The Montreal protocol of 1989 banning the use of chlorofluorocarbons (CFCs) was a laudable achievement for the protection of the environment. However, while this ban was aimed at industries that used large volumes of these harmful materials, it also affected highly beneficial medicinal products, such as pMDIs, which had traditionally contained low levels of these CFCs. The consequence of this has been that existing pMDI products have had to be reformulated to contain hydrofluroalkane systems and new formulations must be developed to contain the replacement propellants. The challenges associated with such efforts have led to an increased popularity in alternative inhalation technologies, namely dry powder inhalers. As the name implies, DPIs contain and deliver the active medicament as a dry powder of suitable aerodynamic size for respiratory therapy. Dry powder particles of suitable size range, generally considered between 1 and 6 ^m (4), can be readily produced. However, such particles have high surface area to mass ratio, making them highly cohesive/adhesive in nature. Consequently, the drug must be formulated in such a way that the energy input during inhalation is sufficient to overcome the contiguous adhesive and cohesive particle forces and aerosolize the powder for respiratory deposition. Although, in principle, this approach may appear straightforward, and there exist many DPI products which achieve this, the physico-chemical nature and interactive mechanisms of the components in a DPI system are still relatively poorly understood. Many commercial products have, by pharmaceutical standards, relatively poor efficiencies, with often less than 20% drug being delivered to the lung (11). This has generated a significant amount of research activity in the fields of pharmaceutics, powder technology, surface, aerosol and colloid science which has focused on understanding the interactions in DPI systems.
In simple terms, DPI technology can be categorized into four areas; Formulation; active pharmaceutical ingredient (API) powder, Device; and Manufacturing. It is clear that understanding and engineering the physico-chemical properties of the materials and processes in DPI technology will allow us to influence, and control, the aerodynamic efficiency and thus therapeutic efficacy. The DPI device will play a pivotal role in efficient API aerosolization, since its geometry and configuration will influence the flow and sheer forces acting on the formulation. Many design approaches have been used to achieve and improve drug liberation, as can be seen from any cursory survey of the patent and product literature. Currently, marketed devices can be generally classified according to their method of energy input, formulation approach and dosing regime, and how these products achieve reproducible delivery of respirable API particulates. Common approaches employed to assure such reproducible delivery of the API (delivered dose) are by formulation of a micron sized drug with a larger inert carrier, agglomeration with an excipient of similar particle size or by simple agglomeration of the drug (where metering dose constraints allow). These formulation approaches may be termed as carrier and agglomeration based systems, respectively. Both systems result in improved powder flow, ease of metering and consistent drug mass entrainment. Examples of commercially available formulations which have been developed using these approaches are represented in Figure 2.
The delivery of the drug particulates to the lung from passive inhaler products is achieved after liberation of the drug from the formulation during the inhalation actuation, as represented in Figure 3.
In addition, recent technological developments in spray drying and particle engineering have resulted in co-processed single dose DPI formulations combining, for example, a mixture of excipients (12) in the commercial insulin product, Exubra® (Pfizer/Nektar) (13), or by the addition of excipients which promote aerosolization efficiency through altering the particle physical morphology (14,15).
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