that the risk remaining in full development is well characterized.

Beyond Phase I. Generally, the activities for completion of the pharmaceutical development cease to be on the critical path once Phase II studies have begun. Therefore, there is little systematic difference in the full development timings for the different inhaler types. Nevertheless, a range of small cans and valves are available for use with low numbers of doses, to simplify the development of sample packs.17

Figure 2 Comparison of DPI and pMDI approval times in the US.

The final stage in the process is to obtain regulatory approval. Here, there is likely to be a significant impact if the delivery system is unfamiliar to the regulators. As shown in Table 1, in the US, FDA has recently taken an average of one extra 9-month review cycle for new dry powder inhalers (DPIs) compared with pMDIs. As can be seen from Figure 2, the gap appears to be growing. While there is a significant trend towards reduced approval times for pMDIs, there is no such correlation for DPIs (r2=0.01) Indeed, given that an experienced developer such as 3M, is now well aware of the regulatory expectations for a pMDI, Xopenex has shown it is possible to gain product approval within a single review cycle.

Table 1 Recent approval times for new inhalers in the US.


The relative ease with which unit dose dry powder formulations can be developed for Phase I, coupled with the ability to move smoothly into later phases of development, have made the DPI the delivery system of choice for many pharmaceutical companies in recent years. As a consequence, DPI unit volumes almost doubled in the period 2000–2003, but they still represent less than 25% of the volume of pMDIs sold.18 However, having solved the technical challenges posed by the phase out of CFCs, the benefits that have led to 500 million devices prescribed each year still remain. Recognizing this, companies such as Kos Pharmaceuticals are even developing macromolecules such as insulin in a pMDI presentation. Thus, the combination of fast to Phase I taken with rapid approval and patient familiarity should see a resurgence in the choice of pMDIs going forward.

John Pritchardis the global manager responsible for inhaled product development at 3M, UK.


1. M.J. Molina and F.S. Rowlands, Nature 249, 810–812 (1974).

2. J.C. Farman, B.G. Gardiner and J.D. Shanklin, Nature 315, 207–210 (1985).

3. The Management Forum, Manuf. Chem. July, 22–23 (1992).

4. Committee for Proprietary Medicinal Products, "Results of the co-ordinated review of 1,1,1,2-tetrafluroethane HFC-134a," European Commission, Brussels (1994).

5. J.N. Pritchard, "Recent advances in drug delivery via pressurised metered-dose inhalers," in L. Gradon and J. Marijnissen, Eds., Optimization of Aerosol Drug Delivery (Kluwer Academic, Dordrech, The Netherlands, 2003) pp 105–122.

6. J.S. Stefely et al., "Equipping the MDI for the 21st century by expanding its formulation options," in R.N. Dalby et al,. Eds, Respiratory Drug Delivery VII (Serentec Press Inc., Raleigh, NC, USA, 2000) pp 82–90.

7. I. Tansey, Brit. J. Clin. Pract. 89 (Suppl), 22–27 (1997).

8. R.J Warby, European Patent Application No. 1208864 (2002).

9. M. Wilby, Drug Del. Sys. Sci. (in press).

10. D. Tiwari et al.,Drug Dev. Ind. Pharm. 24, 345–352 (1998).

11. L. Bradley, K. Hunt and T. Fenn, "The performance of the EPDM Spraymiser valve," Drug Delivery to the Lungs XV (The Aerosol Society, Portishead, UK 2004) pp 101–104.

12. D. Howlett and J. Colwell, "Improvements in extractables from pMDI elastomer systems," Drug Delivery to the Lungs VIII (The Aerosol Society, Portishead, UK, 1997) pp 36–38.

13. A. Clark, J. Biopharm. Sci. 3, 69–76 (1992).

14. B.J. Gabrio, S.W. Stein and D.J. Velasquez, Int. J. Pharm. 186, 3–12 (1999).

15. P. Jinks, "The use of expert system software to improve the efficiency of the inhalation product development process," Drug Delivery to the Lungs XV (The Aerosol Society, Portishead, UK, 2004) pp 107–110.

16. J.N. Pritchard, "Accelerating drug development," Drug Delivery to the Lungs XV (The Aerosol Society, Portishead, UK, 2004) pp 84–87.

17. J. Moore et al., in R.N Dalby et al., Eds, Respiratory Drug Delivery IX (Davis Healthcare International Publishing, River Grove, IL, USA, 2004).