Inhaler devices: what remains to be done?

The 1000 Years of Pharmaceutical Aerosols Conference convened posing the question; "what remains to be done?" When applying this question to the topic of inhaler devices, two hugely different perspectives could be taken. On the one hand, it could be argued that because there is an array of delivery systems available and the industry, prescribing physicians and patients alike have considerable choice, why would we believe it necessary to do anything further? On the other hand, as an industry, we are constantly reminded by our "customers" that the inhaler devices available are less than adequate, and in some cases woefully inadequate, that they are not "patient" friendly, not intuitive to use and importantly do nothing to encourage the patient to take the medication as intended and as prescribed. So, taking the second point of view as more reflective of reality--the Voice of the Customer--our starting point must be that there is still much to do in the field of inhaler devices. The purpose of this article is to outline some key basic requirements for inhaler design and perhaps to question some of the entrenched thinking that has pervaded inhaler product design for too many years.

Pulmonary formulations: what remains to be done?

Significant advances have been made in the last 50 years in developing safe and efficacious aerosol formulations for pulmonary delivery. The key to future innovation may lie at the interface between biology and particle engineering. Improved understanding of biological processes including particle clearance, cellular targeting, intracellular trafficking, and drug absorption are needed to better design formulations that deliver to the "target" with the optimal balance of pharmacodynamic, pharmacokinetic, and safety profiles. More specifically, continued advances are needed in the development of: (1) controlled release formulations; (2) formulations with improved regional targeting within the lungs (e.g., airway versus alveoli and vice versa); (3) formulations containing active targeting moieties; (4) formulation strategies for improving the systemic bioavailability of inhaled macromolecules; (5) formulation strategies for delivering macromolecules, including siRNA and DNA into cells; and (f) formulations with improved dose consistency. It is likely that such innovation will require the development of novel excipients and particle engineering strategies. Future innovation must also take into the account the changing marketplace and the diverse set of customers (patient, healthcare professional, heath authorities, payers, and politicians) who must be satisfied. The pharmacoeconomics of new delivery systems will be closely scrutinized, so it is imperative that cost factors be taken into account. Otherwise, the new technology option may overshoot the evolving inhalation marketplace.

Kinetic and equilibrium studies of anilinoalkanesulfonate formation.

(1)H NMR studies of the reactions of some hydroxyalkanesulfonates, 1, with aniline derivatives, 2, show the formation at equilibrium of anilinoalkanesulfonates, 3. Kinetic studies in water are consistent with a mechanism involving dissociation of 1 to give the parent aldehyde, which reacts with 2 to give a carbinolamine. Acid-catalysed dehydration of the carbinolamine yields an iminium ion which reacts rapidly with sulfite to give the product 3. Study of the variation with pH of the rate constants of the reaction indicates a change in the nature of the rate-determining step from carbinolamine formation to carbinolamine dehydration as the pH is increased. Variations in values of rate and equilibrium constants with the nature of 1 and 2 are discussed in terms of electronic and steric effects.

WITHDRAWN: The Inhalers of the Future? A Review of Dry Powder Devices on the Market Today.

The publisher regrets that this is an accidental duplication of an article that has already been published inPulm. Pharmacol. Ther., 16 (2003) 79-95, doi:10.1016/S1094-5539(02)00147-5. The duplicate article has therefore been withdrawn.

Ability of static and statistical mechanics posturographic measures to distinguish between age and fall risk.

Traditional posturographic analysis and four statistical mechanics techniques were applied to center-of-pressure (COP) trajectories of young, older "low-fall-risk" and older "high-fall-risk" individuals. Low-fall-risk older adults were active 3 days per week in a cardiac rehabilitation program, while high-fall-risk older adults were diagnosed with perilymph fistula. Subjects diagnosed with perilymph fistula must have experienced two of the following vestibular findings: constant disequilibrium, positional vertigo and/or a positive fistula test. Non-parametric statistical tests were used to determine whether the posturographic measures could detect differences between the young and older "low-fall-risk" groups (age comparison) and between the older "low-" and "high-risk" groups (risk of falling comparison). The statistical mechanics techniques were more sensitive than the traditional measures: detecting significant differences between the young and older "low-risk" groups, while none of the traditional measures were significantly different. In addition, interpretation of the statistical mechanics techniques may offer more insight into the nature of the process controlling the COP trajectories. However, the methods offered slightly different explanations. For instance, the Hurst rescaled range analysis suggests that the movement of the COP is governed solely by anti-persistent behavior, whereas the stabilogram diffusion analysis suggests a short-term persistence balanced by a long-term anti-persistence. These discrepancies highlight the need for a model that incorporates the biological systems responsible for maintaining balance and experimental methods to directly quantify their status and roles. Until such a model exists, however, the statistical mechanics techniques appear to have some advantages over traditional posturographic measures for studying balance control.

Lower lumbar hyperextension fracture without paraplegia.

Lumbar shear injuries are a rare injury with few cases documented in the literature. They are the result of hyperextension combined with anteroposterior shearing forces. Those with near-complete displacement are usually associated with significant neurologic deficit. Presented here is a case of L4-L5 fracture-dislocation with no neurologic loss.

The inhalers of the future? A review of dry powder devices on the market today.

International agreements to ban the use of environmentally damaging chlorofluorocarbons (CFCs) have signalled an end to the traditional CFC-propelled pressurised metered dose inhaler (pMDI) which has long been the mainstay of topical asthma therapy. The need for acceptable and cost-effective replacement inhalers, combined with opportunities to develop generic formulations of patent-expired drugs, has fueled a lively response from the pharmaceutical industry. Improvements in pMDI design and reformulation with propellants such as hydrofluoroalkanes may offer significant advantages over CFC-pMDIs and prolong the widespread use of pressurised drug delivery systems for many years to come. In the longer term, however, another likely candidate for success in providing economical, efficient and acceptable inhaled therapies is the breath-actuated, multiple-dose dry powder inhaler (DPI). This review concentrates on the multiple-dose DPIs available within Europe today.