A consensus research agenda for optimising nasal drug delivery.

Nasal drug delivery has specific challenges which are distinct from oral inhalation, alongside which it is often considered. The next generation of nasal products will be required to deliver new classes of molecule, e.g. vaccines, biologics and drugs with action in the brain or sinuses, to local and systemic therapeutic targets. Innovations and new tools/knowledge are required to design products to deliver these therapeutic agents to the right target at the right time in the right patients. We report the outcomes of an expert meeting convened to consider gaps in knowledge and unmet research needs in terms of (i) formulation and devices, (ii) meaningful product characterization and modeling, (iii) opportunities to modify absorption and clearance. Important research questions were identified in the areas of device and formulation innovation, critical quality attributes for different nasal products, development of nasal casts for drug deposition studies, improved experimental models, the use of simulations and nasal delivery in special populations. We offer these questions as a stimulus to research and suggest that they might be addressed most effectively by collaborative research endeavors.

Particle sizing of pharmaceutical aerosols via direct imaging of particle settling velocities.

We present a novel method for characterizing in near real-time the aerodynamic particle size distributions from pharmaceutical inhalers. The proposed method is based on direct imaging of airborne particles followed by a particle-by-particle measurement of settling velocities using image analysis and particle tracking algorithms. Due to the simplicity of the principle of operation, this method has the potential of circumventing potential biases of current real-time particle analyzers (e.g. Time of Flight analysis), while offering a cost effective solution. The simple device can also be constructed in laboratory settings from off-the-shelf materials for research purposes. To demonstrate the feasibility and robustness of the measurement technique, we have conducted benchmark experiments whereby aerodynamic particle size distributions are obtained from several commercially-available dry powder inhalers (DPIs). Our measurements yield size distributions (i.e. MMAD and GSD) that are closely in line with those obtained from Time of Flight analysis and cascade impactors suggesting that our imaging-based method may embody an attractive methodology for rapid inhaler testing and characterization. In a final step, we discuss some of the ongoing limitations of the current prototype and conceivable routes for improving the technique.

Advances in experimental and mechanistic computational models to understand pulmonary exposure to inhaled drugs.

Prediction of local exposure following inhalation of a locally acting pulmonary drug is central to the successful development of novel inhaled medicines, as well as generic equivalents. This work provides a comprehensive review of the state of the art with respect to multiscale computer models designed to provide a mechanistic prediction of local and systemic drug exposure following inhalation. The availability and quality of underpinning in vivo and in vitro data informing the computer based models is also considered. Mechanistic modelling of local exposure has the potential to speed up and improve the chances of successful inhaled API and product development. Although there are examples in the literature where this type of modelling has been used to understand and explain local and systemic exposure, there are two main barriers to more widespread use. There is a lack of generally recognised commercially available computational models that incorporate mechanistic modelling of regional lung particle deposition and drug disposition processes to simulate free tissue drug concentration. There is also a need for physiologically relevant, good quality experimental data to inform such modelling. For example, there are no standardized experimental methods to characterize the dissolution of solid drug in the lungs or measure airway permeability. Hence, the successful application of mechanistic computer models to understand local exposure after inhalation and support product development and regulatory applications hinges on: (i) establishing reliable, bio-relevant means to acquire experimental data, and (ii) developing proven mechanistic computer models that combine: a mechanistic model of aerosol deposition and post-deposition processes in physiologically-based pharmacokinetic models that predict free local tissue concentrations.

Inhalation delivery of complex drugs-the next steps.

Oral inhalation offers the opportunity of targeting drugs locally to different regions of the respiratory tract or alternatively, using the high surface area of the alveoli for systemic delivery. Pulmozyme and the inhaled insulins (i.e. Exubera and Afrezza) are examples of the scope of pulmonary drug delivery of biopharmaceuticals-albeit with strikingly different commercial success. Particularly, the failure of Exubera and the subsequent overreactions (e.g. the unsubstantiated lung cancer fear), lastingly stunned the field of systemically inhaled protein and peptide drugs. Building on the lessons learned from these early products, a new wave of inhaled biomolecules has recently entered clinical trials. Moreover, oral inhalation has become an attractive alternative for the delivery of small molecules with difficult oral pharmacokinetics and/or extensive liver first-pass metabolism. Advances in inhaler design and our increased understanding of lung physiology continue to make oral inhalation of complex drugs an attractive therapeutic option.

A New Spray Device to Deliver Topical Ocular Medication: Penetration of Fluorescein to the Anterior Segment.

PURPOSE: To measure the penetration of fluorescein into the anterior ocular compartments after exposure of the cornea to a mist of aerosol droplets. METHODS: This was an open-label proof-of-principle trial. Eighteen healthy volunteers were asked to participate. A conventional (50 µL) drop of fluorescein solution (20 mg/mL) was administered to the right eye; an ocular mist (10 µL) of the same solution was applied to the left eye. Autofluorescence (photons/s) was measured in the cornea, the anterior chamber (AC), and the lens before administration and at 1, 2, 5, 10, 20, 50, and 100 min thereafter. The area under the curve (AUC) was calculated. For the vitreous cavity, measurements were performed at baseline and after 100 min. RESULTS: All participants completed the study. AUC (mean±SD) for the cornea was (363±431)×10(4) photons after drop application and (154±265)×10(4) photons after the mist (P=0.005). For the AC, these values were (6.9±10.3)×10(4) and (2.9±5.4)×10(4) photons, respectively (P=0.14). Autofluorescence data obtained in the lens did not allow reliable AUC calculations. Autofluorescence in the vitreous at 100 min did not significantly exceed the level at baseline. CONCLUSION: It was demonstrated that fluorescein applied to the ocular surface with the spray device enters the AC. The total amount of fluorescein molecules reaching the ocular surface by the 2 methods of administration, however, is not equivalent. Therefore, no definitive conclusions on relative bioavailability can be drawn from this experiment.

In vivo performance testing of the novel Medspray wet aerosol inhaler.

BACKGROUND: Monodisperse salbutamol inhalers were compared to select the optimal mass median aerodynamic diameter: 4.0, 5.0 or 6.0 microm. METHODS: Fifteen mild asthmatic patients participated. In all a FEV(1)-response of >12% (vs. baseline) or >200 mL after inhalation of 200 microg salbutamol was measured. Each patient was studied four times with intervals of 1 week (three active and one placebo inhaler). First, 10 microg salbutamol was administered, followed by 10, 20, and 40 microg, resulting in cumulative doses of 10, 20, 40, and 80 microg salbutamol. The FEV(1) and other lung function parameters were assessed at baseline and 30 min after inhalation of each consecutive dose. Five minutes later a next inhalation was given. RESULTS: The 4.0- and 5.0-microm droplets did not differ from placebo (p = 0.502, p = 0.127), but the 6.0-microm droplets differed significantly (p = 0.003). The difference between 6.0-4.0 microm droplets was significant (p = 0.020), but not between the 6.0-5.0 microm droplets (p = 0.129). The FEV(1) increase after 80-microg salbutamol for the 6.0-microm droplets was 243 +/- 144 mL. CONCLUSIONS: The study showed that the 6.0-microm droplets differed from the others in terms of FEV(1)-improvement, and hence, are the most efficacious of the three evaluated.

In vitro performance testing of the novel Medspray wet aerosol inhaler based on the principle of Rayleigh break-up.

PURPOSE: A new inhaler (Medspray) for pulmonary drug delivery based on the principle of Rayleigh break-up has been tested with three different spray nozzles (1.5; 2.0 and 2.5 mum) using aqueous 0.1% (w/w) salbutamol and 0.9% (w/w) sodium chloride solutions. MATERIALS AND METHODS: Particle size distributions in the aerosol were measured with the principles of time of flight (APS) and laser diffraction (LDA). RESULTS: The Medspray inhaler exhibits a highly constant droplet size distribution in the aerosol during dose emission. Droplets on the basis of Rayleigh break-up theory are monodisperse, but due to some coalescence the aerosols from the Medspray inhaler are slightly polydisperse. Mass median aerodynamic diameters at 60 l.min(-1) from APS are 1.42; 1.32 and 1.27 times the theoretical droplet diameters (TD's) and median laser diffraction diameters are 1.29; 1.14 and 1.05 times TD for 1.5; 2.0 and 2.5 mum nozzles (TD: 2.84; 3.78 and 4.73 mum respectively). CONCLUSIONS: The narrow particle size distribution in the aerosol from the Medspray is highly reproducible for the range of flow rates from 30 to 60 l.min(-1). The mass median aerodynamic droplet diameter can be well controlled within the size range from 4 to 6 mum at 60 l.min(-1).