Metered Dose Inhalers

As is evident from Fig. 2, the desire to reformulate CFC metered-dose inhalers in order to enable the use of HFA propellants has resulted in a lot of activity in the

Figure 2 Pulmonary technology patent filings per year related to either metered-dose or dry powder inhalers. (Data generated using Aurigin Inc. patent search engine. Numbers may be slight overestimates of total related patents, due to restriction in search terms.)

pMDI area. The major issues that the industry faced at the start of the 1990s were: the need for new materials that were compatible with the new propellants for use in both valve components and filling and packaging lines; the need for new techniques to stabilize MDI suspensions and maintain adequate dose uniformity; toxicology data on the new propellants and valve materials, and a regulatory pathway for approving replacement MDI products.

From a regulatory perspective, the route taken by most of the industry was to design "bioequivalent" products, that is, to formulate existing molecules in HFAs so they exhibited the same performance (emitted-dose and particle-size characteristics) as the CFC products they were to replace. While this approach is logical from a product registration perspective, because it raises fewer clinical issues and concerns, it has been criticized as a lost opportunity for product improvement [6]. Generally speaking, the higher vapor pressures of the HFAs (particularly 134a) have the potential to generate aerosols of higher quality than the "old" CFC formulations. However, except in a few notable instances, potential product improvements have been sacrificed for development costs and time-to-market considerations. Two of the notable exceptions to this have been Qvar, beclomethasone, and Aerospan, flunisolide. Both of these products are based on solution pMDI technology. Deposition data for Qvar [7] indicates that it delivers more than twice the lung dose of the "old" CFC products, with a concomitant reduction in oral deposition. However, the companies that "bit this bullet" and produced new, improved products have had to perform extra clinical trials and generate extra data to support the safety and efficacy of their products in order to enable registration.

The main formulation challenge with HFA pMDI has been the poor solubility of the surfactants that were used in CFC products. Most pMDI formulations are suspensions of fine powder in propellant, and in order to obtain acceptable dose uniformity these suspensions usually require surfactants to stabilize them. The inability to use conventional surfactants has therefore led to a range of diverse formulation approaches. These encompass drug solubilization using cosolvents (Qvar is an example), new surfactants, coating particles with surfactant, and particle engineering (Fig. 3). However, as is the case with most

Figure 3 Flow/formulation diagram for HFA pMDI reformulation efforts.

formulation technologies, no one technique seems to suit all molecules and no one approach seems to be dominating product development. It likely that products that use most of these approaches will reach the market. Individual product choices will be driven by the technical suitability for a particular molecule and the need to avoid patent infringement and ensure freedom to operate.

As would be expected, the large amount of inventive effort and resultant patent activity have produced a patent minefield. The most prominent patents appear to be those of 3M Laboratories. Inc., and the Schering Corporation. 3M holds a broad patent covering the use of 134a [8] and Schering holds a patent covering the use of 227 [9]. Though the situation is a little simpler in Europe, these patents, or slightly different version of them, are still in force in the United States. It appears that company tactics in the U.S. involve licensing deals rather than direct challenges in the U.S. patent courts.

Despite the technical difficulties and the patent issues just outlined, the future for pMDIs looks bright. It would appear that the pMDI is here to stay, at least for the near term.

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