Systematic Evaluation of the Effect of Formulation Variables on In Vitro Performance of Mometasone Furoate Suspension-Metered Dose Inhalers.

The therapeutic benefits of metered dose inhalers (MDIs) in pulmonary disorders are mainly driven by aerosol performance, which depends on formulation variables (drug and excipients), device design, and patient interactions. The present study provides a comprehensive investigation to better understand the effect of formulation variables on mometasone furoate (MF) suspension-based MDI product performance. The effects of MF particle size (volume median diameter; X50) and excipient concentration (ethanol and oleic acid, cosolvent, and surfactant, respectively) on selected critical quality attributes (delivered dose (DD), fine particle dose of particles lesser than 5 µm (FPD < 5), ex-throat dose and median dissolution time (MDT)) were studied. Eight MF-MDI formulations (one per batch) were manufactured based on a reduced factorial design of experiment (DOE) approach, which included relevant formulation levels with varying X50 (1.1 and 2 µm), concentration of ethanol (0.45, 0.9, 1.8, and 3.6%w/w), and oleic acid (0.001 and 0.025%w/w). The in vitro evaluation of these MF-MDI formulations indicated the importance of drug particle's X50, oleic acid, and ethanol canister concentration as critical formulation variables governing the performance of MF suspension-based MDI products. The effect of these formulation variables on DD, FPD < 5, ex-throat dose, and MDT was subsequently utilized to develop empirical relationships linking formulation factors with effects on in vitro performance measures. The developed strategy could be useful for predicting MF-MDI product performance during MDI product development and manufacturing. The systematic DOE approach utilized in this study may provide insights into the understanding of the formulation variables governing the MF-MDI product performance.

Can Pharmacokinetic Studies Assess the Pulmonary Fate of Dry Powder Inhaler Formulations of Fluticasone Propionate?

In the context of streamlining generic approval, this study assessed whether pharmacokinetics (PK) could elucidate the pulmonary fate of orally inhaled drug products (OIDPs). Three fluticasone propionate (FP) dry powder inhaler (DPI) formulations (A-4.5, B-3.8, and C-3.7), differing only in type and composition of lactose fines, exhibited median mass aerodynamic diameter (MMAD) of 4.5 µm (A-4.5), 3.8 µm (B-3.8), and 3.7 µm (C-3.7) and varied in dissolution rates (A-4.5 slower than B-3.8 and C-3.7). In vitro total lung dose (TLDin vitro) was determined as the average dose passing through three anatomical mouth-throat (MT) models and yielded dose normalization factors (DNF) for each DPI formulation X (DNFx = TLDin vitro,x/TLDin vitro,A-4.5). The DNF was 1.00 for A-4.5, 1.32 for B-3.8, and 1.21 for C-3.7. Systemic PK after inhalation of 500 µg FP was assessed in a randomized, double-blind, four-way crossover study in 24 healthy volunteers. Peak concentrations (Cmax) of A-4.5 relative to those of B-3.8 or C-3.7 lacked bioequivalence without or with dose normalization. The area under the curve (AUC0-Inf) was bio-IN-equivalent before dose normalization and bioequivalent after dose normalization. Thus, PK could detect differences in pulmonary available dose (AUC0-Inf) and residence time (dose-normalized Cmax). The differences in dose-normalized Cmax could not be explained by differences in in vitro dissolution. This might suggest that Cmax differences may indicate differences in regional lung deposition. Overall this study supports the use of PK studies to provide relevant information on the pulmonary performance characteristics (i.e., available dose, residence time, and regional lung deposition).

Quantitative Assessment of Pulmonary Targeting of Inhaled Corticosteroids Using Ex Vivo Receptor Binding Studies.

The goal of locally acting inhaled corticosteroids is to achieve distinct pulmonary effects with reduced systemic side effects. The present work using an ex vivo receptor binding model in rats was interested in assessing pulmonary targeting for several commercially available corticosteroids by monitoring receptor occupancies in the lung and systemic organs (liver, kidney, spleen, and brain) after intravenous (IV) injection or intratracheal (IT) instillation of a dry powder administration at a dose of 100 µg/kg. Pulmonary targeting, defined as the difference in cumulative receptor occupancies (AUCE) between the lung and kidney after pulmonary delivery, differed across the investigated corticosteroids (ΔAUCE range, 33 ± 46 to 143 ± 52% *h) with the highest degree found for corticosteroids with high systemic clearance and pronounced lipophilicity (presumably allowing a long pulmonary residence time). Additionally, this study demonstrated differences in the receptor occupancies across systemic organs. Using kidney receptor occupancies as the comparator, liver receptor occupancies were reduced (ΔAUCE range: - 157 ± 43 to 178 ± 42% *h) after IV and IT administration for corticosteroids with high intrinsic clearance, while they were increased for corticosteroid prodrugs due to hepatic activation. Spleen receptor occupancies were increased after IT (ΔAUCE range: 33 ± 35 to 135 ± 28% *h), but not after IV administration. This was especially true for slowly dissolving drugs. Reduced brain uptake was also observed for ciclesonide (CIC) and des-ciclesonide (desCIC), two compounds previously not investigated. In summary, ex vivo receptor binding studies represent a powerful tool to assess the fate of ICSs.

Bone-Specific Alkaline Phosphatase in Patients Who Have Undergone the Fontan Operation.

Bone-specific alkaline phosphatase (BALP) is produced by osteoblasts. A recent series noted a positive association between cardiac index (CI) and BALP in patients with Fontan circulation. CI is low at baseline in these patients, and small decreases in CI may result in diverting of blood away from bone. We prospectively enrolled 15 patients (males ≤ 14 yo, females ≤ 12 yo) who had previously undergone Fontan operation and were undergoing cardiac catheterization. Serum BALP was measured at catheterization, and analysis performed to evaluate association between age-/gender-specific BALP z-score and CI as well as other patient variables. The median age at catheterization was 5.6 years (3.1-13.1), and time from Fontan was 1.5 years (0.1-12.1). The median superior vena cava saturation (SVC) was 65 % (52-74), median average between SVC and inferior vena cava (IVC) saturations was 62.5 % (51-70), and median CI was 3.8 L/min/m(2) (2.0-8.4). The median BALP was 65 IU/L and BALP z-score was -2.1 (-3.2 to 0.9). BALP z-score was not associated with CI (ρ = -0.1, p = 0.7), but a positive correlation was noted with the average of SVC and IVC saturation (ρ = 0.5, p = 0.052) and with SVC saturation (ρ = 0.4, p = 0.07), both nearly reaching statistical significance. In our cohort of children with Fontan circulation undergoing catheterization, BALP z-score was not associated with CI, but an association with estimates of mixed venous saturation was noted that nearly reached statistical significance. We hypothesize that BALP is a marker of oxygen delivery in those with Fontan circulation and may represent a valuable biomarker in this population.

Transcatheter Patent Ductus Arteriosus Occlusion in Small Infants.

BACKGROUND: Transcatheter patent ductus arteriosus (PDA) occlusion is feasible in small infants and may improve lung function in symptomatic patients. We aimed to describe transcatheter PDA closure in small infants including predictors of technical success and rate of complication and to identify factors associated with improved respiratory status after closure. METHODS: All patients in the NICU at our center who were referred for transcatheter PDA occlusion between 1/2010 and 11/2014 were retrospectively identified. Relevant details were extracted. Additionally, a modification of the respiratory severity score (RSS) (FiO2 × mean airway pressure) was used to characterize degree of pulmonary support before and at intervals after catheterization. RESULTS: Twenty patients were identified with median age of 96 days (13-247) and weight of 3.1 kg (1.7-4.7). The PDA was type F morphology in 14 (70%) patients. The PDA was successfully occluded in 16 (80%) patients. Ratio of minimum PDA diameter/length was >0.5 in all unsuccessful attempts and <0.4 in all successful cases (P = .01). Of the 16 cases of occlusion, Amplatzer Vascular Plug II was used in 15 (94%). No deaths or pulse loss occurred. Five (25%) patients required blood transfusion and transfusion was associated with lower hemoglobin (P = .049), lower weight (P = .008), and lower aortic pressure (P = .04). Excluding 1 patient with significant congenital heart disease, the RSS improved at 3 days in 9 (60%) patients and at 7 days in 12 (80%) compared with preintervention value. Patient factors were not associated with improved RSS at 3 or 7 days. CONCLUSIONS: In our cohort of symptomatic infants, transcatheter PDA occlusion was successful in most and a ratio of minimum PDA diameter/length of <0.4 was predictive of technical success. Using a surrogate for pulmonary support, the majority of patients were on less support 7 days after closure.