Limitations And Issues

Unlike the majority of controlled-, sustained-, or extended-release systems in use, the extent of response in the lungs will be limited by intrinsic clearance mechanisms [110]. It will be surprising, but not unwelcome, if any deposited dosage form can extend the effective duration of action much beyond a day. Twenty-four hours would, in fact, be a significant achievement.

Another issue is reproducibility. The formulation may work perfectly in an in vitro test system, but the dosage form requires aerosolization, and lung deposition is a function of the characteristics of the aerosol (dose, mass concentration, droplet/particle size, etc.) and the nature of the inspiratory maneuver, a factor that the patient has control over. These factors can influence performance to a far greater extent than can be "built" into a particle, and thus the term controlled does not seem a defensible objective for pulmonary delivery. The vagaries of the deposition profile and of the amount that will deposit also imply that sustaining a certain drug concentration is a difficult proposition, but the loosest definition extended release, seems an acceptable goal within the boundaries set by the clearance mechanisms.

A basic concern is the limited set of materials that can be safely packaged with a drug. It is the inactive components that impart flexibility to a dosage form. Unfortunately, relatively few materials have been thoroughly evaluated for use in pulmonary products, and only one excipient, lactose, is approved for general use. From a pharmaceutical perspective, lactose is less than ideal, being a reducing sugar, a characteristic that can have implications for protein and peptide stability [111,112]. Not surprisingly therefore, various other sugars, such as nonreducing trehalose, are being used with the tacit but reasonable assumption that they are safe. Several others are found in combination with a specific product (e.g., the components of lung surfactant) and thus have been employed in delivery systems. Other, untested compounds that are generally regarded as safe (GRAS) by other routes of administration might also be evaluated. However, the use by one route does not mean that the use via another is appropriate. Despite the efficiency of the clearance mechanisms, there are general concerns that the introduction of polymeric carriers, for example, may result in toxicity through chronic use. This may be via gradual accumulation of poorly absorbed components of limited biodegradability or, if degraded, the byproducts could result in local inflammation. So the context of the use and the characteristics of the proposed material must be carefully weighed. The more adventurous investigators and companies have also begun to explore novel entities such as sugar-lipid conjugates [Quadrant—Elan] that ultimately should expand the choice of materials that can be used in pulmonary products.

The boundary between classification as an excipient or as an active component is not always easy to differentiate. Testing required in stability programs and accompanying documentation must be expanded to satisfy chemistry, manufacturing, and control (CMC) requirements during clinical development. Thus, the additional efforts and costs to develop the formulation must be balanced by the benefits expected from the inclusion of the additives. The state of the excipient must also be considered. Is the dosage form dominated by an amorph or crystalline polymorph of an identical excipient? Will the product be affected by phase transitions occurring at body temperature that would not be seen at room-temperature storage? Does the cellular response to the additive(s) differ from that using the drug alone? Are there acute changes in tonicity after lung deposition? Multiple questions like these may have to be addressed, if not to provide supporting application data, then to provide peace of mind to the developer.

Experimental modeling and analytical testing is an ever-present problem. The lining layer of a human lung consists of an ill-defined steady-state volume of approximately 40 mL spread over a surface area of between 70 and 140 m2 [113]. Furthermore, the surface of the alveolar lining fluid consists of an ever-changing lipid-protein monolayer [114], whereas within the airways this layer is a complicated mixture of mucopolysaccharides, surfactant, DNA and various proteins [115-117]. It is not a simple matter to mimic such a medium on the bench: Lavage fluid has been used, but this is a highly diluted, variable, and often-contaminated solution (blood, cells) and fails to represent the medium in a physiologically relevant arrangement. Dissolution from a rotating disk or within a standard dissolution apparatus will always generate data, but there is no assurance that this information will predict what may happen in vivo. A number of attempts have been made to resolve, at least in part, this situation. McConville et al. [118] have been exploring the use of modified twin-stage impinger to deposit and monitor drug release, while other attempts have monitored release from aerosol deposits on filters [119]. No approach is ideal, and significantly more work is necessary to establish a test apparatus that can generate data at a reasonable experimental throughput and that investigators can have confidence in.

Why is an in vitro test system needed? Because it is far easier to generate formulations for testing than it is to conduct a thorough evaluation in small-animal models whose relevance to the human lung architecture is tenuous at best [120]. Furthermore, the mode of delivery often dictates the data that will be observed. Intratracheal instillation or insufflation is not representative of aerosol delivery and is difficult to perform reproducibly. The technique is useful for initially determining if a pharmacological response will be observed or if absorption takes place, but no conclusions should be drawn regarding the nature of absorption-vs.-time profiles. In contrast, aerosol delivery is expensive, complicated to set up and monitor, and time consuming. There is also no standardization of models or delivery technique. The upshot is that results cannot be generated rapidly and that even under the best of circumstances data will be highly variable, requiring a large number of animals to statistically discriminate between formulations.

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