Journal of Aerosol Medicine and Pulmonary Drug Delivery

Aerosol masks were originally developed for adults and downsized for children. Overall fit to minimize dead space and a tight seal are problematic, because children's faces undergo rapid and marked topographic and internal anthropometric changes in their first few months/years of life. Facial three-dimensional (3D) anthropometric data were used to design an optimized pediatric mask.

Children's faces (n=271, aged 1 month to 4 years) were scanned with 3D technology. Data for the distance from the bridge of the nose to the tip of the chin (H) and the width of the mouth opening (W) were used to categorize the scans into “small,” “medium,” and “large” “clusters.”

“Average” masks were developed from each cluster to provide an optimal seal with minimal dead space. The resulting computerized contour, W and H, were used to develop the SootherMask^® that enables children, “suckling” on their own pacifier, to keep the mask on their face, mainly by means of subatmospheric pressure. The relatively wide and flexible rim of the mask accommodates variations in facial size within and between clusters.

Unique pediatric face masks were developed based on anthropometric data obtained through computerized 3D face analysis. These masks follow facial contours and gently seal to the child's face, and thus may minimize aerosol leakage and dead space.

The object of this study was to assess whether a capsule-based and multidose dry powder inhaler containing salmeterol (as xinafoate salt) 50 μg plus fluticasone propionate (FP) 250 μg [combination (SFC 50/250)] could be equivalent in terms of in vivo drug delivery and systemic exposure.

This was a randomized, double-blind, double-dummy, replicate treatment design comparative bioavailability study of SFC 50/250 delivered in a capsule-based inhaler (Rotahaler^®) and a multidose dry powder inhaler (Diskus^®). Subjects with asthma or chronic obstructive pulmonary (COPD) disease (n=60) were randomized to receive twice-daily SFC 50/250 via a Rotahaler and via Diskus each for two 10-day treatment periods (GlaxoSmithKline Protocol ASR114334).

For FP and salmeterol, the in vitro aerodynamic particle size profiles were within±15% of Diskus for the fine particle mass (FPM) and emitted dose (ED) using the Andersen Cascade Impactor, and ED, mass median aerodynamic diameter, and geometric standard deviation using the New Generation Impactor (NGI). This was also the case for FP but not salmeterol for FPM and fine particle dose using the NGI. For the combined asthma and COPD subjects, the plasma AUC and C_max for FP and salmeterol were higher for Rotahaler:Rotahaler/Diskus geometric mean ratios (90% confidence intervals) for FP AUC_0–τ of 1.52 (1.37–1.67) and C_max of 1.94 (1.75–2.10) and salmeterol AUC_0–τ of 1.15 (1.09–1.21) and C_max of 1.56 (1.42–1.67). Corresponding values for the primary pharmacodynamic endpoint, weighted mean (0–12 hr) serum cortisol, were 0.928 (0.886–0.971). Inhaled FP/salmeterol via both inhalers was well-tolerated. One serious adverse event, considered possibly related to study medication, resulted in subject withdrawal from the study.

The in vitro tests and systemic pharmacodynamic endpoints revealed no major differences between the two inhalers, but lacked predictive power and sensitivity to guide in vivo drug delivery performance and systemic exposure. Based on pharmacokinetic endpoints, the inhalers were not considered bioequivalent in terms of systemic exposure. Further studies to refine the Rotahaler performance are ongoing.

During the aerosol delivery device design and optimization process, in vitro lung dose (LD) measurements are often performed using soft face models, which may provide a more clinically relevant representation of face mask dead volume (MDV) and face mask seal (FMS) than hard face models. However, a comparison of MDV, FMS, and LD for hard and soft face models is lacking.

Metal, silicone, and polyurethane represented hard, soft, and very soft facial materials, respectively. MDV was measured using a water displacement technique. FMS was measured using a valved holding chamber (VHC) flow rate technique. The LD of beclomethasone dipropionate (BDP) delivered via a 100-μg Qvar^® pressurized metered dose inhaler with AeroChamber Plus^® Flow-Vu^® VHC and Small Mask, defined as that which passes through the nasal airways of the idealized infant geometry, was measured using a bias tidal flow system with a filter. MDV, FMS, and LD were measured at 1.5 lb and 3.5 lb of applied force. A mathematical model was used to predict LD based on experimental measurements of MDV and FMS.

Experimental BDP LD measurements for ABS, silicone, and polyurethane at 1.5 lb were 0.9 (0.6) μg, 2.4 (1.9) μg, and 19.3 (0.9) μg, respectively. At 3.5 lb, the respective LD was 10.0 (1.5) μg, 13.8 (1.4) μg, and 14.2 (0.9) μg. Parametric analysis with the mathematical model showed that differences in FMS between face models had a greater impact on LD than differences in MDV.

The use of soft face models resulted in higher LD than hard face models, with a greater difference at 1.5 lb than at 3.5 lb. A lack of a FMS led to decreased dose consistency; therefore, a sealant should be used when measuring LD with a hard ABS or soft silicone face model at 1.5 lb of applied force or less.

Repeated courses of intravenous (IV) aminoglycosides in cystic fibrosis (CF) patients are associated with cumulative nephrotoxicity. Targeting their delivery through the inhaled route during acute pulmonary exacerbations may also be effective, but without systemic side effects.

Using a randomized crossover trial design, in a pilot study we compared 14 days of IV tobramycin with nebulized tobramycin 300 mg twice a day (TNS) in acute respiratory exacerbations in 20 CF adults chronically infected with Pseudomonas aeruginosa (Psa). Patients also received IV colistin in both arms.

Improvement in spirometry was similar between the two groups [mean change in FEV₁ % predicted: IV group 16.4 (standard deviation 8.5) versus TNS group 19.9 (11.3), p=0.26], but there was more suppression of sputum Psa in the TNS group [mean difference between treatments 0.85 log₁₀ colony-forming units/mL (CI 0.03 to 1.67), p=0.05]. IV tobramycin was associated with a greater urinary protein leak [mean difference between treatments 0.59 mg/24 hr (0.30 to 0.87), p=0.0005] and higher urinary levels of markers of acute renal tubular injury: N-acetylglucosaminidase [0.72 IU/mmol (0.37 to 1.07), p=0.0004], alanine aminopeptidase [1.19 IU/mmol (0.70 to 1.68), p=0.0001], and β₂-microglobulin [0.44 μg/mmol (0.16 to 0.72), p=0.0046] than TNS. Compared with IV tobramycin, TNS treatment prolonged the time to next exacerbation requiring hospitalization (p<0.001). Patient satisfaction was similar with both treatments, and no serious adverse effects were recorded.

TNS is effective in treating acute exacerbations of Psa in CF patients, but with a renal sparing potential compared with the IV preparation.

Ventilator-associated pneumonia (VAP) caused by methicillin-resistant Staphylococcus aureus is a major cause of mortality in mechanically ventilated patients. Nebulization of teicoplanin is an alternative way of administration that may provide higher lung tissue concentrations than intravenous (IV) delivery. The aim of this study was to compare the administration of teicoplanin via aerosol with the IV route by measuring the lung and the serum teicoplanin concentrations in a rat model.

Eighty healthy male Sprague-Dawley rats were anesthetized and received a single dose of teicoplanin by the IV or aerosol route. After sacrifice, lung and blood samples were collected and teicoplanin concentrations were measured with fluorescence polarization. A noncompartmental approach was used. The area under the concentration curve/minimal inhibition concentration ratio (AUC/MIC), AUC, absorbed fraction, mean residence time (MRT), and mean absorption time (MAT) of teicoplanin were calculated.

Mean±SD lung tissue concentrations of teicoplanin in the aerosol group were significantly higher than those in the IV group (p<0.0001). The mean lung tissue concentration achieved at 15 min was 1.94±1.33 mg/g in the aerosol group and 0.04±0.01 mg/g in the IV group. The mean AUC_lung was 67.4 mg hr⁻¹g⁻¹ after aerosol and 0.8 mg hr⁻¹g⁻¹ after the IV route. In the aerosol group, AUC_serum/MIC ratio was 605/2, and in the IV route, AUC_serum/MIC ratio was 682/2. MAT was longer after aerosol than after the IV route (0.91 hr versus 0.06 hr), and MRT was longer after aerosol than after IV bolus administration (6.52 hr versus 5.61 hr).

Teicoplanin concentrations in the lung tissue of the rat model were significantly higher by the aerosol route than by the IV route. The AUC_lung after nebulization was 84 times higher than delivery by the IV route, and the AUC_lung/MIC ratio after nebulization met the recommended target to eradicate Staphylococcus aureus. Administration of teicoplanin by the aerosol route could represent one of the new therapeutic weapons of the treatment of the VAP.